Trial Outcomes & Findings for 54135419SUI3002: 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 NCT03097133)

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

230 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 + Standard of Care (SOC) Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Overall Study STARTED	115	115
Overall Study Treated	113	114
Overall Study COMPLETED	85	81
Overall Study NOT COMPLETED	30	34

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo + Standard of Care (SOC) Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Overall Study Lost to Follow-up	3	2
Overall Study Withdrawal by Subject	2	5
Overall Study Discontinued DB, not entered FU Phase	21	25
Overall Study Other	3	2
Overall Study Adverse Event	1	0

Baseline Characteristics

54135419SUI3002: 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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).	Total n=227 Participants Total of all reporting groups
Age, Continuous	41.4 years STANDARD_DEVIATION 13.43 • n=5 Participants	40.2 years STANDARD_DEVIATION 12.73 • n=7 Participants	40.8 years STANDARD_DEVIATION 13.07 • n=5 Participants
Sex: Female, Male Female	67 Participants n=5 Participants	69 Participants n=7 Participants	136 Participants n=5 Participants
Sex: Female, Male Male	46 Participants n=5 Participants	45 Participants n=7 Participants	91 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	8 Participants n=5 Participants	7 Participants n=7 Participants	15 Participants n=5 Participants
Race (NIH/OMB) White	87 Participants n=5 Participants	92 Participants n=7 Participants	179 Participants n=5 Participants
Race (NIH/OMB) More than one race	6 Participants n=5 Participants	8 Participants n=7 Participants	14 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	8 Participants n=5 Participants	6 Participants n=7 Participants	14 Participants n=5 Participants
Region of Enrollment ARGENTINA	9 Participants n=5 Participants	7 Participants n=7 Participants	16 Participants n=5 Participants
Region of Enrollment AUSTRIA	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
Region of Enrollment BELGIUM	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment BRAZIL	18 Participants n=5 Participants	18 Participants n=7 Participants	36 Participants n=5 Participants
Region of Enrollment CANADA	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment CZECH REPUBLIC	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment FRANCE	9 Participants n=5 Participants	15 Participants n=7 Participants	24 Participants n=5 Participants
Region of Enrollment LITHUANIA	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment POLAND	15 Participants n=5 Participants	18 Participants n=7 Participants	33 Participants n=5 Participants
Region of Enrollment SPAIN	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Region of Enrollment TURKEY	10 Participants n=5 Participants	13 Participants n=7 Participants	23 Participants n=5 Participants
Region of Enrollment UNITED STATES	36 Participants n=5 Participants	30 Participants n=7 Participants	66 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 DB treatment phase and had both baseline and post baseline 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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=113 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at 24 Hours Post First Dose (Last Observation Carried Forward [LOCF] Data): Double-blind (DB) Treatment Phase	-12.4 units on a scale Standard Deviation 10.43	-15.7 units on a scale Standard Deviation 11.56

PRIMARY outcome

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

Population: Analysis was performed on full efficacy analysis set. Here 'N' (number of participants analyzed) signifies number of participants analyzed for this outcome measure.

Clinical global impression-severity of suicidality-revised (CGI-SS-R) scale is revised version of 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 summarizes the clinician's overall impression of severity of suicidality on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal participants), based on the totality of information available to the clinician. Higher score indicates a more severe condition. Negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=113 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Change From Baseline in Clinical Global Impression-Severity of Suicidality - Revised (CGI-SS-R) Scale at 24 Hours Post First Dose (LOCF Data): DB Treatment Phase	-1.0 units on a scale Interval -5.0 to 2.0	-1.0 units on a scale Interval -6.0 to 2.0

SECONDARY outcome

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

Population: Analysis was performed on full efficacy analysis set.

Outcome measures

Outcome measures
Measure	Placebo + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Number of Participants With Remission of Major Depressive Disorder (MADRS Total Score Less Than or Equal to [<=] 12): DB Treatment Phase Day 1: 4 hours post dose	4 Participants	12 Participants
Number of Participants With Remission of Major Depressive Disorder (MADRS Total Score Less Than or Equal to [<=] 12): DB Treatment Phase Day 2	12 Participants	25 Participants
Number of Participants With Remission of Major Depressive Disorder (MADRS Total Score Less Than or Equal to [<=] 12): DB Treatment Phase Day 4	20 Participants	26 Participants
Number of Participants With Remission of Major Depressive Disorder (MADRS Total Score Less Than or Equal to [<=] 12): DB Treatment Phase Day 8	23 Participants	28 Participants
Number of Participants With Remission of Major Depressive Disorder (MADRS Total Score Less Than or Equal to [<=] 12): DB Treatment Phase Day 11	26 Participants	32 Participants
Number of Participants With Remission of Major Depressive Disorder (MADRS Total Score Less Than or Equal to [<=] 12): DB Treatment Phase Day 15	29 Participants	36 Participants
Number of Participants With Remission of Major Depressive Disorder (MADRS Total Score Less Than or Equal to [<=] 12): DB Treatment Phase Day 18	32 Participants	29 Participants
Number of Participants With Remission of Major Depressive Disorder (MADRS Total Score Less Than or Equal to [<=] 12): DB Treatment Phase Day 22	37 Participants	42 Participants
Number of Participants With Remission of Major Depressive Disorder (MADRS Total Score Less Than or Equal to [<=] 12): DB Treatment Phase Day 25: Predose	31 Participants	49 Participants
Number of Participants With Remission of Major Depressive Disorder (MADRS Total Score Less Than or Equal to [<=] 12): DB Treatment Phase Day 25: 4 hours postdose	42 Participants	54 Participants

SECONDARY outcome

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

Population: Analysis was performed on full efficacy analysis set. Here 'n' (number analyzed) signifies number of participants analyzed for each specified time point.

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

Outcome measures

Outcome measures
Measure	Placebo + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Change From Baseline in MADRS Total Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 1: 4 hours postdose	-8.2 units on a scale Standard Deviation 7.62	-12.2 units on a scale Standard Deviation 9.87
Change From Baseline in MADRS Total Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 2	-12.4 units on a scale Standard Deviation 10.51	-16.0 units on a scale Standard Deviation 11.52
Change From Baseline in MADRS Total Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 4	-15.7 units on a scale Standard Deviation 11.50	-17.7 units on a scale Standard Deviation 11.94
Change From Baseline in MADRS Total Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 8	-17.4 units on a scale Standard Deviation 11.29	-20.1 units on a scale Standard Deviation 11.47
Change From Baseline in MADRS Total Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 11	-19.5 units on a scale Standard Deviation 11.60	-21.3 units on a scale Standard Deviation 11.45
Change From Baseline in MADRS Total Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 15	-20.0 units on a scale Standard Deviation 12.54	-23.4 units on a scale Standard Deviation 10.62
Change From Baseline in MADRS Total Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 18	-21.4 units on a scale Standard Deviation 12.90	-23.1 units on a scale Standard Deviation 11.39
Change From Baseline in MADRS Total Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 22	-22.0 units on a scale Standard Deviation 12.12	-24.5 units on a scale Standard Deviation 11.57
Change From Baseline in MADRS Total Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 25: Predose	-22.5 units on a scale Standard Deviation 12.23	-26.2 units on a scale Standard Deviation 11.09
Change From Baseline in MADRS Total Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 25: 4 hours postdose	-26.4 units on a scale Standard Deviation 11.18	-28.7 units on a scale Standard Deviation 10.88

SECONDARY outcome

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

Population: Analysis was performed on full efficacy analysis set. Here 'n' (number analyzed) signifies number of participants analyzed for each specified time point.

Outcome measures

Outcome measures
Measure	Placebo + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Change From Baseline in CGI-SS-R Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 1: 4 hours postdose	-1.0 units on a scale Interval -4.0 to 1.0	-1.0 units on a scale Interval -6.0 to 1.0
Change From Baseline in CGI-SS-R Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 2	-1.0 units on a scale Interval -5.0 to 2.0	-1.0 units on a scale Interval -6.0 to 2.0
Change From Baseline in CGI-SS-R Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 4	-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 CGI-SS-R Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment 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 2.0
Change From Baseline in CGI-SS-R Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 11	-2.0 units on a scale Interval -6.0 to 2.0	-3.0 units on a scale Interval -6.0 to 1.0
Change From Baseline in CGI-SS-R Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 15	-3.0 units on a scale Interval -5.0 to 2.0	-3.0 units on a scale Interval -6.0 to 0.0
Change From Baseline in CGI-SS-R Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 18	-3.0 units on a scale Interval -6.0 to 1.0	-3.0 units on a scale Interval -5.0 to 0.0
Change From Baseline in CGI-SS-R Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 22	-3.0 units on a scale Interval -5.0 to 3.0	-3.0 units on a scale Interval -5.0 to 0.0
Change From Baseline in CGI-SS-R Score at 4 Hours Post First Dose at Day 1 (4 Hours Post First Dose), and 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 25	-3.0 units on a scale Interval -6.0 to 4.0	-3.0 units on a scale Interval -6.0 to 0.0

SECONDARY outcome

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

Population: Analysis was performed on full efficacy analysis set.

CGI-SS-R is revised version of the CGI-S. The CGI-SS-R summarizes the clinician's overall impression of severity of suicidality on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal participants), based on the totality of information available to the clinician. Higher score indicates a more severe condition. A participant was considered to have achieved 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). Participants who did not met such criterion or discontinued prior to the time point for any reason were not considered to have resolution of suicidality.

Outcome measures

Outcome measures
Measure	Placebo + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1): DB Treatment Phase Day 1: 4 hours postdose	20 Participants	38 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1): DB Treatment Phase Day 2	35 Participants	36 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1): DB Treatment Phase Day 4	51 Participants	52 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1): DB Treatment Phase Day 8	54 Participants	53 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1): DB Treatment Phase Day 11	58 Participants	62 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1): DB Treatment Phase Day 15	58 Participants	65 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1): DB Treatment Phase Day 18	59 Participants	62 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1): DB Treatment Phase Day 22	65 Participants	68 Participants
Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1): DB Treatment Phase Day 25	66 Participants	69 Participants

SECONDARY outcome

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

Population: Analysis was performed on full efficacy analysis set. Here, 'n' (number analyzed) signifies the number of participants analyzed at each specified time point.

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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 1: 4 hours postdose	0.0 units on a scale Interval -4.0 to 2.0	-1.0 units on a scale Interval -6.0 to 3.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 2	-1.0 units on a scale Interval -4.0 to 2.0	-1.0 units on a scale Interval -6.0 to 2.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 4	-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) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment 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 2.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment 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 2.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 15	-3.0 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) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 18	-3.0 units on a scale Interval -5.0 to 2.0	-3.0 units on a scale Interval -5.0 to 1.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 22	-3.0 units on a scale Interval -5.0 to 2.0	-3.0 units on a scale Interval -5.0 to 0.0
Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment 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: Analysis was performed on full efficacy analysis set. Here, 'n' (number analyzed) signifies number of participants analyzed for each specified time point.

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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Change From Baseline in Beck Hopelessness Scale (BHS) Total Score at Days 8 and 25 in DB Treatment Phase Change at Day 8	-6.3 units on a scale Standard Deviation 6.31	-6.1 units on a scale Standard Deviation 6.17
Change From Baseline in Beck Hopelessness Scale (BHS) Total Score at Days 8 and 25 in DB Treatment Phase Change at Day 25	-7.0 units on a scale Standard Deviation 6.47	-8.0 units on a scale Standard Deviation 6.31

SECONDARY outcome

Timeframe: Baseline, Days 2, 11 and 25

Population: Analysis was performed on full efficacy analysis set. Here, 'n' (number analyzed) signifies the number of participants analyzed for each specified time point.

EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). EQ-5D-5L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (no problem, slight, moderate, severe and extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate Health Status Index (HSI). HSI ranges from 0 (dead) to 1.00 (full health). EQ-VAS self-rating records respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst imaginable health)-100 (best imaginable health). Sum score ranges from 0 -100. Sum score=(sum of the scores from the 5 dimensions minus 5)\*5. Higher score indicates worse health state. Negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Change From Baseline in European Quality of Life Group, 5-Dimension, 5-Level (EQ-5D-5L) Sum Score at Days 2, 11 and 25 of the DB Treatment Phase Change at Day 2	-9.0 units on a scale Standard Deviation 12.30	-11.8 units on a scale Standard Deviation 14.45
Change From Baseline in European Quality of Life Group, 5-Dimension, 5-Level (EQ-5D-5L) Sum Score at Days 2, 11 and 25 of the DB Treatment Phase Change at Day 11	-15.1 units on a scale Standard Deviation 16.32	-15.0 units on a scale Standard Deviation 15.51
Change From Baseline in European Quality of Life Group, 5-Dimension, 5-Level (EQ-5D-5L) Sum Score at Days 2, 11 and 25 of the DB Treatment Phase Change at Day 25	-15.3 units on a scale Standard Deviation 15.78	-18.8 units on a scale Standard Deviation 16.96

SECONDARY outcome

Timeframe: Baseline, Days 2, 11 and 25

Population: Analysis was performed on full efficacy analysis set. Here, 'n' (number analyzed) signifies the number of participants analyzed for each specified time point.

EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. The EQ VAS self-rating records the respondent's own assessment of his or her overall health status at the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine). Positive change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Change From Baseline in European Quality of Life Group, Visual Analogue Scale (EQ-VAS) Score at Days 2, 11 and 25 of the DB Treatment Phase Change at Day 2	9.7 units on a scale Standard Deviation 15.57	13.4 units on a scale Standard Deviation 22.58
Change From Baseline in European Quality of Life Group, Visual Analogue Scale (EQ-VAS) Score at Days 2, 11 and 25 of the DB Treatment Phase Change at Day 11	17.6 units on a scale Standard Deviation 24.87	21.4 units on a scale Standard Deviation 26.95
Change From Baseline in European Quality of Life Group, Visual Analogue Scale (EQ-VAS) Score at Days 2, 11 and 25 of the DB Treatment Phase Change at Day 25	18.6 units on a scale Standard Deviation 25.39	27.0 units on a scale Standard Deviation 27.54

SECONDARY outcome

Timeframe: Baseline, Days 2, 11 and 25

Population: Analysis was performed on full efficacy analysis set. Here, 'n' (number analyzed) signifies the number of participants analyzed for each specified time point.

EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 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 HSI. HSI ranges from 0 (dead) to 1.00 (full health). Positive change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Change From Baseline in EQ-5D-5L Health Status Index at Days 2, 11 and 25 of the DB Treatment Phase Change at Day 2	0.129 units on a scale Standard Deviation 0.1732	0.160 units on a scale Standard Deviation 0.1872
Change From Baseline in EQ-5D-5L Health Status Index at Days 2, 11 and 25 of the DB Treatment Phase Change at Day 11	0.194 units on a scale Standard Deviation 0.2173	0.202 units on a scale Standard Deviation 0.2051
Change From Baseline in EQ-5D-5L Health Status Index at Days 2, 11 and 25 of the DB Treatment Phase Change at Day 25	0.194 units on a scale Standard Deviation 0.2149	0.235 units on a scale Standard Deviation 0.2228

SECONDARY outcome

Timeframe: Baseline, Days 2, 11 and 25

Population: Analysis was performed on full efficacy analysis set. Here, 'n' (number analyzed) signifies the number of participants analyzed for each specified time point.

The QLDS is a disease-specific patient-reported outcome designed to assess health-related quality of life in patients with MDD, it captures the impact of depression and its treatment from the participant's perspective. The instrument has a recall period of "at the moment" and contains 34 items with "true"/"not true" response options. 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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Change From Baseline in Quality of Life in Depression Scale (QLDS) Total Score at Days 2, 11 and 25 of the DB Treatment Phase Change at Day 2	-2.5 units on a scale Standard Deviation 3.93	-3.5 units on a scale Standard Deviation 4.93
Change From Baseline in Quality of Life in Depression Scale (QLDS) Total Score at Days 2, 11 and 25 of the DB Treatment Phase Change at Day 11	-5.2 units on a scale Standard Deviation 5.55	-5.1 units on a scale Standard Deviation 6.16
Change From Baseline in Quality of Life in Depression Scale (QLDS) Total Score at Days 2, 11 and 25 of the DB Treatment Phase Change at Day 25	-5.5 units on a scale Standard Deviation 6.03	-6.3 units on a scale Standard Deviation 6.26

SECONDARY outcome

Timeframe: Days 15 and 25

Population: Analysis was performed on full efficacy analysis. Here, 'n' (number analyzed) signifies the number of participants analyzed for each specified time point.

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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Treatment Satisfaction Questionnaire for Medication (TSQM-9) Domain Score at Days 15 and 25: DB Treatment Phase Effectiveness: Day 15	55.3 units on a scale Standard Deviation 27.93	63.5 units on a scale Standard Deviation 26.05
Treatment Satisfaction Questionnaire for Medication (TSQM-9) Domain Score at Days 15 and 25: DB Treatment Phase Effectiveness: Day 25	54.8 units on a scale Standard Deviation 28.84	68.8 units on a scale Standard Deviation 25.41
Treatment Satisfaction Questionnaire for Medication (TSQM-9) Domain Score at Days 15 and 25: DB Treatment Phase Convenience: Day 15	77.2 units on a scale Standard Deviation 16.73	71.3 units on a scale Standard Deviation 18.38
Treatment Satisfaction Questionnaire for Medication (TSQM-9) Domain Score at Days 15 and 25: DB Treatment Phase Convenience: Day 25	76.9 units on a scale Standard Deviation 17.92	77.0 units on a scale Standard Deviation 18.66
Treatment Satisfaction Questionnaire for Medication (TSQM-9) Domain Score at Days 15 and 25: DB Treatment Phase Global Satisfaction: Day 15	59.7 units on a scale Standard Deviation 27.12	63.6 units on a scale Standard Deviation 27.69
Treatment Satisfaction Questionnaire for Medication (TSQM-9) Domain Score at Days 15 and 25: DB Treatment Phase Global Satisfaction: Day 25	56.8 units on a scale Standard Deviation 28.31	71.5 units on a scale Standard Deviation 24.85

SECONDARY outcome

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

Population: Analysis was performed on full efficacy analysis set. Here, 'n' (number analyzed) signifies the number of participants analyzed for each specified time point.

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).

Outcome measures

Outcome measures
Measure	Placebo + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Participant-Reported Frequency of Suicidal Thinking) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 1: 4 hours postdose	-1.0 units on a scale Interval -3.0 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 (Participant-Reported Frequency of Suicidal Thinking) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment 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 (Participant-Reported Frequency of Suicidal Thinking) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 4	-1.0 units on a scale Interval -4.0 to 1.0	-1.0 units on a scale Interval -4.0 to 4.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Participant-Reported Frequency of Suicidal Thinking) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 8	-2.0 units on a scale Interval -4.0 to 1.0	-2.0 units on a scale Interval -4.0 to 4.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Participant-Reported Frequency of Suicidal Thinking) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 11	-2.0 units on a scale Interval -4.0 to 1.0	-2.0 units on a scale Interval -4.0 to 4.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Participant-Reported Frequency of Suicidal Thinking) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 15	-2.0 units on a scale Interval -4.0 to 0.0	-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 (Participant-Reported Frequency of Suicidal Thinking) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 18	-2.0 units on a scale Interval -4.0 to 2.0	-2.0 units on a scale Interval -4.0 to 3.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Participant-Reported Frequency of Suicidal Thinking) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 22	-2.0 units on a scale Interval -4.0 to 1.0	-2.0 units on a scale Interval -4.0 to 3.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Participant-Reported Frequency of Suicidal Thinking) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment 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 4.0

SECONDARY outcome

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

Population: Analysis was performed on full efficacy analysis set. Here, 'n' (number analyzed) signifies the number of participants analyzed for each specified time point.

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 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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 (Clinician-rated Frequency of Suicidal Thinking [FoST]) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 1: 4 hours postdose	-1.0 units on a scale Interval -4.0 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 Frequency of Suicidal Thinking [FoST]) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment 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 Frequency of Suicidal Thinking [FoST]) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 4	-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 Frequency of Suicidal Thinking [FoST]) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 8	-2.0 units on a scale Interval -4.0 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 Frequency of Suicidal Thinking [FoST]) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment 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 1.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 (Clinician-rated Frequency of Suicidal Thinking [FoST]) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment 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 0.0
Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 (Clinician-rated Frequency of Suicidal Thinking [FoST]) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 18	-2.0 units on a scale Interval -5.0 to 1.0	-3.0 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 Frequency of Suicidal Thinking [FoST]) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 22	-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 Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 (Clinician-rated Frequency of Suicidal Thinking [FoST]) Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25: DB Treatment Phase Change at Day 25	-2.0 units on a scale Interval -5.0 to 4.0	-3.0 units on a scale Interval -5.0 to 2.0

SECONDARY outcome

Timeframe: Up to Day 25

Population: Safety analysis set (SAS) 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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Number of Participants With Treatment Emergent Adverse Events (TEAEs): DB Treatment Phase	87 Participants	104 Participants

SECONDARY outcome

Timeframe: Up to Day 25

Population: SAS: all randomized participants who received at least 1 dose of study drug in DB phase. 'N'(number of participants analyzed) signifies number of participants analyzed for this OM. 'n' (number analyzed) signifies number of participants analyzed for each specified category. mmol/L=millimoles per liter; g/L=gram per liter; ULN=upper limit of normal

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 + Standard of Care (SOC) n=101 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=101 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase ALT: ALT>3*ULN	2 Participants	2 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase ALT: Abnormal High	0 Participants	0 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	0 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	3 Participants	1 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Glucose: Abnormal High	0 Participants	1 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	0 Participants	1 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Potassium: Abnormal High	1 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	0 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	2 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	1 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	1 Participants	0 Participants
Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase Leukocytes: Abnormal Low	0 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	2 Participants	1 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	1 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	1 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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
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 Epistaxis: Mild	1 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	0 Participants	1 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	1 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 Erythema: Mild	1 Participants	4 Participants
Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase Nasal Erythema: Moderate	1 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. Here 'N' (number of participants analyzed) signifies number of participants analyzed for this outcome measure.

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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=112 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Number of Participants With Treatment Emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase Heart Rate <= 50 bpm	9 Participants	2 Participants
Number of Participants With Treatment Emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase Heart Rate >= 100 bpm	3 Participants	2 Participants
Number of Participants With Treatment Emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase PR Duration >= 210 msec	2 Participants	2 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	1 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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
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	3 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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Number of Participants With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase Pulse rate (bpm): Decrease of >=15 to <=50	2 Participants	1 Participants
Number of Participants With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase Pulse rate (bpm): Increase of >=15 to >=100	11 Participants	12 Participants
Number of Participants With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase SBP: Decrease of >=20 to <=90	5 Participants	2 Participants
Number of Participants With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase SBP (mmHg): Increase of >=20 to >=180	2 Participants	3 Participants
Number of Participants With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase DBP (mmHg): Decrease of >=15 to <=50	4 Participants	4 Participants
Number of Participants With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase DBP (mmHg): Increase of >=15 to >=105	3 Participants	6 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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
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	4 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	3 Participants	21 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	65 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 + Standard of Care (SOC) n=113 Participants Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 Participants Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 15	11 Participants	68 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 18	8 Participants	53 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 22	7 Participants	58 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 25	4 Participants	56 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 1	28 Participants	106 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 4	21 Participants	86 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 8	16 Participants	75 Participants
Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase Day 11	8 Participants	68 Participants

Adverse Events

Placebo + Standard of Care (SOC)

Serious events: 6 serious events

Other events: 74 other events

Deaths: 0 deaths

Esketamine 84 mg + SOC

Serious events: 5 serious events

Other events: 98 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo + Standard of Care (SOC) n=113 participants at risk Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 participants at risk Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Cardiac disorders Arrhythmia	0.88% 1/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	0.00% 0/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Cardiac disorders Pericardial Effusion	0.88% 1/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	0.00% 0/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Psychiatric disorders Depersonalisation/Derealisation Disorder	0.00% 0/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	0.88% 1/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Psychiatric disorders Depression	0.88% 1/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	0.00% 0/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Psychiatric disorders Suicidal Ideation	1.8% 2/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	0.88% 1/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Psychiatric disorders Suicide Attempt	2.7% 3/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	2.6% 3/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.88% 1/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	0.00% 0/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug 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 + Standard of Care (SOC) n=113 participants at risk Participants self-administered intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) twice per week for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with SOC antidepressant treatment (determined by the physician based on clinical judgment and practice guidelines) on Day 1 and continued for the duration of the double-blind (DB) treatment phase (Days 1 to 25).	Esketamine 84 mg + SOC n=114 participants at risk Participants self-administered esketamine 84 milligram (mg) (1 spray containing esketamine 14 mg in each nostril at 0, 5, 10 minutes using 3 devices on single day) twice per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, 25 along with SOC antidepressant treatment (determined by physician based on clinical judgment and practice guidelines) on Day 1 continued for DB treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to 56 mg was permitted if a participant was unable to tolerate intranasal esketamine 84 mg dose. Participants for whom dose was reduced continued to receive reduced dose for duration of DB treatment phase (Days 1 to 25).
Ear and labyrinth disorders Vertigo	0.00% 0/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	6.1% 7/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Eye disorders Diplopia	0.00% 0/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	5.3% 6/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Eye disorders Vision Blurred	5.3% 6/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	14.9% 17/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Gastrointestinal disorders Constipation	8.0% 9/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	6.1% 7/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Gastrointestinal disorders Dry Mouth	4.4% 5/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	7.0% 8/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Gastrointestinal disorders Hypoaesthesia Oral	1.8% 2/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	6.1% 7/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Gastrointestinal disorders Nausea	14.2% 16/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	33.3% 38/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Gastrointestinal disorders Paraesthesia Oral	2.7% 3/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	12.3% 14/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Gastrointestinal disorders Vomiting	4.4% 5/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	15.8% 18/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
General disorders Feeling Drunk	0.88% 1/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	5.3% 6/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Investigations Blood Pressure Increased	2.7% 3/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	6.1% 7/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Nervous system disorders Dizziness	18.6% 21/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	41.2% 47/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Nervous system disorders Dizziness Postural	0.88% 1/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	7.9% 9/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Nervous system disorders Dysgeusia	15.9% 18/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	25.4% 29/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Nervous system disorders Headache	23.0% 26/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	21.9% 25/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Nervous system disorders Hypoaesthesia	0.88% 1/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	10.5% 12/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Nervous system disorders Paraesthesia	6.2% 7/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	20.2% 23/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Nervous system disorders Sedation	2.7% 3/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	14.0% 16/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Nervous system disorders Somnolence	10.6% 12/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	22.8% 26/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Psychiatric disorders Anxiety	6.2% 7/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	14.9% 17/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Psychiatric disorders Depersonalisation/Derealisation Disorder	0.00% 0/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	7.9% 9/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Psychiatric disorders Dissociation	8.0% 9/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	38.6% 44/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Psychiatric disorders Euphoric Mood	0.88% 1/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	11.4% 13/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Psychiatric disorders Insomnia	9.7% 11/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	7.9% 9/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Respiratory, thoracic and mediastinal disorders Nasal Discomfort	8.0% 9/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	8.8% 10/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Respiratory, thoracic and mediastinal disorders Oropharyngeal Pain	2.7% 3/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	5.3% 6/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Respiratory, thoracic and mediastinal disorders Throat Irritation	3.5% 4/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	5.3% 6/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.
Skin and subcutaneous tissue disorders Hyperhidrosis	2.7% 3/113 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.	5.3% 6/114 • Up to Day 25 Safety analysis set included all randomized participants who received at least 1 dose of study drug in the double-blind treatment phase.