Trial Outcomes & Findings for 54135419SUI3001: A Study to Evaluate the Efficacy and Safety of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Adult Participants Assessed to be at Imminent Risk for Suicide (NCT NCT03039192)

Last Updated: 2025-04-29

Results Overview

MADRS is clinician-rated scale designed to be used in participants with Major Depressive Disorder (MDD) to measure depression severity and detect changes due to antidepressant treatment. It evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic and suicidal thoughts. Scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms), summed for total possible score of 0 to 60. Higher scores represent more severe condition. Negative change in score indicates improvement.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

226 participants

Primary outcome timeframe

Baseline (Day 1, predose) and 24 hours first post dose (Day 2)

Results posted on

2025-04-29

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Plus SOC Antidepressant Treatment Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Overall Study STARTED	112	114
Overall Study Treated	112	113
Overall Study COMPLETED	80	84
Overall Study NOT COMPLETED	32	30

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Plus SOC Antidepressant Treatment Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Overall Study Lost to Follow-up	4	4
Overall Study Adverse event, serious fatal	0	1
Overall Study Adverse event, non-fatal	0	2
Overall Study Withdrawal by Subject	6	9
Overall Study Discontinued from treatment phase	19	12
Overall Study Other	3	2

Baseline Characteristics

54135419SUI3001: A Study to Evaluate the Efficacy and Safety of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Adult Participants Assessed to be at Imminent Risk for Suicide

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=113 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.	Total n=225 Participants Total of all reporting groups
Age, Continuous	37.9 years STANDARD_DEVIATION 12.54 • n=5 Participants	40.8 years STANDARD_DEVIATION 13.11 • n=7 Participants	39.3 years STANDARD_DEVIATION 12.88 • n=5 Participants
Sex: Female, Male Female	73 Participants n=5 Participants	66 Participants n=7 Participants	139 Participants n=5 Participants
Sex: Female, Male Male	39 Participants n=5 Participants	47 Participants n=7 Participants	86 Participants n=5 Participants
Race/Ethnicity, Customized Asian	28 Participants n=5 Participants	28 Participants n=7 Participants	56 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	7 Participants n=5 Participants	5 Participants n=7 Participants	12 Participants n=5 Participants
Race/Ethnicity, Customized More than one race	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized White	74 Participants n=5 Participants	77 Participants n=7 Participants	151 Participants n=5 Participants
Region of Enrollment BULGARIA	10 Participants n=5 Participants	9 Participants n=7 Participants	19 Participants n=5 Participants
Region of Enrollment ESTONIA	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment GERMANY	10 Participants n=5 Participants	8 Participants n=7 Participants	18 Participants n=5 Participants
Region of Enrollment HUNGARY	8 Participants n=5 Participants	7 Participants n=7 Participants	15 Participants n=5 Participants
Region of Enrollment MALAYSIA	9 Participants n=5 Participants	7 Participants n=7 Participants	16 Participants n=5 Participants
Region of Enrollment SOUTH AFRICA	8 Participants n=5 Participants	7 Participants n=7 Participants	15 Participants n=5 Participants
Region of Enrollment SOUTH KOREA	10 Participants n=5 Participants	10 Participants n=7 Participants	20 Participants n=5 Participants
Region of Enrollment SPAIN	20 Participants n=5 Participants	24 Participants n=7 Participants	44 Participants n=5 Participants
Region of Enrollment TAIWAN	8 Participants n=5 Participants	9 Participants n=7 Participants	17 Participants n=5 Participants
Region of Enrollment UNITED STATES	28 Participants n=5 Participants	29 Participants n=7 Participants	57 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1, predose) and 24 hours first post dose (Day 2)

Population: Full efficacy analysis set included all randomized participants who received at least 1 dose of intranasal study agent during double-blind phase and have had both a baseline and a postbaseline evaluation for MADRS total score or CGI-SS-R. Here, N (number of participants analyzed) signifies number of participants analyzed for this outcome measure.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=111 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at 24 Hours After the First Dose (Day 2) (Last Observation Carried Forward [LOCF] Data) During Double-blind Phase	-12.8 units on a scale Standard Deviation 10.73	-16.4 units on a scale Standard Deviation 11.95

SECONDARY outcome

Timeframe: Baseline (Day 1, predose) and 24 hours first post dose (Day 2)

CGI-SS-R was derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a participants illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal participants). A higher score indicates a more severe condition and a reduction in score indicates improvement (that is, lower severity of suicidality).

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=111 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Change From Baseline in Clinical Global Impression of Severity of Suicidality- Revised (CGI-SS-R) Score at 24 Hours After the First Dose (Day 2) (LOCF Data) During Double-blind Phase	-1.0 units on a scale Interval -5.0 to 1.0	-1.0 units on a scale Interval -6.0 to 2.0

SECONDARY outcome

Timeframe: Days 1 (4 hours postdose), 2, 4, 8, 11, 15, 18, 22 and Day 25 (predose and 4 hours postdose)

Population: Full efficacy analysis set included all randomized participants who received at least 1 dose of intranasal study agent during the double-blind phase and have had both a baseline and a post-baseline evaluation for the MADRS total score or CGI-SS-R.

Participants who had a MADRS total score of \<=12 were considered remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition and a negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Number of Participants Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase Day 4	13 Participants	28 Participants
Number of Participants Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase Day 1 (4 Hours postdose)	9 Participants	12 Participants
Number of Participants Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase Day 2	10 Participants	21 Participants
Number of Participants Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase Day 8	23 Participants	30 Participants
Number of Participants Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase Day 11	26 Participants	33 Participants
Number of Participants Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase Day 15	29 Participants	38 Participants
Number of Participants Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase Day 18	30 Participants	42 Participants
Number of Participants Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase Day 22	25 Participants	41 Participants
Number of Participants Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase Day 25 (Predose)	38 Participants	46 Participants
Number of Participants Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase Day 25 (4 hours postdose)	42 Participants	60 Participants

SECONDARY outcome

Timeframe: Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 (predose and 4 hours postdose)

Population: Full efficacy analysis set included all randomized participants who received at least 1 dose of intranasal study agent during double-blind phase and have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of participants who were analyzed at specified time points.

MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition and a negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 1	-10.9 units on a scale Standard Deviation 9.69	-13.5 units on a scale Standard Deviation 10.89
Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 2	-12.9 units on a scale Standard Deviation 10.72	-16.4 units on a scale Standard Deviation 11.95
Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 4	-14.5 units on a scale Standard Deviation 11.39	-19.1 units on a scale Standard Deviation 12.29
Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 8	-17.4 units on a scale Standard Deviation 12.59	-19.7 units on a scale Standard Deviation 12.91
Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 11	-19.0 units on a scale Standard Deviation 12.08	-21.8 units on a scale Standard Deviation 12.20
Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 15	-20.4 units on a scale Standard Deviation 12.19	-22.3 units on a scale Standard Deviation 11.70
Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 18	-21.4 units on a scale Standard Deviation 12.00	-23.9 units on a scale Standard Deviation 11.77
Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 22	-21.6 units on a scale Standard Deviation 12.32	-24.0 units on a scale Standard Deviation 12.38
Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 25: predose	-23.0 units on a scale Standard Deviation 12.41	-24.8 units on a scale Standard Deviation 13.63
Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 25 (4 hours postdose)	-25.8 units on a scale Standard Deviation 10.94	-29.5 units on a scale Standard Deviation 10.89

SECONDARY outcome

Timeframe: Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25

Population: Full efficacy analysis set included all randomized participants who received at least 1 dose of intranasal study agent during double-blind phase and have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of participants who were analyzed at specified time points.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Change From Baseline in Clinical Global Impression- Severity of Suicidality-Revised (CGI-SS-R) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 1	0.0 units on a scale Interval -5.0 to 1.0	-1.0 units on a scale Interval -6.0 to 1.0
Change From Baseline in Clinical Global Impression- Severity of Suicidality-Revised (CGI-SS-R) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 2	-1.0 units on a scale Interval -5.0 to 1.0	-1.0 units on a scale Interval -6.0 to 2.0
Change From Baseline in Clinical Global Impression- Severity of Suicidality-Revised (CGI-SS-R) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 4	-1.0 units on a scale Interval -5.0 to 1.0	-2.0 units on a scale Interval -6.0 to 2.0
Change From Baseline in Clinical Global Impression- Severity of Suicidality-Revised (CGI-SS-R) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 8	-2.0 units on a scale Interval -5.0 to 0.0	-2.0 units on a scale Interval -6.0 to 1.0
Change From Baseline in Clinical Global Impression- Severity of Suicidality-Revised (CGI-SS-R) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 11	-2.0 units on a scale Interval -5.0 to 1.0	-3.0 units on a scale Interval -6.0 to 1.0
Change From Baseline in Clinical Global Impression- Severity of Suicidality-Revised (CGI-SS-R) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 15	-2.0 units on a scale Interval -5.0 to 0.0	-3.0 units on a scale Interval -5.0 to 0.0
Change From Baseline in Clinical Global Impression- Severity of Suicidality-Revised (CGI-SS-R) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 18	-2.5 units on a scale Interval -5.0 to 0.0	-3.0 units on a scale Interval -6.0 to 1.0
Change From Baseline in Clinical Global Impression- Severity of Suicidality-Revised (CGI-SS-R) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 22	-3.0 units on a scale Interval -5.0 to 1.0	-3.0 units on a scale Interval -6.0 to 1.0
Change From Baseline in Clinical Global Impression- Severity of Suicidality-Revised (CGI-SS-R) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 25	-3.0 units on a scale Interval -5.0 to 1.0	-3.0 units on a scale Interval -6.0 to 1.0

SECONDARY outcome

Timeframe: Days 1, 2, 4, 8, 11, 15, 18, 22 and 25

CGI-SS-R was derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a participants illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal participants). A higher score indicates a more severe condition. Negative change in score indicates improvement. A participant was considered to achieve resolution of suicidality at a given time point if the CGI-SS-R score was 0 (normal, not at all suicidal) or 1 (questionably suicidal).

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1) Through Double-blind Phase Day 1	25 Participants	37 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1) Through Double-blind Phase Day 2	39 Participants	42 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1) Through Double-blind Phase Day 4	45 Participants	49 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1) Through Double-blind Phase Day 8	48 Participants	53 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1) Through Double-blind Phase Day 11	46 Participants	60 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1) Through Double-blind Phase Day 15	52 Participants	68 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1) Through Double-blind Phase Day 18	55 Participants	68 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1) Through Double-blind Phase Day 22	62 Participants	70 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1) Through Double-blind Phase Day 25	57 Participants	71 Participants

SECONDARY outcome

Timeframe: Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25

Population: Full efficacy analysis set included all randomized participants who received at least 1 dose of intranasal study agent during double-blind phase and have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of participants who were analyzed at specified time points.

The CGI-SR-I is a scale summarizing the clinician's best assessment of the likelihood that the participant will attempt suicide in the next 7 days. The CGI-SR-I rating is scored on a 7-point scale: where' 0 (no imminent suicide risk); 1 (minimal imminent suicide risk), 2 (mild imminent suicide risk), 3 (moderate imminent suicide risk), 4 (marked imminent suicide risk), 5 (severely imminent suicide risk), 6 (extreme imminent suicide risk). Higher score indicates a more severe condition. Negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 1	0.0 units on a scale Interval -4.0 to 2.0	-1.0 units on a scale Interval -5.0 to 3.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 2	-1.0 units on a scale Interval -5.0 to 2.0	-1.0 units on a scale Interval -5.0 to 2.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 4	-1.0 units on a scale Interval -5.0 to 2.0	-2.0 units on a scale Interval -5.0 to 2.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 8	-2.0 units on a scale Interval -5.0 to 2.0	-2.0 units on a scale Interval -6.0 to 1.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 11	-2.0 units on a scale Interval -5.0 to 1.0	-2.0 units on a scale Interval -6.0 to 1.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 15	-2.0 units on a scale Interval -5.0 to 2.0	-3.0 units on a scale Interval -5.0 to 2.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 18	-3.0 units on a scale Interval -5.0 to 1.0	-3.0 units on a scale Interval -5.0 to 2.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 22	-3.0 units on a scale Interval -5.0 to 1.0	-3.0 units on a scale Interval -6.0 to 1.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 25	-3.0 units on a scale Interval -5.0 to 2.0	-3.0 units on a scale Interval -6.0 to 1.0

SECONDARY outcome

Timeframe: Baseline, Days 8 and 25

Population: Full efficacy analysis set included all randomized participants who received at least 1 dose of intranasal study agent during double-blind phase and have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of participants who were analyzed at specified time points.

BHS is a self-reported measure to assess one's level of negative expectations or pessimism regarding future. It consists of 20 true-false items that examine respondent's attitude over past week by either endorsing a pessimistic statement or denying an optimistic statement; 9 are keyed false and 11 are keyed true. For every statement, each response was assigned score of 0 or 1. Total BHS score is sum of item responses, ranged from 0-20, where higher score represented higher level of hopelessness.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Change From Baseline in Beck Hopelessness Scale (BHS) Total Score at Days 8 and 25 During Double-blind Phase Change at Day 8	-4.4 units on a scale Standard Deviation 6.03	-5.3 units on a scale Standard Deviation 6.06
Change From Baseline in Beck Hopelessness Scale (BHS) Total Score at Days 8 and 25 During Double-blind Phase Change at Day 25	-6.6 units on a scale Standard Deviation 6.63	-6.9 units on a scale Standard Deviation 6.92

SECONDARY outcome

Timeframe: Baseline and Days 2, 11 and 25

Population: Full efficacy analysis set included all randomized participants who received at least 1 dose of intranasal study agent during double-blind phase, have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of participants who were analyzed at specified time points.

EQ-5D-5L measures health outcome. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). EQ-5D-5L system comprises following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of 5 dimensions is divided into 5 levels of perceived problems (Level 1-no problem, Level 2-slight problems, Level 3-moderate problems, Level 4-severe problems, Level 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a health status index (HSI). Health Status Index ranges from 0.148 - 0.949, anchored at 0 (dead) and 1 (full health). Positive change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) at Days 2, 11 and 25 During Double-blind Phase: Health Status Index Change at Day 2	0.096 units on a scale Standard Deviation 0.1785	0.156 units on a scale Standard Deviation 0.1944
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) at Days 2, 11 and 25 During Double-blind Phase: Health Status Index Change at Day 11	0.169 units on a scale Standard Deviation 0.2139	0.206 units on a scale Standard Deviation 0.2043
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) at Days 2, 11 and 25 During Double-blind Phase: Health Status Index Change at Day 25	0.189 units on a scale Standard Deviation 0.2336	0.227 units on a scale Standard Deviation 0.2078

SECONDARY outcome

Timeframe: Baseline, Days 2, 11 and 25

EQ-5D-5L measures health outcome. It consists of EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ-VAS). EQ-VAS score from 0 (worst health) to 100 (best health), positive change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) at Days 2, 11 and 25 During Double-blind Phase: EQ-Visual Analogue Scale (EQ-VAS) Change at Day 2	7.8 units on a scale Standard Deviation 17.32	13.5 units on a scale Standard Deviation 20.78
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) at Days 2, 11 and 25 During Double-blind Phase: EQ-Visual Analogue Scale (EQ-VAS) Change at Day 11	16.3 units on a scale Standard Deviation 22.27	17.9 units on a scale Standard Deviation 24.55
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) at Days 2, 11 and 25 During Double-blind Phase: EQ-Visual Analogue Scale (EQ-VAS) Change at Day 25	20.0 units on a scale Standard Deviation 23.49	21.4 units on a scale Standard Deviation 26.71

SECONDARY outcome

Timeframe: Baseline, Days 2, 11 and 25

EQ-5D-5L measures health outcome. It consists of EQ-5D-5L system and EQ-VAS. EQ-5D-5L system comprises following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of 5 dimensions is divided into 5 levels of perceived problems (Level 1-no problem, Level 2-slight problems, Level 3-moderate problems, Level 4-severe problems, and Level 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a health status index (HSI). Health Status Index ranges from 0.148 - 0.949, anchored at 0 (dead) and 1 (full health), a lower score indicates worse health. Sum score=(sum of the scores from the 5 dimensions minus 5)\*5. Sum score ranges from 0-100. Higher score indicates a more severe problem. Negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) at Days 2, 11 and 25 During Double-blind Phase: Sum Score Change at Day 2	-6.1 units on a scale Standard Deviation 12.28	-11.2 units on a scale Standard Deviation 14.87
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) at Days 2, 11 and 25 During Double-blind Phase: Sum Score Change at Day 11	-12.3 units on a scale Standard Deviation 16.23	-15.2 units on a scale Standard Deviation 15.75
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) at Days 2, 11 and 25 During Double-blind Phase: Sum Score Change at Day 25	-13.4 units on a scale Standard Deviation 18.05	-16.8 units on a scale Standard Deviation 16.30

SECONDARY outcome

Timeframe: Baseline and Days 2, 11 and 25

Population: Full efficacy analysis set included all randomized participants who received at least 1 dose of intranasal study agent during double-blind phase and have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of participants who were analyzed at specified time points.

The QLDS is a disease specific patient-reported outcome designed to assess health related quality of life in participants with major depressive disorder (MDD). The instrument has a recall period of "at the moment", contains 34-items with "true"/"not true" response options and takes approximately 5-10 minutes to complete. The total score range is from 0 (good quality of life) to 34 (very poor quality of life). A higher score indicates a more severe condition. Negative change indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Change From Baseline in Quality of Life in Depression Scale (QLDS) Total Score at Days 2, 11 and 25 During Double-blind Phase Change at Day 2	-2.5 units on a scale Standard Deviation 4.55	-3.1 units on a scale Standard Deviation 5.14
Change From Baseline in Quality of Life in Depression Scale (QLDS) Total Score at Days 2, 11 and 25 During Double-blind Phase Change at Day 11	-4.4 units on a scale Standard Deviation 5.93	-5.6 units on a scale Standard Deviation 5.92
Change From Baseline in Quality of Life in Depression Scale (QLDS) Total Score at Days 2, 11 and 25 During Double-blind Phase Change at Day 25	-5.6 units on a scale Standard Deviation 5.99	-6.8 units on a scale Standard Deviation 5.97

SECONDARY outcome

Timeframe: Days 15 and 25

Population: Full efficacy analysis set included all randomized participants who received at least 1 dose of intranasal study agent during double-blind phase and have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of participants who were analyzed at specified time points.

The TSQM-9 is a 9-item generic patient-reported outcome instrument to assess participants' satisfaction with medication. It covers domains of effectiveness, convenience, and global satisfaction. The TSQM-9 domain scores were calculated as recommended by the instrument authors. (i) Effectiveness = \[(item 1 + item 2 + item 3) - 3\]/18\*100, (ii) Convenience = \[(item 4 + item 5 + item 6) - 3\]/18\*100 and (iii) Global satisfaction = \[(item 7 + item 8 + item 9) - 3\]/14\*100. Each domain score can be calculated only if all the three items considered in the calculation of that score are not missing. The TSQM-9 domain score ranges from 0 to 100, with higher scores representing higher satisfaction.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Treatment Satisfaction Questionnaire for Medication (TSQM-9) Total Score at Days 15 and 25 During Double-blind Phase Global Satisfaction: Day 25	55.7 units on a scale Standard Deviation 27.44	68.5 units on a scale Standard Deviation 25.51
Treatment Satisfaction Questionnaire for Medication (TSQM-9) Total Score at Days 15 and 25 During Double-blind Phase Effectiveness: Day 15	51.7 units on a scale Standard Deviation 25.74	63.5 units on a scale Standard Deviation 23.72
Treatment Satisfaction Questionnaire for Medication (TSQM-9) Total Score at Days 15 and 25 During Double-blind Phase Effectiveness: Day 25	57.6 units on a scale Standard Deviation 24.66	65.8 units on a scale Standard Deviation 25.23
Treatment Satisfaction Questionnaire for Medication (TSQM-9) Total Score at Days 15 and 25 During Double-blind Phase Convenience: Day 15	70.9 units on a scale Standard Deviation 19.57	70.5 units on a scale Standard Deviation 20.75
Treatment Satisfaction Questionnaire for Medication (TSQM-9) Total Score at Days 15 and 25 During Double-blind Phase Convenience: Day 25	74.0 units on a scale Standard Deviation 19.38	71.3 units on a scale Standard Deviation 19.69
Treatment Satisfaction Questionnaire for Medication (TSQM-9) Total Score at Days 15 and 25 During Double-blind Phase Global Satisfaction: Day 15	52.2 units on a scale Standard Deviation 28.57	64.5 units on a scale Standard Deviation 24.62

SECONDARY outcome

Timeframe: Baseline, Days 1, 2, 4, 8, 11, 15, 18, 22 and 25

Population: Full efficacy analysis set included all randomized participants who received at least 1 dose of intranasal study agent during double-blind phase and have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of participants who were analyzed at specified time points.

SIBAT is an assessment tool that captures suicidal ideation, behavior, and risk. It permits assessment of change in suicidal ideation and behavior and documents clinician assessment of severity of suicidality and suicide risk. SIBAT is organized into 8 modules divided into 2 major divisions: patient-reported section (Modules 1-5) and clinician-rated section (Modules 6-8). Patient-reported section has modules of demographics and suicide history, risk/protective factors, suicidal thinking, suicide behavior, and suicide risk. Question 3 from Module 5 asks participants to describe their thinking about suicide right now from 5 response options ranging from 0 (I have no suicidal thoughts) to 4 (I have suicidal thoughts all of time). SIBAT Module 5 (My Risk) Question 3 (Patient-reported FoST) total score ranges from 0 to 4; a higher score indicates a more severe condition. Negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Patient-reported FoST) Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 1	0.0 units on a scale Interval -4.0 to 2.0	0.0 units on a scale Interval -3.0 to 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Patient-reported FoST) Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 2	-1.0 units on a scale Interval -4.0 to 1.0	-1.0 units on a scale Interval -4.0 to 2.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Patient-reported FoST) Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 4	-1.0 units on a scale Interval -4.0 to 2.0	-1.0 units on a scale Interval -4.0 to 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Patient-reported FoST) Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 8	-1.0 units on a scale Interval -4.0 to 1.0	-1.0 units on a scale Interval -4.0 to 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Patient-reported FoST) Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 11	-1.0 units on a scale Interval -4.0 to 1.0	-1.5 units on a scale Interval -4.0 to 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Patient-reported FoST) Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 15	-1.0 units on a scale Interval -4.0 to 1.0	-2.0 units on a scale Interval -4.0 to 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Patient-reported FoST) Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 18	-2.0 units on a scale Interval -4.0 to 1.0	-2.0 units on a scale Interval -4.0 to 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Patient-reported FoST) Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 22	-2.0 units on a scale Interval -4.0 to 2.0	-2.0 units on a scale Interval -4.0 to 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Patient-reported FoST) Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 25	-2.0 units on a scale Interval -4.0 to 1.0	-2.0 units on a scale Interval -4.0 to 1.0

SECONDARY outcome

Timeframe: Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25

Population: Full efficacy analysis set included all randomized participants who received at least 1 dose of intranasal study agent during double-blind phase and have had both a baseline and a post-baseline evaluation for MADRS total score or CGI-SS-R. Here, 'n' (number analyzed) signifies number of participants who were analyzed at specified time points.

SIBAT is assessment tool that captures suicidal ideation, behavior, and risk. It permits assessment of change in suicidal ideation and behavior and documents clinician assessment of severity of suicidality and suicide risk. SIBAT has 8 modules divided into 2 major divisions: patient-reported section (Modules 1-5) and clinician-rated section (Modules 6-8). Clinician-rated section has modules for semi-structured interview, clinical global impressions of current severity of suicidality and imminent suicide risk, clinical global impression of long-term suicide risk, and clinical judgment of optimal suicide management. The score anchor point as in participant report frequency of suicidal thinking (FoST) that is, response options from never to all the time. Module 7-FoST score ranges from 0-5; higher score indicates more severe condition. Negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 - Clinician-rated FoST Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 4	-1.0 units on a scale Interval -5.0 to 1.0	-2.0 units on a scale Interval -5.0 to 2.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 - Clinician-rated FoST Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 1	-1.0 units on a scale Interval -5.0 to 2.0	-1.0 units on a scale Interval -5.0 to 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 - Clinician-rated FoST Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 2	-1.0 units on a scale Interval -5.0 to 1.0	-1.0 units on a scale Interval -5.0 to 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 - Clinician-rated FoST Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 8	-2.0 units on a scale Interval -5.0 to 2.0	-2.0 units on a scale Interval -5.0 to 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 - Clinician-rated FoST Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 11	-2.0 units on a scale Interval -5.0 to 2.0	-2.0 units on a scale Interval -5.0 to 2.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 - Clinician-rated FoST Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 15	-2.0 units on a scale Interval -5.0 to 0.0	-2.0 units on a scale Interval -5.0 to 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 - Clinician-rated FoST Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 18	-2.0 units on a scale Interval -5.0 to 1.0	-2.0 units on a scale Interval -5.0 to 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 - Clinician-rated FoST Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 22	-2.0 units on a scale Interval -5.0 to 1.0	-2.0 units on a scale Interval -5.0 to 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 - Clinician-rated FoST Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase Change at Day 25	-2.0 units on a scale Interval -5.0 to 1.0	-3.0 units on a scale Interval -5.0 to 1.0

SECONDARY outcome

Timeframe: Up to Day 25

Population: Safety analysis set included all randomized participants who received at least 1 dose of study drug in the DB treatment phase.

An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non investigational) product, whether or not related to that medicinal (investigational or non-investigational) product. A TEAE is categorized as related if assessed by the investigator as possibly, probably, or very likely related to study agent.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=113 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Number of Participants With Treatment Emergent Adverse Events (TEAEs): DB Treatment Phase	83 Participants	100 Participants

SECONDARY outcome

Timeframe: Up to Day 25

Population: Safety analysis set included all randomized participants who received at least 1 dose of study drug in the DB treatment phase. Here 'n' (number analyzed) signifies number of participants analyzed for each specified category.ULN=upper limit of normal; mmol/L= millimoles per liter; micromol/L=micromole/liter; g/L=gram per liter

Low/high abnormal values are: Alanine aminotransferase (ALT)-high=200 Units per liter(U/L); ALP-high=250U/L; aspartate aminotransferase(AST)-high=250U/L; gamma glutamyl transferase(GGT)=300U/L; Albumin(low=24g/L,high=60 g/L); Bicarbonate(low=15.1, high=34.9mmol/L); Bilirubin(high=51.3micromol/L); calcium(low=1.5,high=3mmol/L);Chloride(low=94,high=112mmol/L); CK(High=990U/L); Creatinine(High=265.2micromol/L); Eosinophils(High=10%); Erythrocytes(low=3.0\*1012/L,high=6.4\*1012/L); Glucose(low=2.2,high=16.7mmol/L); Hemoglobin(low=80g/L,high=190g/L);Hematocrit(low=0.28, high=0.55 fraction); LD(high=500U/L); Leukocytes(low=2.5\*109/L,high=15.5\*109/L); Lymphocytes(low=10%,high=60%); Monocytes(high=20%); Neutrophils(low=30%,high=90%); Phosphate(low=0.7 mmol/L,high=2.6mmol/L); Platelet count(low=100\*109/L,high=600\*109/L\]; Potassium(low=3.0mmol/L,high=5.8 mmol/L\]; Protein(low=50 g/L); Sodium(low=125 mmol/L,high=155 mmol/L); Urate(low=89.2 micromol/L,high=594.8micromol/L); Urine(high=8.0 pH).

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=113 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase ALT>3*ULN	1 Participants	1 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase ALT: Abnormal High	1 Participants	1 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Albumin: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Albumin: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Alkaline phosphatase (ALP): Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase AST: AST>3*ULN	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase AST: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Bicarbonate: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Bicarbonate: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Bilirubin: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Calcium: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Calcium: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Chloride: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Chloride: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Creatine Kinase (CK): Abnormal High	0 Participants	1 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Creatinine: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase GGT: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Glucose: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Glucose: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase ALT>3ULN or AST>3ULN and BILI>2*ULN	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Lactate Dehydrogenase(LD): Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Phosphate: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Phosphate: Abnormal Low	1 Participants	2 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Potassium: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Potassium: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Protein: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Sodium: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Sodium: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Urate: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Urate: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Basophils: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Eosinophils: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Erythrocytes: Abnormal High	1 Participants	1 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Erythrocytes: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Hematocrit: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Hematocrit: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Hemoglobin(Hb): Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Hemoglobin: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Leukocytes: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Leukocytes: Abnormal Low	1 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Lymphocytes: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Lymphocytes: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Monocytes: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Neutrophils: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Neutrophils: Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Platelets: Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Platelets: Abnormal Low	0 Participants	2 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Urine pH: Abnormal High	0 Participants	0 Participants

SECONDARY outcome

Timeframe: At Day 25

Population: Safety analysis set included all randomized participants who received at least 1 dose of study drug in the DB treatment phase. Here, 'n' (number analyzed) signifies number of participants analyzed for each specified category.

Number of participants with abnormal nasal examination were reported. Nasal examination of visual inspection of the epistaxis, nasal crusts, nasal discharge, and nasal erythema was performed.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=113 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase Epistaxis: Mild	0 Participants	1 Participants
Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase Epistaxis: Moderate	0 Participants	0 Participants
Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase Epistaxis: Severe	0 Participants	0 Participants
Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase Nasal Crusts: Mild	1 Participants	0 Participants
Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase Nasal Crusts: Moderate	0 Participants	0 Participants
Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase Nasal Crusts: Severe	0 Participants	0 Participants
Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase Nasal Discharge: Mild	0 Participants	3 Participants
Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase Nasal Discharge: Moderate	0 Participants	0 Participants
Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase Nasal Discharge: Severe	0 Participants	0 Participants
Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase Nasal Erythema: Mild	4 Participants	3 Participants
Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase Nasal Erythema: Moderate	0 Participants	0 Participants
Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase Nasal Erythema: Severe	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to Day 25

Population: Safety analysis set included all randomized participants who received at least 1 dose of study drug in the DB treatment phase.

Number of participants with treatment emergent abnormal ECG values for variables including heart rate (abnormally low refers to less than or equal to \[\<=\] 50 beats per minute \[bpm\] , abnormally high refers greater than or equal to \[\>=\] 100 bpm), pulse rate (PR) interval (abnormally high refers to \>= 210 milliseconds \[msec\]), QRS interval (abnormally Low refers to \<= 50, abnormally high refers to \>= 120 msec) and QT interval (abnormally low refers to \<= 200, abnormally high \>= 500 msec) were reported.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=113 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Number of Participants With Treatment Emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase Heart Rate <= 50 bpm	8 Participants	2 Participants
Number of Participants With Treatment Emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase Heart Rate >= 100 bpm	4 Participants	5 Participants
Number of Participants With Treatment Emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase PR Duration >= 210 msec	3 Participants	5 Participants
Number of Participants With Treatment Emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase QRS Duration <= 50 msec	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase QRS Duration >= 120 msec	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase QT Duration <= 200 msec	0 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase QT Duration >= 500 msec	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to Day 25

Population: Safety analysis set included all randomized participants who received at least 1 dose of study drug in the DB treatment phase.

Pulse oximetry was used to measure arterial SpO2 levels. On each dosing day, the device was attached to the finger, toe, or ear, and SpO2 was monitored and documented. If oxygen saturation levels were less than (\<) 93% at any time during the 1.5 hours postdose interval, pulse oximetry was recorded every 5 minutes until levels return to \>= 93% or until the participant is referred for appropriate medical care, if clinically indicated. Participants with at least 2 consecutive postdose oxygen saturation below 93% during the DB treatment phase were reported.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=113 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Number of Participants With Abnormal Arterial Oxygen Saturation (SpO2) Levels (Less Than [<] 93%) as Assessed by Pulse Oximetry at Any Time: DB Treatment Phase	2 Participants	1 Participants

SECONDARY outcome

Timeframe: Up to Day 25

Population: Safety analysis set included all randomized participants who received at least 1 dose of study drug in the DB treatment phase.

Number of participants with treatment emergent vital signs abnormalities (pulse rate in bpm \[abnormally low = a decrease from baseline of \>= 15 to a value \<= 50; abnormally high = an increase from baseline of \>=15 to a value \>=100\] , systolic blood pressure \[SBP\] in mmHg \[abnormally low = a decrease from baseline of \>= 20 to a value \<= 90; abnormally high = an increase from baseline of \>= 20 to a value \>= 180\], and diastolic blood pressure \[DBP\] in mmHg \[abnormally low= a decrease from baseline of \>=15 to a value \<= 50; abnormally high = an increase from baseline of \>= 15 to a value \>= 105) were reported.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=113 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Number of Participants With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase Pulse rate (bpm): Decrease of >=15 to <=50	2 Participants	3 Participants
Number of Participants With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase Pulse rate (bpm): Increase of >=15 to >=100	6 Participants	13 Participants
Number of Participants With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase SBP (mmHg): Decrease of >=20 to <=90	4 Participants	0 Participants
Number of Participants With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase SBP (mmHg): Increase of >=20 to >=180	0 Participants	2 Participants
Number of Participants With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase DBP (mmHg): Decrease of >=15 to <=50	4 Participants	0 Participants
Number of Participants With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase DBP (mmHg): Increase of >=15 to >=105	1 Participants	11 Participants

SECONDARY outcome

Timeframe: Up to Day 25

Population: Safety analysis set included all randomized participants who received at least 1 dose of study drug in the DB treatment phase.

MOAA/S was used to measure treatment-emergent sedation with correlation to levels of sedation defined by the American society of anesthesiologists (ASA) continuum. The MOAA/S scores range from 0 to 5 where,0 = no response to painful stimulus; ASA continuum = general anesthesia, 1 = responds to trapezius squeeze; ASA continuum = deep sedation, 2 = purposeful response to mild prodding or mild shaking; ASA continuum = moderate sedation, 3 = responds after name called loudly or repeatedly; ASA continuum = moderate sedation, 4 = lethargic response to name spoken in normal tone; ASA continuum = moderate sedation and 5 = readily responds to name spoken in normal tone (awake); ASA continuum = minimal sedation.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=113 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Number of Sedated Participants as Assessed by Modified Observer's Assessment of Alertness/Sedation (MOAA/S) Score at Any Time: DB Treatment Phase Score <=2: Yes	0 Participants	3 Participants
Number of Sedated Participants as Assessed by Modified Observer's Assessment of Alertness/Sedation (MOAA/S) Score at Any Time: DB Treatment Phase Score <=3: Yes	1 Participants	13 Participants
Number of Sedated Participants as Assessed by Modified Observer's Assessment of Alertness/Sedation (MOAA/S) Score at Any Time: DB Treatment Phase Score <=4: Yes	20 Participants	43 Participants

SECONDARY outcome

Timeframe: Days 1, 4, 8, 11, 15, 18, 22 and 25

Population: Safety analysis set included all randomized participants who received at least 1 dose of study drug in the DB treatment phase. Here, 'n' (number analyzed) signifies the number of participants analyzed for each specified time point.

The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization (with score range from 0 to 28), derealization (with score range from 0 to 52), and amnesia (with score range from 0 to 8). Participants responses are coded on a 5-point scale (0 = "Not at all", 1 = "Mild", 2 = "Moderate", 3 = 'Severe" and 4 = "Extreme"). The total score is sum of the 23 items and range from 0 to 92, where 0 (best) and 92 (worst). A higher score indicates a more severe condition. Number of participants with an increase in CADSS total score (increase based on maximum CADSS total score change from predose of \> 0) was reported.

Outcome measures

Outcome measures
Measure	Placebo Plus SOC Antidepressant Treatment n=112 Participants Participants self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1.	Esketamine 84 mg Plus SOC Antidepressant Treatment n=113 Participants Participants self-administered esketamine 84 milligrams (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) and received SOC antidepressant treatment which was initiated or optimized on Day 1.
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 25	14 Participants	72 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 1	34 Participants	95 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 4	23 Participants	84 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 8	29 Participants	81 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 11	19 Participants	77 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 15	17 Participants	69 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 18	19 Participants	70 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 22	16 Participants	70 Participants

Adverse Events

Placebo Plus SOC Antidepressant Treatment

Serious events: 6 serious events

Other events: 66 other events

Deaths: 0 deaths

Esketamine 84 mg Plus SOC Antidepressant Treatment

Serious events: 4 serious events

Other events: 91 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo Plus SOC Antidepressant Treatment n=112 participants at risk Subjects self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1 during double blind phase (DB).	Esketamine 84 mg Plus SOC Antidepressant Treatment n=113 participants at risk Subjects self-administered esketamine 84 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received SOC antidepressant treatment which was initiated or optimized on Day 1 during double blind phase.
Hepatobiliary disorders Hypertransaminasaemia	0.89% 1/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	0.00% 0/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Metabolism and nutrition disorders Diabetic Ketoacidosis	0.00% 0/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	0.88% 1/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Psychiatric disorders Aggression	0.89% 1/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	0.00% 0/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Psychiatric disorders Depression	0.89% 1/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	0.88% 1/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Psychiatric disorders Depression Suicidal	0.89% 1/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	1.8% 2/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Psychiatric disorders Suicidal Ideation	1.8% 2/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	0.00% 0/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Psychiatric disorders Suicide Attempt	0.89% 1/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	0.88% 1/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.

Other adverse events

Additional Information

Senior Director

Janssen Research & Development, LLC

Phone: 844-434-4210

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo Plus SOC Antidepressant Treatment n=112 participants at risk Subjects self-administered placebo matched to esketamine intranasally (1 spray of placebo to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received standard of care (SOC) antidepressant treatment which was initiated or optimized on Day 1 during double blind phase (DB).	Esketamine 84 mg Plus SOC Antidepressant Treatment n=113 participants at risk Subjects self-administered esketamine 84 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) twice per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) plus received SOC antidepressant treatment which was initiated or optimized on Day 1 during double blind phase.
Ear and labyrinth disorders Vertigo	0.89% 1/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	6.2% 7/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Eye disorders Vision Blurred	4.5% 5/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	8.8% 10/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Gastrointestinal disorders Constipation	4.5% 5/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	13.3% 15/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Gastrointestinal disorders Nausea	13.4% 15/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	20.4% 23/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Gastrointestinal disorders Vomiting	6.2% 7/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	7.1% 8/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Investigations Blood Pressure Increased	5.4% 6/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	16.8% 19/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Nervous system disorders Dizziness	8.9% 10/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	35.4% 40/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Nervous system disorders Dizziness Postural	1.8% 2/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	5.3% 6/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Nervous system disorders Dysgeusia	9.8% 11/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	14.2% 16/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Nervous system disorders Headache	17.9% 20/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	18.6% 21/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Nervous system disorders Hypoaesthesia	1.8% 2/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	7.1% 8/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Nervous system disorders Sedation	1.8% 2/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	6.2% 7/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Nervous system disorders Somnolence	9.8% 11/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	18.6% 21/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Psychiatric disorders Anxiety	8.9% 10/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	5.3% 6/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Psychiatric disorders Dissociation	3.6% 4/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	29.2% 33/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.
Psychiatric disorders Insomnia	6.2% 7/112 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.	6.2% 7/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study agent in the double-blind treatment phase.