Trial Outcomes & Findings for A Study to Evaluate the Safety, Tolerability, and Efficacy of SAGE-217 Compared to Placebo in Adult Participants With Comorbid Major Depressive Disorder (MDD) and Insomnia (NCT NCT03771664)

NCT ID: NCT03771664

Last Updated: 2023-11-29

Results Overview

Sleep Efficiency (SE) is the percentage of time in bed spent asleep, determined during an 8-hour overnight PSG recording. The PSG measures the physiological process of sleep by monitoring body functions including brain waves, eye movements, muscle activity or skeletal muscle activation, heart rhythm, blood oxygen saturation, and breathing functions. Stages of sleep include rapid eye movement (REM), non-rapid eye movement (NREM), NREM stage 1 (N1), NREM stage 2 (N2), and NREM stage 3 (N3), scored through evaluation of the electroencephalogram (EEG) signal. The average of 2 nights' PSG measurements at Days 13 and 14 is reported in this outcome measure.

• Recruitment status: TERMINATED
• Study phase: PHASE3
• Target enrollment: 87 participants
• Primary outcome timeframe: Baseline and Days 13, 14
• Results posted on: 2023-11-29

Participant Flow

Participants were enrolled in the study at 27 investigative sites in the United States from 04 February 2019 to 17 January 2020.

A total of 87 participants were randomized and 86 received drug or placebo. This study consisted of up to a 2-day single-blind placebo run-in, a 14-day double-blind treatment followed by a 7-day single-blind placebo run-out and a follow-up of up to 27 days.

Participant milestones

Measure	Placebo Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out \[polysomnography (PSG)\] on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	SAGE-217 Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 milligrams (mg) capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Overall Study STARTED	43	44
Overall Study Full Analysis Set (FAS)	43	43
Overall Study Safety Set	43	43
Overall Study COMPLETED	40	39
Overall Study NOT COMPLETED	3	5

Reasons for withdrawal

Measure	Placebo Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out \[polysomnography (PSG)\] on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	SAGE-217 Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 milligrams (mg) capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Overall Study Adverse Event	1	0
Overall Study Lost to Follow-up	1	0
Overall Study Withdrawal by Participant	1	4
Overall Study Randomized but not Treated	0	1

Baseline Characteristics

A Study to Evaluate the Safety, Tolerability, and Efficacy of SAGE-217 Compared to Placebo in Adult Participants With Comorbid Major Depressive Disorder (MDD) and Insomnia

Baseline characteristics by cohort

Measure	Placebo n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	SAGE-217 n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Total n=86 Participants Total of all reporting groups
Age, Continuous	42.0 years STANDARD_DEVIATION 11.60 • n=5 Participants	44.6 years STANDARD_DEVIATION 12.50 • n=7 Participants	43.3 years STANDARD_DEVIATION 12.06 • n=5 Participants
Sex: Female, Male Female	31 Participants n=5 Participants	28 Participants n=7 Participants	59 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants	15 Participants n=7 Participants	27 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	7 Participants n=5 Participants	13 Participants n=7 Participants	20 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	36 Participants n=5 Participants	30 Participants n=7 Participants	66 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 Race · White	30 Participants n=5 Participants	31 Participants n=7 Participants	61 Participants n=5 Participants
Race/Ethnicity, Customized Race · Black or African-American	12 Participants n=5 Participants	11 Participants n=7 Participants	23 Participants n=5 Participants
Race/Ethnicity, Customized Race · Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · Other	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Days 13, 14

Population: Full analysis set (FAS) included all randomized participants who received at least 1 dose of double-blind investigational product (IP) with valid baseline and at least one post-baseline efficacy evaluation. Number analyzed signifies the number of participants with data available for analyses at the specified time point.

Sleep Efficiency (SE) is the percentage of time in bed spent asleep, determined during an 8-hour overnight PSG recording. The PSG measures the physiological process of sleep by monitoring body functions including brain waves, eye movements, muscle activity or skeletal muscle activation, heart rhythm, blood oxygen saturation, and breathing functions. Stages of sleep include rapid eye movement (REM), non-rapid eye movement (NREM), NREM stage 1 (N1), NREM stage 2 (N2), and NREM stage 3 (N3), scored through evaluation of the electroencephalogram (EEG) signal. The average of 2 nights' PSG measurements at Days 13 and 14 is reported in this outcome measure.

Outcome measures

Measure	SAGE-217 n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Average Change From Baseline in Sleep Efficiency (SE) as Assessed by Polysomnogram (PSG) at Days 13 and 14 Average Change From Baseline at Days 13, 14	4.692 percentage of time asleep Standard Deviation 8.5619	3.921 percentage of time asleep Standard Deviation 12.1835
Average Change From Baseline in Sleep Efficiency (SE) as Assessed by Polysomnogram (PSG) at Days 13 and 14 Baseline	73.667 percentage of time asleep Standard Deviation 9.8100	67.702 percentage of time asleep Standard Deviation 14.9367

SECONDARY outcome

Timeframe: Baseline, Day 14: Overall duration (8 hours) and each 2-hour quarter duration (quarter 1: 0 to 2 hours, quarter 2: 2 to 4 hours, quarter 3: 4 to 6 hours, quarter 4: 6 to 8 hours) of PSG recording

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

WASO is the total wake time (in minutes) calculated from persistent sleep onset to lights-on (final wake time). In this outcome measure, change from baseline at Day 14 in overall (for the whole 8-hour period) WASO and in each quarter (for the each 2-hour duration) WASO of the 8-hour PSG recording is reported.

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in Wake After Sleep Onset (WASO) From Persistent Sleep Onset to Lights-on (Final Wake Time) Change From Baseline in WASO for Overall Duration	-20.0 minutes Standard Error 5.85	-7.0 minutes Standard Error 5.87
Change From Baseline in Wake After Sleep Onset (WASO) From Persistent Sleep Onset to Lights-on (Final Wake Time) Change From Baseline in WASO in Quarter 1	-1.6 minutes Standard Error 1.18	-1.5 minutes Standard Error 1.23
Change From Baseline in Wake After Sleep Onset (WASO) From Persistent Sleep Onset to Lights-on (Final Wake Time) Change From Baseline in WASO in Quarter 2	-5.6 minutes Standard Error 2.33	-1.3 minutes Standard Error 2.33
Change From Baseline in Wake After Sleep Onset (WASO) From Persistent Sleep Onset to Lights-on (Final Wake Time) Change From Baseline in WASO in Quarter 3	-3.9 minutes Standard Error 2.90	3.1 minutes Standard Error 2.89
Change From Baseline in Wake After Sleep Onset (WASO) From Persistent Sleep Onset to Lights-on (Final Wake Time) Change From Baseline in WASO in Quarter 4	-11.0 minutes Standard Error 3.11	-4.9 minutes Standard Error 3.09

SECONDARY outcome

Timeframe: Baseline, Day 14: Overall duration (8 hours) and each 2-hour quarter duration (quarter 1: 0 to 2 hours, quarter 2: 2 to 4 hours, quarter 3: 4 to 6 hours, quarter 4: 6 to 8 hours) of PSG recording

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

TST is the duration of total sleep time (NREM + REM) (in minutes) from lights off to lights on during PSG recording. In this outcome measure, change from baseline at Day 14 in overall (for the whole 8-hour period) TST and in each quarter (for the each 2-hour duration) TST of the 8-hour PSG recording is reported.

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in Total Sleep Time (TST) Change From Baseline in TST for Overall Duration	28.2 minutes Standard Error 7.69	12.5 minutes Standard Error 7.73
Change From Baseline in Total Sleep Time (TST) Change From Baseline in TST in Quarter 1	7.1 minutes Standard Error 4.01	2.4 minutes Standard Error 4.00
Change From Baseline in Total Sleep Time (TST) Change From Baseline in TST in Quarter 2	8.5 minutes Standard Error 3.03	4.7 minutes Standard Error 3.02
Change From Baseline in Total Sleep Time (TST) Change From Baseline in TST in Quarter 3	3.3 minutes Standard Error 2.94	-2.7 minutes Standard Error 2.93
Change From Baseline in Total Sleep Time (TST) Change From Baseline in TST in Quarter 4	11.5 minutes Standard Error 3.12	5.0 minutes Standard Error 3.10

SECONDARY outcome

Timeframe: Baseline and Day 14 (EODBT)

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

LPS is duration in minutes from lights off to the first epoch of 20 consecutive non-wake epochs.

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in Latency to Persistent Sleep (LPS)	-9.4 minutes Standard Error 5.77	-6.9 minutes Standard Error 5.73

SECONDARY outcome

Timeframe: Baseline and Day 14 (EODBT)

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

NAW was calculated from the onset of persistent sleep until lights on. An awakening is defined as at least 2 consecutive epochs of wake. Individual awakenings were separated by at least 1 epoch of Stage N2 (also fairly light, with sudden increases in brain wave frequency known as sleep spindles), N3 (slow wave or deep sleep) or REM sleep.

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in Number of Awakenings (NAW)	-0.2 awakenings Standard Error 0.61	0.1 awakenings Standard Error 0.60

SECONDARY outcome

Timeframe: Baseline, Day 14: Overall duration (8 hours) and each 2-hour quarter duration (quarter 1: 0 to 2 hours, quarter 2: 2 to 4 hours, quarter 3: 4 to 6 hours, quarter 4: 6 to 8 hours) of PSG recording

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

An awakening is defined as at least 2 consecutive epochs of wake. Mean duration of awakenings is an arithmetic mean calculated as the sum of duration of all awakenings (in minutes) divided by the number of awakenings. In this outcome measure, change from baseline at Day 14 in overall (for the whole 8-hour period) mean duration of awakenings and in each quarter (for the each 2-hour duration) mean duration of awakenings is reported.

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in Mean Duration of Awakenings Change From Baseline in Mean Duration of Awakenings in Overall	-3.3 minutes Standard Error 1.24	-0.3 minutes Standard Error 1.23
Change From Baseline in Mean Duration of Awakenings Change From Baseline in Mean Duration of Awakenings in Quarter 1	-2.1 minutes Standard Error 0.77	-1.2 minutes Standard Error 0.80
Change From Baseline in Mean Duration of Awakenings Change From Baseline in Mean Duration of Awakenings in Quarter 2	-2.3 minutes Standard Error 2.22	1.2 minutes Standard Error 2.21
Change From Baseline in Mean Duration of Awakenings Change From Baseline in Mean Duration of Awakenings in Quarter 3	-4.0 minutes Standard Error 2.46	-0.5 minutes Standard Error 2.43
Change From Baseline in Mean Duration of Awakenings Change From Baseline in Mean Duration of Awakenings in Quarter 4	-2.3 minutes Standard Error 0.50	-1.8 minutes Standard Error 0.49

SECONDARY outcome

Timeframe: Baseline and Day 14 (EODBT)

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

The change in duration (minutes) of NREM sleep stages: N1 (light sleep), N2 (also fairly light, with sudden increases in brain wave frequency known as sleep spindles), N3 (slow wave or deep sleep) and REM sleep time from lights off to lights on during PSG recording was reported.

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in Duration of Stage N1, N2, N3, and REM Sleep (in Minutes) Change From Baseline in Duration of Stage N1 Sleep	0.1 minutes Standard Error 1.83	-0.3 minutes Standard Error 1.78
Change From Baseline in Duration of Stage N1, N2, N3, and REM Sleep (in Minutes) Change From Baseline in Duration of Stage N2 Sleep	31.7 minutes Standard Error 5.95	13.1 minutes Standard Error 5.90
Change From Baseline in Duration of Stage N1, N2, N3, and REM Sleep (in Minutes) Change From Baseline in Duration of Stage N3 Sleep	4.5 minutes Standard Error 4.09	-0.4 minutes Standard Error 4.08
Change From Baseline in Duration of Stage N1, N2, N3, and REM Sleep (in Minutes) Change From Baseline in Duration of REM Sleep	-9.5 minutes Standard Error 3.46	0.7 minutes Standard Error 3.46

SECONDARY outcome

Timeframe: Baseline and Day 14 (EODBT)

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

The change from baseline in duration of sleep time (percentage) of NREM sleep stages N1 (light sleep), N2 (also fairly light, with sudden increases in brain wave frequency known as sleep spindles), N3 (slow wave or deep sleep) and REM sleep was reported. Duration of sleep time was calculated from lights off to lights on during PSG recording.

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in Percentage of N1, N2, N3 Stages, and REM Sleep Duration Change From Baseline in Percentage of Stage N3 Sleep	0.5 percentage of sleep time Standard Error 1.11	-0.7 percentage of sleep time Standard Error 1.10
Change From Baseline in Percentage of N1, N2, N3 Stages, and REM Sleep Duration Change From Baseline in Percentage of REM Sleep	-3.9 percentage of sleep time Standard Error 0.79	-0.1 percentage of sleep time Standard Error 0.78
Change From Baseline in Percentage of N1, N2, N3 Stages, and REM Sleep Duration Change From Baseline in Percentage of Stage N1 Sleep	-1.0 percentage of sleep time Standard Error 0.59	-0.9 percentage of sleep time Standard Error 0.59
Change From Baseline in Percentage of N1, N2, N3 Stages, and REM Sleep Duration Change From Baseline in Percentage of Stage N2 Sleep	4.3 percentage of sleep time Standard Error 1.14	1.6 percentage of sleep time Standard Error 1.13

SECONDARY outcome

Timeframe: Baseline and Day 14 (EODBT)

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation.

Latency to REM sleep (REML) for first period is the number of non-REM epochs in terms of minutes (stages N1 [light sleep], N2 [also fairly light, with sudden increases in brain wave frequency known as sleep spindles], N3 [slow wave or deep sleep]) from LPS to the first epoch of REM sleep. REML for second and subsequent REM periods is the number of non-REM and REM epochs in terms of minutes (stages N1, N2, N3, and REM) from LPS to the first epoch of the 2nd REM period, or subsequent REM period.

Outcome measures

Measure	SAGE-217 n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in Latency to the First Period and Each Subsequent Period (Periods 2, 3, 4) of REM Sleep Change From Baseline in Latency to the Second REM Period	41.5 minutes Standard Error 8.16	-1.6 minutes Standard Error 8.34
Change From Baseline in Latency to the First Period and Each Subsequent Period (Periods 2, 3, 4) of REM Sleep Change From Baseline in Latency to the Third REM Period	34.9 minutes Standard Error 8.33	-3.3 minutes Standard Error 8.79
Change From Baseline in Latency to the First Period and Each Subsequent Period (Periods 2, 3, 4) of REM Sleep Change From Baseline in Latency to the First REM Period	36.6 minutes Standard Error 9.17	3.0 minutes Standard Error 9.17
Change From Baseline in Latency to the First Period and Each Subsequent Period (Periods 2, 3, 4) of REM Sleep Change From Baseline in Latency to the Fourth REM Period	45.2 minutes Standard Error 13.88	19.2 minutes Standard Error 15.42

SECONDARY outcome

Timeframe: Baseline and Day 14 (EODBT)

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

REM density is the total number of REMs divided by the total duration of REM sleep in hours during time in bed (TIB).

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=39 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in REM Density	-185.3 number of REM per hour Standard Error 33.89	-14.2 number of REM per hour Standard Error 34.30

SECONDARY outcome

Timeframe: Baseline and Day 14 (EODBT)

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

REMA is the total number of REMs during REM sleep, observed on the electrooculographic (EOG) channels of the PSG. The rapid eye movements must be at least 25 microvolts (uV) in amplitude.

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in REM Activity (REMA)	-281.3 number of REM Standard Error 50.85	6.7 number of REM Standard Error 50.33

SECONDARY outcome

Timeframe: Baseline and Day 15

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

ISI is a validated questionnaire designed to assess the nature, severity, and impact of insomnia. The ISI uses a 5-point Likert scale to measure various aspects of insomnia severity (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe), satisfaction with current sleep pattern (0 = very satisfied, 1 = satisfied, 2 = neutral, 3 = dissatisfied, 4 = very dissatisfied), and various aspects of the impact of insomnia on daily functioning (0 = not at all, 1 = a little, 2 = somewhat, 3 = much, 4 = very much). The ISI possible total score range is from 0 to 28, categorized as follows: 0 to 7 = "no clinically significant insomnia", 8 to 14 = "subthreshold insomnia", 15 to 21 = "clinical insomnia (moderate severity)", and 22 to 28 = "clinical insomnia (severe)". Higher scores indicate severe insomnia.

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=39 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in Insomnia Severity Index (ISI) Score	-6.4 score on a scale Standard Deviation 6.10	-4.1 score on a scale Standard Deviation 5.41

SECONDARY outcome

Timeframe: Baseline and Day 15

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

The CSD-C collects subjective responses to a series of questions related to participant's daily sleep pattern (i.e., time to bed, time to fall asleep, time to final awakening, and a question related to quality of sleep). Sleep parameters including subjective sleep latency (sSL), subjective TST (sTST), subjective WASO (sWASO), and subjective sleep quality (sSQ), were derived from the CSD-C responses. Change from baseline in sSL, sTST and sWASO was reported in this outcome measure.

Outcome measures

Measure	SAGE-217 n=39 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=39 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in Consensus Sleep Diary - Core (CSD-C) Parameters Change From Baseline in sTST	50.3 minutes Standard Error 10.76	39.9 minutes Standard Error 10.59
Change From Baseline in Consensus Sleep Diary - Core (CSD-C) Parameters Change From Baseline in sWASO	-27.4 minutes Standard Error 4.76	-16.5 minutes Standard Error 4.72
Change From Baseline in Consensus Sleep Diary - Core (CSD-C) Parameters Change From Baseline in sSL	-9.1 minutes Standard Error 5.31	-15.7 minutes Standard Error 5.26

SECONDARY outcome

Timeframe: Baseline and Day 15

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

The CSD-C collects subjective responses to a series of questions related to participant's daily sleep pattern (i.e., time to bed, time to fall asleep, time to final awakening, and a question related to quality of sleep). Sleep parameters including sSL, sTST, sWASO, and sSQ, were derived from the CSD-C responses. Change from baseline in sSQ was reported in this outcome measure. Sleep quality is rated on a 5-point Likert scale ranging from 1 (very poor) to 5 (very good). Higher ratings indicate better sleep quality.

Outcome measures

Measure	SAGE-217 n=39 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=39 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in CSD-C Parameter: Subjective Sleep Quality (sSQ)	0.521 units on a scale Standard Deviation 0.6175	0.341 units on a scale Standard Deviation 0.6615

SECONDARY outcome

Timeframe: Baseline and Day 15

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

The severity of illness for each participant was rated using the CGI-S on a 7-point Likert scale with a total score range of 1-7 where a higher score represented a worse outcome. The participants were rated 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. In this study, the CGI-S was assessed based on the severity of insomnia disorder.

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=39 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in Clinical Global Impression - Severity (CGI-S) Scale	-1.1 score on a scale Standard Deviation 1.03	-0.8 score on a scale Standard Deviation 1.07

SECONDARY outcome

Timeframe: Day 15

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

The overall improvement in the participant's condition was assessed using CGI-I on a 7-point Likert scale with a total score range of 0-7 where a higher score represented a worse outcome. The participants were rated as: 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. In this study, the CGI-I was assessed based on the improvement of insomnia disorder.

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=39 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Mean Score of the Clinical Global Impression - Improvement (CGI-I) Scale	2.9 score on a scale Standard Deviation 0.97	3.4 score on a scale Standard Deviation 0.96

SECONDARY outcome

Timeframe: Baseline and Day 15

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

The 17-item HAM-D was used to rate the severity of depression in participants who were already diagnosed as depressed. 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. The HAM-D total score was calculated as the sum of the 17 individual item scores and could range from 0 to 52. Higher scores indicate severe depression.

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=39 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) Total Score	-7.9 score on a scale Standard Deviation 7.60	-6.4 score on a scale Standard Deviation 6.53

SECONDARY outcome

Timeframe: Baseline and Day 15

Population: FAS included all randomized participants who received at least 1 dose of double-blind IP with valid baseline and at least one post-baseline efficacy evaluation. Overall number of participants analyzed indicates the number of participants with data available for analysis for this outcome measure.

PHQ-9 is a participant-rated depressive symptom severity scale to monitor severity over time for newly diagnosed participants or participants in current treatment for depression. 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 total score was calculated as the sum of the 9 individual item scores. The PHQ-9 total score was 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. Higher scores indicate severe depression.

Outcome measures

Measure	SAGE-217 n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=39 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in the 9-item Patient Health Questionnaire (PHQ-9) Score	-7.4 score on a scale Standard Deviation 6.50	-5.8 score on a scale Standard Deviation 5.69

SECONDARY outcome

Timeframe: From first dose of drug up to last follow-up visit (approximately 72 days)

Population: Safety set included all participants who received at least 1 dose of double-blind study drug.

An adverse event (AE) is any untoward medical occurrence in a clinical trial 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 (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is an AE that occurs after the first administration of double-blind study drug or placebo. SAE is any untoward medical occurrence that at any dose results in death, is immediately life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital abnormality or birth defect.

Outcome measures

Measure	SAGE-217 n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAEs	24 Participants	28 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAEs	1 Participants	1 Participants

SECONDARY outcome

Timeframe: Screening up to last follow-up visit (approximately 72 days)

Population: Safety set included all participants who received at least 1 dose of double-blind study drug.

Potentially clinically significant vital signs reported include supine and standing systolic blood pressure (SBP) [millimeters of mercury (mmHg)]: <90, >180, increase and decrease from baseline of >=30; Supine and standing diastolic blood pressure (DBP) (mmHg): Increase and decrease from baseline >=20; Standing heart rate (>120 beats per minute); Orthostatic SBP (>=20); Orthostatic DBP (>=10); Orthostatic hypotension (SBP >=20 and DBP >=10, SBP >=20 or DBP >=10).

Outcome measures

Measure	SAGE-217 n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Number of Participants With Potentially Clinically Significant Vital Signs Supine SBP (mmHg): Increase From Baseline of >= 30	2 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Supine SBP (mmHg): <90	0 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Supine SBP (mmHg): Decrease From Baseline of >= 30	2 Participants	3 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Standing SBP (mmHg): <90	2 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Standing SBP (mmHg): >180	1 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Standing SBP (mmHg): Decrease From Baseline of >= 30	2 Participants	3 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Standing SBP (mmHg): Increase From Baseline of >= 30	3 Participants	2 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Supine DBP (mmHg): Decrease From Baseline of >= 20	3 Participants	2 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Supine DBP (mmHg): Increase From Baseline of >= 20	1 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Standing DBP (mmHg): Decrease From Baseline of >= 20	2 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Standing DBP (mmHg): Increase From Baseline of >= 20	4 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Standing Heart Rate (beats per minute): >120	0 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Orthostatic SBP: >= 20	5 Participants	7 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Orthostatic DBP: >= 10	3 Participants	9 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Orthostatic Hypotension: SBP>=20 and DBP>=10	2 Participants	2 Participants
Number of Participants With Potentially Clinically Significant Vital Signs Orthostatic Hypotension: SBP>=20 or DBP>=10	7 Participants	14 Participants

SECONDARY outcome

Timeframe: Screening up to last follow-up visit (approximately 72 days)

Population: Safety set included all participants who received at least 1 dose of double-blind study drug.

Laboratory parameters include serum chemistry- Alanine aminotransferase: >3x upper limit of normal (ULN); Alanine aminotransferase or aspartate aminotransferase: >3x ULN; Bilirubin: >1.5x ULN, >2x ULN; Calcium: <2.0 millimoles per liter (mmol/L); Gamma Glutamyl Transferase [units per liter (U/L)]: >3xULN; Potassium: >5.4 mmol/L; Sodium: >150 mmol/L; Hematology- Hematocrit : Male <0.385 liter/liter (L/L) and Female <0.345 L/L and Male >0.55 L/L and Female >0.49 L/L; Hemoglobin: Male <115 grams/liter (g/L) and Female <100 g/L; Neutrophils: <1.5 10^9/L.

Outcome measures

Measure	SAGE-217 n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Alanine Aminotransferase: >3x ULN	3 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Alanine Aminotransferase or Aspartate Aminotransferase: >3x ULN	3 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Bilirubin: >1.5x ULN	1 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Bilirubin: >2x ULN	1 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Calcium: <2.0 mmol/L	0 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Gamma Glutamyl Transferase (U/L): >3xULN	2 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Potassium: >5.4 mmol/L	4 Participants	2 Participants
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Sodium: >150 mmol/L	1 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Hematocrit: Male <0.385 L/L, Female <0.345 L/L	3 Participants	5 Participants
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Hematocrit: Male >0.55 L/L, Female >0.49 L/L	0 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Hemoglobin: Male <115 g/L, Female <100 g/L	1 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Neutrophils: <1.5 10^9/L	0 Participants	3 Participants

SECONDARY outcome

Timeframe: Screening up to last follow-up visit (approximately 72 days)

Population: Safety set included all participants who received at least 1 dose of double-blind study drug.

Supine 12-lead ECGs were performed in triplicate and the standard intervals (heart rate, PR, QRS, QT, and QTcF) as well as any rhythm abnormalities were recorded. Criteria for potentially clinically significant ECG abnormalities included QTcF interval (msec)- females: >450 to 480, male: >450 to 470, females: >480 to 500, male: >470 to 500 or >500.

Outcome measures

Measure	SAGE-217 n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Screening up to last follow-up visit (approximately 72 days)

Population: Safety set included all participants who received at least 1 dose of double-blind study drug.

C-SSRS scale was used to monitor suicidality. The C-SSRS includes 'yes' or 'no' responses for 5 questions for assessment of suicidal ideation and behavior. Any suicidal behavior: when response is "yes" for any these questions- actual attempt to suicide, engaged in non-suicidal self-injurious behavior, interrupted attempt, aborted attempt, preparatory acts. Any suicidal ideation: when response is "yes" for any of these questions- wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent to suicide.

Outcome measures

Measure	SAGE-217 n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Number of Participants With Suicidal Ideation and Suicidal Behavior Using the Columbia Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation	7 Participants	7 Participants
Number of Participants With Suicidal Ideation and Suicidal Behavior Using the Columbia Suicide Severity Rating Scale (C-SSRS) Suicidal Behavior	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline, Days 18, 22, 28, 35 and 42

Population: Safety set included all participants who received at least 1 dose of double-blind study drug. Overall number of participants analyzed signifies the number of participants with data available for analyses for this outcome measure. Number analyzed signifies the number of participants with data available for analyses at the specified time point.

The PWC-20 was used to monitor for the presence of potential withdrawal symptoms following discontinuation of IP. It consists of a list of 20 symptoms (loss of appetite, nausea-vomiting, diarrhea, anxiety-nervousness, irritability, dysphoric mood-depression, insomnia, fatigue-lethargy-lack of energy, poor coordination, restlessness-agitation, diaphoresis, tremor-tremulousness, dizziness-lightheadedness, headaches, muscle aches or stiffness, weakness, increased acuity [sound, smell, touch, pain], paresthesia, difficulty concentrating and remembering, depersonalization-derealization) that were rated by the investigator on a scale of 0 (not present) to 3 (severe). The total score was derived as the sum of individual item scores, which ranges from 0 to 60. Higher scores indicate severe withdrawal. The total scores of PWC-20 were reported in this outcome measure.

Outcome measures

Measure	SAGE-217 n=43 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	Placebo n=40 Participants Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Change From Baseline in the Withdrawal Symptoms as Measured by the Physician Withdrawal Checklist (PWC-20) Total Score Change From Baseline at Day 18	-1.0 score on a scale Standard Deviation 5.18	-1.2 score on a scale Standard Deviation 4.70
Change From Baseline in the Withdrawal Symptoms as Measured by the Physician Withdrawal Checklist (PWC-20) Total Score Change From Baseline at Day 22	-2.5 score on a scale Standard Deviation 4.81	-0.9 score on a scale Standard Deviation 5.08
Change From Baseline in the Withdrawal Symptoms as Measured by the Physician Withdrawal Checklist (PWC-20) Total Score Change From Baseline at Day 28	-0.1 score on a scale Standard Deviation 6.37	-1.2 score on a scale Standard Deviation 5.56
Change From Baseline in the Withdrawal Symptoms as Measured by the Physician Withdrawal Checklist (PWC-20) Total Score Change From Baseline at Day 35	0.1 score on a scale Standard Deviation 5.20	-0.6 score on a scale Standard Deviation 6.47
Change From Baseline in the Withdrawal Symptoms as Measured by the Physician Withdrawal Checklist (PWC-20) Total Score Change From Baseline at Day 42	-0.8 score on a scale Standard Deviation 5.83	-1.6 score on a scale Standard Deviation 6.58

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 18 other events

Deaths: 0 deaths

SAGE-217

Serious events: 1 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=43 participants at risk Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	SAGE-217 n=43 participants at risk Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Nervous system disorders Focal dyscognitive seizures	0.00% 0/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.	2.3% 1/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.
Hepatobiliary disorders Cholecystitis	2.3% 1/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.	0.00% 0/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.

Other adverse events

Measure	Placebo n=43 participants at risk Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217 matching placebo capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217 matching placebo capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.	SAGE-217 n=43 participants at risk Participants received SAGE-217 matching placebo capsules (single-blind), orally, once daily prior to Day 1 (Days -2 and -1) followed by self-administration of SAGE-217, 30 mg capsules, orally, once daily for 12 days. Thereafter participants received SAGE-217, 30 mg capsules, orally, once daily, 30 minutes prior to lights out (PSG) on Days 13 and 14 (double-blind). Thereafter participants self-administered SAGE-217 matching placebo capsules (single-blind), orally, once daily on Days 15 to 21.
Nervous system disorders Somnolence	7.0% 3/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.	14.0% 6/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.
Nervous system disorders Headache	2.3% 1/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.	11.6% 5/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.
Nervous system disorders Dizziness	0.00% 0/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.	9.3% 4/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.
Infections and infestations Upper respiratory tract infection	20.9% 9/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.	7.0% 3/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.
Infections and infestations Nasopharyngitis	4.7% 2/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.	7.0% 3/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.
Gastrointestinal disorders Diarrhoea	7.0% 3/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.	7.0% 3/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.
Gastrointestinal disorders Nausea	14.0% 6/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.	4.7% 2/43 • From first dose of drug up to last follow-up visit (approximately 72 days) Safety set included all participants who received at least 1 dose of double-blind study drug.

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