Trial Outcomes & Findings for A Comparative Study of Sage-217 Plus an Antidepressant (ADT) Versus Placebo Plus an ADT in Adults With Major Depressive Disorder (NCT NCT04476030)

NCT ID: NCT04476030

Last Updated: 2023-12-22

Results Overview

The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. A negative change from baseline indicated improvement. Least Squares (LS) mean was estimated using mixed effects model for repeated measures (MMRM) analysis.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 440 participants
• Primary outcome timeframe: Baseline, Day 3
• Results posted on: 2023-12-22

Participant Flow

Participants took part in the study at 53 investigative sites in the United States from 9 November 2020 to 22 December 2021.

A total of 440 participants were enrolled in the study of which 430 participants received at least 1 dose of the assigned treatment. The study consisted of a 28-day Screening period, a 14-day Double-blind Treatment Period, and a 28-day antidepressant therapy (ADT) continuation period.

Participant milestones

Measure	Placebo + Assigned ADT Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT Participants received SAGE-217, 50 milligrams (mg), orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Overall Study STARTED	220	220
Overall Study Safety Population	218	212
Overall Study COMPLETED	177	180
Overall Study NOT COMPLETED	43	40

Reasons for withdrawal

Measure	Placebo + Assigned ADT Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT Participants received SAGE-217, 50 milligrams (mg), orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Overall Study Withdrawal by Subject	20	16
Overall Study Adverse Event	10	11
Overall Study Lost to Follow-up	7	4
Overall Study Physician Decision	1	1
Overall Study Protocol Deviation	2	0
Overall Study Non-compliance with Investigational Product (IP)	1	0
Overall Study Randomized but not Dosed	2	8

Baseline Characteristics

A Comparative Study of Sage-217 Plus an Antidepressant (ADT) Versus Placebo Plus an ADT in Adults With Major Depressive Disorder

Baseline characteristics by cohort

Measure	Placebo + Assigned ADT n=218 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=212 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	Total n=430 Participants Total of all reporting groups
Age, Continuous	37.7 years STANDARD_DEVIATION 12.28 • n=5 Participants	38.6 years STANDARD_DEVIATION 12.72 • n=7 Participants	38.1 years STANDARD_DEVIATION 12.49 • n=5 Participants
Sex: Female, Male Female	140 Participants n=5 Participants	129 Participants n=7 Participants	269 Participants n=5 Participants
Sex: Female, Male Male	78 Participants n=5 Participants	83 Participants n=7 Participants	161 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	52 Participants n=5 Participants	41 Participants n=7 Participants	93 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	166 Participants n=5 Participants	171 Participants n=7 Participants	337 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White	168 Participants n=5 Participants	153 Participants n=7 Participants	321 Participants n=5 Participants
Race/Ethnicity, Customized Black or African-American	31 Participants n=5 Participants	46 Participants n=7 Participants	77 Participants n=5 Participants
Race/Ethnicity, Customized Asian	12 Participants n=5 Participants	6 Participants n=7 Participants	18 Participants n=5 Participants
Race/Ethnicity, Customized Other	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Race/Ethnicity, Customized More than one race	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Race/Ethnicity, Customized American-Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
17-item Hamilton Rating Scale for Depression (HAMD-17) Total Score	26.6 score on a scale STANDARD_DEVIATION 2.58 • n=5 Participants	26.8 score on a scale STANDARD_DEVIATION 2.51 • n=7 Participants	26.7 score on a scale STANDARD_DEVIATION 2.54 • n=5 Participants
Clinical Global Impression - Severity (CGI-S) Score	4.9 score on a scale STANDARD_DEVIATION 0.57 • n=5 Participants	5.0 score on a scale STANDARD_DEVIATION 0.54 • n=7 Participants	4.9 score on a scale STANDARD_DEVIATION 0.55 • n=5 Participants
Hamilton Anxiety Rating Scale (HAM-A) Total Score	20.4 score on a scale STANDARD_DEVIATION 5.80 • n=5 Participants	19.9 score on a scale STANDARD_DEVIATION 5.28 • n=7 Participants	20.1 score on a scale STANDARD_DEVIATION 5.55 • n=5 Participants
Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score	34.9 score on a scale STANDARD_DEVIATION 4.89 • n=5 Participants	35.2 score on a scale STANDARD_DEVIATION 4.70 • n=7 Participants	35.0 score on a scale STANDARD_DEVIATION 4.80 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Day 3

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, 9-item Patient Health Questionnaire (PHQ-9) or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or Clinical Global Impression - Improvement (CGI-I) score. Overall number of participants analyzed is the number of participants with data available for analysis.

The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. A negative change from baseline indicated improvement. Least Squares (LS) mean was estimated using mixed effects model for repeated measures (MMRM) analysis.

Outcome measures

Measure	Placebo + Assigned ADT n=210 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=204 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Change From Baseline in the HAMD-17 Total Score at Day 3	-7.0 score on a scale Standard Error 0.38	-8.9 score on a scale Standard Error 0.39

SECONDARY outcome

Timeframe: Baseline through Day 15

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score.

The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. A negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis. The data reported is summary of data collected and analyzed during double-blind treatment period at Baseline, Day 3, Day 8, Day 12, and Day 15 using equal weights for the scheduled visits.

Outcome measures

Measure	Placebo + Assigned ADT n=215 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=210 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Change From Baseline in the HAMD-17 Total Score Over the Double-Blind Treatment Period	-10.1 score on a scale Standard Error 0.39	-11.7 score on a scale Standard Error 0.40

SECONDARY outcome

Timeframe: Baseline, Days 15 and 42

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score.

The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. A negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis. The missing values were imputed for the analysis.

Outcome measures

Measure	Placebo + Assigned ADT n=215 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=210 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Change From Baseline in the HAMD-17 Total Score at Days 15 and 42 Day 15	-12.9 score on a scale Standard Error 0.49	-13.7 score on a scale Standard Error 0.50
Change From Baseline in the HAMD-17 Total Score at Days 15 and 42 Day 42	-14.9 score on a scale Standard Error 0.56	-14.9 score on a scale Standard Error 0.56

SECONDARY outcome

Timeframe: Baseline, End of blinded treatment assessment (i.e., average of Days 12, 15 , and 18)

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score.

The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. A negative change from baseline indicated improvement. End of blinded treatment was defined as the average of change from baseline values of Days 12, 15 and 18. LS mean was estimated using MMRM analysis.

Outcome measures

Measure	Placebo + Assigned ADT n=215 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=210 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Change From Baseline in the HAMD-17 Total Score Around End of Blinded Treatment	-12.7 score on a scale Standard Error 0.45	-13.2 score on a scale Standard Error 0.46

SECONDARY outcome

Timeframe: At Days 15 and 42

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Number analyzed is the number of participants with data available for analysis at the specified time points.

HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. Percentages were rounded off to the first decimal point.

Outcome measures

Measure	Placebo + Assigned ADT n=215 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=210 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Percentage of Participants With HAMD-17 Response at Day 15 and Day 42 Day 15	49.2 percentage of participants	53.4 percentage of participants
Percentage of Participants With HAMD-17 Response at Day 15 and Day 42 Day 42	65.3 percentage of participants	59.9 percentage of participants

SECONDARY outcome

Timeframe: Days 15 and 42

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Number analyzed is number of participants with data available for analysis at the specified time points.

HAM-D remission was defined as having a HAM-D total score of ≤7. The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. Percentages were rounded off to the first decimal point.

Outcome measures

Measure	Placebo + Assigned ADT n=215 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=210 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Percentage of Participants With HAMD-17 Remission at Day 15 and Day 42 Day 15	21.8 percentage of participants	29.1 percentage of participants
Percentage of Participants With HAMD-17 Remission at Day 15 and Day 42 Day 42	39.2 percentage of participants	37.9 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Day 15

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Overall number of participants analyzed is the number of participants with data available for analysis.

The CGI-S uses a 7-point Likert scale to rate the severity of the participant's illness at the time of assessment, relative to the clinician's past experience with participants who have the same diagnosis. Considering total clinical experience, the investigator rated the participant 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. LS mean was estimated using MMRM analysis.

Outcome measures

Measure	Placebo + Assigned ADT n=197 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=189 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Change From Baseline in CGI-S Score at Day 15	-1.7 score on a scale Standard Error 0.09	-1.9 score on a scale Standard Error 0.09

SECONDARY outcome

Timeframe: Days 3 and 15

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Number analyzed is the number of participants with data available for analysis at the specified time points.

CGI-I response was defined as having a CGI-I score of "very much improved" or "much improved." The CGI-I employs a 7-point Likert scale to measure the overall improvement in the participant's condition post-treatment. The investigator rated the participant's total improvement whether or not it was due entirely to IP. 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. By definition, all CGI-I assessments are evaluated against baseline conditions. Higher scores indicated worse condition. Percentages were rounded off to the first decimal point.

Outcome measures

Measure	Placebo + Assigned ADT n=215 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=210 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Percentage of Participants With CGI-I Response, at Day 3 and Day 15 Day 3	12.9 percentage of participants	22.9 percentage of participants
Percentage of Participants With CGI-I Response, at Day 3 and Day 15 Day 15	54.3 percentage of participants	56.6 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Day 15

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Overall number of participants analyzed is the number of participants with data available for analysis.

The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders. The MADRS total score was calculated as the sum of the 10 individual item scores. Each item yields a score of 0 (no symptoms) to 6 (symptoms of maximum severity). The total MADRS score (sum of all individual items) ranges from 0 (symptoms absent) to 60 (severe depression). Higher MADRS scores indicated more severe depression. A negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis.

Outcome measures

Measure	Placebo + Assigned ADT n=197 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=188 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Change From Baseline in MADRS Total Score at Day 15	-15.9 score on a scale Standard Error 0.75	-17.2 score on a scale Standard Error 0.76

SECONDARY outcome

Timeframe: Day 15

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Overall number of participants analyzed is the number of participants with data available for analysis.

MADRS response was defined as having a 50% or greater reduction from baseline in MADRS total score. The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders. The MADRS total score was calculated as the sum of the 10 individual item scores. Each item yields a score of 0 (no symptoms) to 6 (symptoms of maximum severity). The total MADRS score (sum of all individual items) ranges from 0 (symptoms absent) to 60 (severe depression). Higher MADRS scores indicated more severe depression. Percentages were rounded off to the first decimal point.

Outcome measures

Measure	Placebo + Assigned ADT n=197 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=188 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Percentage of Participants With MADRS Response at Day 15	48.2 percentage of participants	51.6 percentage of participants

SECONDARY outcome

Timeframe: Day 15

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Overall number of participants analyzed is the number of participants with data available for analysis.

MADRS remission was defined as having a MADRS total score of ≤10. The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders. The MADRS total score was calculated as the sum of the 10 individual item scores. Each item yields a score of 0 (no symptoms) to 6 (symptoms of maximum severity). The total MADRS score (sum of all individual items) ranges from 0 (symptoms absent) to 60 (severe depression). Higher MADRS scores indicated more severe depression. Percentages were rounded off to the first decimal point.

Outcome measures

Measure	Placebo + Assigned ADT n=197 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=188 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Percentage of Participants With MADRS Remission at Day 15	28.4 percentage of participants	30.9 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Day 15

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Overall number of participants analyzed is the number of participants with data available for analysis.

Each of the 14 items in the HAM-A was defined by a series of symptoms, and measured both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints). The HAM-A total score was calculated as sum of the 14 individual item scores, each rated on a five point scale ranging from 0 (not present) to 4 (very severe). The total score (sum of all individual items) range from 0 to 56, where <17 indicated mild severity, 18 to 24 indicated mild to moderate severity, and 25 to 30 indicated moderate to severe severity. Higher scores indicated more severe disease. Negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis.

Outcome measures

Measure	Placebo + Assigned ADT n=197 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=188 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Change From Baseline in HAM-A Total Score at Day 15	-9.0 score on a scale Standard Error 0.44	-9.5 score on a scale Standard Error 0.44

SECONDARY outcome

Timeframe: From first dose of study drug up to first HAMD-17 response (up to approximately 65 days)

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score.

HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either 3-point (0=none to 2=severe) or 5-point scale (0=none/absent to 4=most severe). Total score is the sum of individual items, ranging from 0 (not depressed) to 52 (severely depressed); where a higher score indicates more depression. Time (in days) from first dose of study drug to time of first HAMD response was reported in this outcome measure.

Outcome measures

Measure	Placebo + Assigned ADT n=215 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=210 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Time to First HAMD-17 Response	15 days Interval 2.0 to 50.0	13 days Interval 2.0 to 61.0

SECONDARY outcome

Timeframe: Baseline and Day 15

Population: Full analysis set included all randomized participants who administered blinded IP with a valid baseline total score and at least 1 valid postbaseline total score in at least 1 of HAMD-17, HAM-A, MADRS, PHQ-9 or had a valid baseline and at least 1 valid postbaseline value in at least 1 of CGI-S or CGI-I score. Overall number of participants analyzed is the number of participants with data available for analysis.

The PHQ-9 is a participant-rated depressive symptom severity scale. The PHQ-9 total score is calculated as the sum of the 9 individual item scores. For individual items, scoring is based on responses to specific questions, as follows: 0 = not at all; 1 = several days; 2 = more than half the days; and 3 = nearly every day. The PHQ-9 possible total score range is 0 to 27, with higher scores reflecting greater depressive symptoms, and is categorized as follows: 0 to 4 = minimal depression, 5 to 9 = mild depression, 10 to 14 = moderate depression, 15 to 19 = moderately severe depression, and 20 to 27 = severe depression. Negative change from baseline indicated improvement. LS mean was estimated using MMRM analysis.

Outcome measures

Measure	Placebo + Assigned ADT n=196 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=188 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Change From Baseline in Depressive Symptoms at Day 15, as Assessed by PHQ-9	-8.7 score on a scale Standard Error 0.44	-8.9 score on a scale Standard Error 0.44

SECONDARY outcome

Timeframe: Up to approximately 58 weeks

Population: Safety Set was defined as all participants who administered blinded IP.

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. A TEAE was defined as an AE with onset after the start of IP, or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study.

Outcome measures

Measure	Placebo + Assigned ADT n=218 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=212 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	65.6 percentage of participants	74.1 percentage of participants

SECONDARY outcome

Timeframe: Up to approximately 58 weeks

Population: Safety Set was defined as all participants who administered blinded IP.

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. A TEAE was defined as an AE with onset after the start of IP, or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study. The severity was graded as mild, moderate and severe.

Outcome measures

Measure	Placebo + Assigned ADT n=218 Participants Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=212 Participants Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Percentage of Participants With TEAEs, Graded by Severity Moderate	25.2 percentage of participants	34.4 percentage of participants
Percentage of Participants With TEAEs, Graded by Severity Severe	2.3 percentage of participants	3.8 percentage of participants
Percentage of Participants With TEAEs, Graded by Severity Mild	38.1 percentage of participants	35.8 percentage of participants

Adverse Events

Placebo + Assigned ADT

Serious events: 0 serious events

Other events: 113 other events

Deaths: 0 deaths

SAGE-217 + Assigned ADT

Serious events: 2 serious events

Other events: 123 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo + Assigned ADT n=218 participants at risk Participants received SAGE-217-matching placebo capsules, orally, once daily aong with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=212 participants at risk Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Nervous system disorders Seizure like phenomena	0.00% 0/218 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.	0.47% 1/212 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/218 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.	0.47% 1/212 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.

Other adverse events

Measure	Placebo + Assigned ADT n=218 participants at risk Participants received SAGE-217-matching placebo capsules, orally, once daily aong with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.	SAGE-217 + Assigned ADT n=212 participants at risk Participants received SAGE-217, 50 mg, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.
Nervous system disorders Somnolence	8.3% 18/218 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.	18.4% 39/212 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.
Nervous system disorders Dizziness	7.3% 16/218 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.	13.2% 28/212 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.
Nervous system disorders Headache	14.7% 32/218 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.	11.8% 25/212 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.
Nervous system disorders Sedation	2.8% 6/218 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.	5.7% 12/212 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.
Nervous system disorders Tremor	1.4% 3/218 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.	5.2% 11/212 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.
Gastrointestinal disorders Dry mouth	8.7% 19/218 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.	9.4% 20/212 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.
Gastrointestinal disorders Nausea	23.4% 51/218 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.	9.0% 19/212 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.
Gastrointestinal disorders Diarrhoea	9.6% 21/218 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.	6.1% 13/212 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.
Psychiatric disorders Insomnia	7.8% 17/218 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.	9.9% 21/212 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.
General disorders Fatigue	5.0% 11/218 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.	8.5% 18/212 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.
Metabolism and nutrition disorders Decreased appetite	3.2% 7/218 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.	5.7% 12/212 • Up to approximately 58 weeks The All-cause mortality is reported for all randomized participants and serious and other adverse events are reported for safety set that included all participants who administered blinded IP.

Additional Information

US Biogen Clinical Trial Center

Biogen

Phone: 866-633-4636

Email: clinicaltrials@biogen.com

Results disclosure agreements

• Principal investigator is a sponsor employee Our agreement is subject to confidentiality but generally the PI can publish, for non-commercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
• Publication restrictions are in place

Restriction type: OTHER