Trial Outcomes & Findings for A Study to Evaluate the Efficacy of Sage-217 in the Treatment of Adult Participants With Major Depressive Disorder (MDD) (NCT NCT04442490)

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

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

543 participants

Primary outcome timeframe

Baseline, Day 15

Results posted on

2023-12-22

Participant Flow

Participants were enrolled in the study at 39 centers in the United States from 12 May 2020 to 21 April 2021.

A total of 543 participants were randomized, of which 543 were enrolled in this study and 537 received Investigational Product (IP). Part B was started after all participants in Part A (NCT03672175) completed Day 42 of the previous study.

Participant milestones

Participant milestones
Measure	Placebo Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 milligrams (mg) received 40 mg for the remainder of the treatment period as per discretion of investigator.
Overall Study STARTED	272	271
Overall Study Safety Set	269	268
Overall Study COMPLETED	235	242
Overall Study NOT COMPLETED	37	29

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 milligrams (mg) received 40 mg for the remainder of the treatment period as per discretion of investigator.
Overall Study Withdrawal by Subject	18	10
Overall Study Lost to Follow-up	7	7
Overall Study Adverse Event	2	6
Overall Study Noncompliance	3	1
Overall Study Physician Decision	2	1
Overall Study Reason not Specified	2	1
Overall Study Randomized but not Treated	3	3

Baseline Characteristics

"Number analyzed" = Number of participants evaluable for the specified baseline measure.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=269 Participants Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=268 Participants Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.	Total n=537 Participants Total of all reporting groups
Race (NIH/OMB) White	206 Participants n=269 Participants	169 Participants n=268 Participants	375 Participants n=537 Participants
Race (NIH/OMB) More than one race	5 Participants n=269 Participants	7 Participants n=268 Participants	12 Participants n=537 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=269 Participants	2 Participants n=268 Participants	6 Participants n=537 Participants
Age, Continuous	40.1 years STANDARD_DEVIATION 12.64 • n=269 Participants	39.4 years STANDARD_DEVIATION 12.30 • n=268 Participants	39.7 years STANDARD_DEVIATION 12.46 • n=537 Participants
Sex: Female, Male Female	166 Participants n=269 Participants	186 Participants n=268 Participants	352 Participants n=537 Participants
Sex: Female, Male Male	103 Participants n=269 Participants	82 Participants n=268 Participants	185 Participants n=537 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	54 Participants n=269 Participants	58 Participants n=268 Participants	112 Participants n=537 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	215 Participants n=269 Participants	210 Participants n=268 Participants	425 Participants n=537 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=269 Participants	0 Participants n=268 Participants	0 Participants n=537 Participants
Race (NIH/OMB) American Indian or Alaska Native	3 Participants n=269 Participants	1 Participants n=268 Participants	4 Participants n=537 Participants
Race (NIH/OMB) Asian	4 Participants n=269 Participants	13 Participants n=268 Participants	17 Participants n=537 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=269 Participants	1 Participants n=268 Participants	2 Participants n=537 Participants
Race (NIH/OMB) Black or African American	46 Participants n=269 Participants	75 Participants n=268 Participants	121 Participants n=537 Participants
17-item Hamilton Rating Scale for Depression (HAM-D) Total Score	26.9 score on a scale STANDARD_DEVIATION 2.67 • n=269 Participants	26.8 score on a scale STANDARD_DEVIATION 2.60 • n=268 Participants	26.9 score on a scale STANDARD_DEVIATION 2.64 • n=537 Participants
Clinical Global Impression - Severity (CGIS) Score	4.8 score on a scale STANDARD_DEVIATION 0.52 • n=269 Participants	4.7 score on a scale STANDARD_DEVIATION 0.55 • n=268 Participants	4.7 score on a scale STANDARD_DEVIATION 0.54 • n=537 Participants
Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score	35.0 score on a scale STANDARD_DEVIATION 4.73 • n=269 Participants	35.2 score on a scale STANDARD_DEVIATION 4.83 • n=268 Participants	35.1 score on a scale STANDARD_DEVIATION 4.78 • n=537 Participants
Hamilton Anxiety Rating Scale (HAM-A) Total Score	20.7 score on a scale STANDARD_DEVIATION 5.51 • n=268 Participants • "Number analyzed" = Number of participants evaluable for the specified baseline measure.	21.4 score on a scale STANDARD_DEVIATION 5.15 • n=268 Participants • "Number analyzed" = Number of participants evaluable for the specified baseline measure.	21.0 score on a scale STANDARD_DEVIATION 5.34 • n=536 Participants • "Number analyzed" = Number of participants evaluable for the specified baseline measure.

PRIMARY outcome

Timeframe: Baseline, Day 15

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

Outcome measures

Outcome measures
Measure	Placebo n=251 Participants Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=248 Participants Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.
Change From Baseline in the 17-item HAM-D Total Score at Day 15	-12.3 score on a scale Standard Error 0.50	-14.1 score on a scale Standard Error 0.51

SECONDARY outcome

Timeframe: Baseline, Day 15

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

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

Outcome measures

Outcome measures
Measure	Placebo n=268 Participants Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=266 Participants Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.
Change From Baseline in the CGI-S Score at Day 15	-1.6 score on a scale Standard Error 0.08	-1.8 score on a scale Standard Error 0.08

SECONDARY outcome

Timeframe: Baseline, Days 3, 8, and 42

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

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

Outcome measures

Outcome measures
Measure	Placebo n=268 Participants Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=266 Participants Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.
Change From Baseline in the HAM-D Total Score at Days 3, 8 and 42 Change from Baseline at Day 3	-6.8 score on a scale Standard Error 0.38	-9.8 score on a scale Standard Error 0.38
Change From Baseline in the HAM-D Total Score at Days 3, 8 and 42 Change from Baseline at Day 8	-9.5 score on a scale Standard Error 0.45	-12.0 score on a scale Standard Error 0.45
Change From Baseline in the HAM-D Total Score at Days 3, 8 and 42 Change from Baseline at Day 42	-12.6 score on a scale Standard Error 0.55	-13.5 score on a scale Standard Error 0.55

SECONDARY outcome

Timeframe: Days 15 and 42

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

Outcome measures

Outcome measures
Measure	Placebo n=268 Participants Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=266 Participants Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.
Percentage of Participants Achieving HAM-D Response Day 42	45.9 percentage of participants	52.9 percentage of participants
Percentage of Participants Achieving HAM-D Response Day 15	47.0 percentage of participants	56.0 percentage of participants

SECONDARY outcome

Timeframe: Days 15 and 42

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

Outcome measures

Outcome measures
Measure	Placebo n=268 Participants Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=266 Participants Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.
Percentage of Participants Achieving HAM-D Remission Day 15	27.1 percentage of participants	29.8 percentage of participants
Percentage of Participants Achieving HAM-D Remission Day 42	29.6 percentage of participants	30.8 percentage of participants

SECONDARY outcome

Timeframe: Day 15

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

Outcome measures

Outcome measures
Measure	Placebo n=251 Participants Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=248 Participants Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.
Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Response at Day 15	51.0 percentage of participants	62.1 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Day 15

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

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

Outcome measures

Outcome measures
Measure	Placebo n=251 Participants Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=247 Participants Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.
Change From Baseline in MADRS Total Score at Day 15	-15.1 score on a scale Standard Error 0.76	-17.5 score on a scale Standard Error 0.77

SECONDARY outcome

Timeframe: Baseline, Day 15

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

The 14-item HAM-A is comprised of a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). The HAM-A total score was calculated as the sum of the 14 individual item scores. The scoring for HAM-A is calculated by assigning scores of 0 (not present) to 4 (very severe) to each item, with a total HAM-A score range of 0 to 56, where \<17 indicates mild severity, 18 to 24 indicates mild to moderate severity, and 25 to 30 indicates moderate to severe severity. A negative change from baseline indicates improvement. MMRM was used for the analysis.

Outcome measures

Outcome measures
Measure	Placebo n=251 Participants Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=247 Participants Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.
Change From Baseline in HAM-A Total Score at Day 15	-9.1 score on a scale Standard Error 0.43	-10.4 score on a scale Standard Error 0.43

SECONDARY outcome

Timeframe: Up to Day 57

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

Outcome measures

Outcome measures
Measure	Placebo n=166 Participants Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=197 Participants Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.
Time to First HAM-D Response	15 days Interval 2.0 to 57.0	11 days Interval 2.0 to 54.0

SECONDARY outcome

Timeframe: Baseline, Days 8, 15, 28 and 42

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

Outcome measures

Outcome measures
Measure	Placebo n=268 Participants Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=266 Participants Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Physical Functioning Domain Score: Change from Baseline at Day 8	1.9 score on a scale Standard Error 0.36	2.4 score on a scale Standard Error 0.37
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Physical Functioning Domain Score: Change from Baseline at Day 15	2.3 score on a scale Standard Error 0.38	3.1 score on a scale Standard Error 0.39
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Physical Functioning Domain Score: Change from Baseline at Day 28	2.3 score on a scale Standard Error 0.40	3.2 score on a scale Standard Error 0.41
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Physical Functioning Domain Score: Change from Baseline at Day 42	2.4 score on a scale Standard Error 0.43	3.3 score on a scale Standard Error 0.43
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Role-Physical Domain Score: Change from Baseline at Day 8	1.9 score on a scale Standard Error 0.43	1.8 score on a scale Standard Error 0.44
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Role-Physical Domain Score: Change from Baseline at Day 15	3.2 score on a scale Standard Error 0.45	3.1 score on a scale Standard Error 0.46
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Role-Physical Domain Score: Change from Baseline at Day 28	3.1 score on a scale Standard Error 0.46	3.0 score on a scale Standard Error 0.46
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Role-Physical Domain Score: Change from Baseline at Day 42	3.2 score on a scale Standard Error 0.46	3.5 score on a scale Standard Error 0.46
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Bodily Pain Domain Score: Change from Baseline at Day 8	3.3 score on a scale Standard Error 0.46	3.8 score on a scale Standard Error 0.47
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Bodily Pain Domain Score: Change from Baseline at Day 15	4.7 score on a scale Standard Error 0.49	4.9 score on a scale Standard Error 0.50
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Bodily Pain Domain Score: Change from Baseline at Day 28	4.7 score on a scale Standard Error 0.51	5.0 score on a scale Standard Error 0.51
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Bodily Pain Domain Score: Change from Baseline at Day 42	4.2 score on a scale Standard Error 0.54	5.2 score on a scale Standard Error 0.54
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 General Health Domain Score: Change from Baseline at Day 8	2.4 score on a scale Standard Error 0.36	3.6 score on a scale Standard Error 0.37
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 General Health Domain Score: Change from Baseline at Day 15	3.4 score on a scale Standard Error 0.39	4.4 score on a scale Standard Error 0.40
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 General Health Domain Score: Change from Baseline at Day 28	3.3 score on a scale Standard Error 0.43	3.8 score on a scale Standard Error 0.43
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 General Health Domain Score: Change from Baseline at Day 42	3.5 score on a scale Standard Error 0.45	4.6 score on a scale Standard Error 0.45
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Vitality Domain Score: Change from Baseline at Day 8	7.2 score on a scale Standard Error 0.64	9.8 score on a scale Standard Error 0.65
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Vitality Domain Score: Change from Baseline at Day 15	9.7 score on a scale Standard Error 0.75	12.8 score on a scale Standard Error 0.76
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Vitality Domain Score: Change from Baseline at Day 28	9.1 score on a scale Standard Error 0.75	10.9 score on a scale Standard Error 0.76
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Vitality Domain Score: Change from Baseline at Day 42	9.7 score on a scale Standard Error 0.81	11.7 score on a scale Standard Error 0.81
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Social Functioning Domain Score: Change from Baseline at Day 8	8.2 score on a scale Standard Error 0.66	9.5 score on a scale Standard Error 0.67
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Social Functioning Domain Score: Change from Baseline at Day 15	11.4 score on a scale Standard Error 0.72	12.5 score on a scale Standard Error 0.73
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Social Functioning Domain Score: Change from Baseline at Day 28	11.6 score on a scale Standard Error 0.76	11.9 score on a scale Standard Error 0.76
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Social Functioning Domain Score: Change from Baseline at Day 42	11.4 score on a scale Standard Error 0.78	13.2 score on a scale Standard Error 0.78
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Role-Emotional Domain Score: Change from Baseline at Day 8	9.4 score on a scale Standard Error 0.77	10.5 score on a scale Standard Error 0.78
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Role-Emotional Domain Score: Change from Baseline at Day 15	12.1 score on a scale Standard Error 0.82	13.6 score on a scale Standard Error 0.83
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Role-Emotional Domain Score: Change from Baseline at Day 28	11.8 score on a scale Standard Error 0.84	13.7 score on a scale Standard Error 0.84
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Role-Emotional Domain Score: Change from Baseline at Day 42	12.3 score on a scale Standard Error 0.89	13.5 score on a scale Standard Error 0.89
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Mental Health Domain Score: Change from Baseline at Day 8	9.4 score on a scale Standard Error 0.68	11.0 score on a scale Standard Error 0.69
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Mental Health Domain Score: Change from Baseline at Day 15	12.2 score on a scale Standard Error 0.76	14.0 score on a scale Standard Error 0.77
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Mental Health Domain Score: Change from Baseline at Day 28	11.6 score on a scale Standard Error 0.81	12.7 score on a scale Standard Error 0.81
Change From Baseline in Patient- Reported Outcome (PRO) Measures of Health-Related Quality of Life, as Assessed by the 36-item Short Form Version 2 (SF-36v2) Score at Days 8, 15, 28 and 42 Mental Health Domain Score: Change from Baseline at Day 42	12.2 score on a scale Standard Error 0.85	13.9 score on a scale Standard Error 0.85

SECONDARY outcome

Timeframe: Baseline, Days 8, 15, 28 and 42

The PHQ-9 is a participant-rated depressive symptom severity scale where scoring is based on responses to specific questions. The score was calculated as the sum of the 9 individual item scores. The PHQ-9 total score ranges from 0 to 27 categorized as follows: 1 to 4 = minimal depression, 5 to 9 = mild depression, 10 to 14 = moderate depression, 15 to 19 = moderately severe depression, and 20 to 27 = severe depression with a higher score indicating more depression. A negative change indicates improvements. MMRM was used for analysis.

Outcome measures

Outcome measures
Measure	Placebo n=268 Participants Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=266 Participants Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.
Change From Baseline in PRO Measures of Depressive Symptoms, as Assessed by the 9-item Patient Health Questionnaire (PHQ-9) Total Score at Days 8, 15, 28 and 42 Change from Baseline at Day 8	-6.8 score on a scale Standard Error 0.42	-7.8 score on a scale Standard Error 0.42
Change From Baseline in PRO Measures of Depressive Symptoms, as Assessed by the 9-item Patient Health Questionnaire (PHQ-9) Total Score at Days 8, 15, 28 and 42 Change from Baseline at Day 15	-8.3 score on a scale Standard Error 0.45	-9.4 score on a scale Standard Error 0.46
Change From Baseline in PRO Measures of Depressive Symptoms, as Assessed by the 9-item Patient Health Questionnaire (PHQ-9) Total Score at Days 8, 15, 28 and 42 Change from Baseline at Day 28	-7.8 score on a scale Standard Error 0.46	-8.8 score on a scale Standard Error 0.46
Change From Baseline in PRO Measures of Depressive Symptoms, as Assessed by the 9-item Patient Health Questionnaire (PHQ-9) Total Score at Days 8, 15, 28 and 42 Change from Baseline at Day 42	-8.5 score on a scale Standard Error 0.48	-9.0 score on a scale Standard Error 0.48

Adverse Events

Placebo

Serious events: 2 serious events

Other events: 59 other events

Deaths: 0 deaths

SAGE-217 50 mg

Serious events: 2 serious events

Other events: 111 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=269 participants at risk Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=268 participants at risk Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.
Investigations Aspartate Aminotransferase Increased	0.37% 1/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	0.00% 0/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Investigations Blood Alkaline Phosphatase Increased	0.37% 1/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	0.00% 0/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Investigations Gamma-glutamyltransferase Increased	0.37% 1/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	0.00% 0/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Injury, poisoning and procedural complications Lower Limb Fracture	0.00% 0/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	0.37% 1/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Nervous system disorders Slow Speech	0.00% 0/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	0.37% 1/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Psychiatric disorders Psychotic Disorder	0.00% 0/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	0.37% 1/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Vascular disorders Deep Vein Thrombosis	0.00% 0/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	0.37% 1/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Eye disorders Retinal Detachment	0.37% 1/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	0.00% 0/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Investigations Alanine Aminotransferase Increased	0.37% 1/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	0.00% 0/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.

Other adverse events

Other adverse events
Measure	Placebo n=269 participants at risk Participants self-administered SAGE-217 matched-placebo capsules, once daily at approximately 8 PM with fat-containing food for 14 days.	SAGE-217 50 mg n=268 participants at risk Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.
Nervous system disorders Somnolence	3.0% 8/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	15.3% 41/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Nervous system disorders Dizziness	2.2% 6/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	13.8% 37/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Nervous system disorders Headache	7.8% 21/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	10.8% 29/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Nervous system disorders Sedation	0.37% 1/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	7.5% 20/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Gastrointestinal disorders Nausea	4.5% 12/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	4.1% 11/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Gastrointestinal disorders Dry Mouth	3.7% 10/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	3.7% 10/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Gastrointestinal disorders Diarrhoea	5.2% 14/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	3.0% 8/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.
Nervous system disorders Tremor	0.00% 0/269 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.	3.0% 8/268 • From inform consent signing up to 28 days after the last dose (Up to 70 days) Safety set included all participants who were administered IP.

Additional Information

US Biogen Clinical Trial Center

Biogen

Phone: 866-633-4636

Email: [email protected]

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