Trial Outcomes & Findings for A Long-term Safety Study of Esketamine Nasal Spray in Treatment-resistant Depression (NCT NCT02782104)

Last Updated: 2025-04-29

Results Overview

This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. The DET is a measure of psychomotor function and uses a well-validated simple reaction time. In this outcome measure, speed of performance of subjects (calculated as mean of the logarithmic base 10 transformed reaction times) for correct responses was reported. Total score ranged from 2 to 3.3 log 10 milliseconds (msec). Lower score indicated better performance. Higher change from baseline indicated better performance.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1148 participants

Primary outcome timeframe

IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

Results posted on

2025-04-29

Participant Flow

Participant milestones

Participant milestones
Measure	Esketamine Nasal Spray Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years). Participants who entered the optimization and maintenance phase (OP/MA) from the IND phase of study NCT02782104 continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or ESKETINTRD3006 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered from study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in OP/MP.
Overall Study STARTED	1148
Overall Study IND Phase	458
Overall Study OP/MA Phase	1110
Overall Study COMPLETED	680
Overall Study NOT COMPLETED	468

Reasons for withdrawal

Reasons for withdrawal
Measure	Esketamine Nasal Spray Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years). Participants who entered the optimization and maintenance phase (OP/MA) from the IND phase of study NCT02782104 continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or ESKETINTRD3006 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered from study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in OP/MP.
Overall Study Other	215
Overall Study Induction Day 28 Non Responder	9
Overall Study Non-Compliance with Study Drug	2
Overall Study Death	8
Overall Study Pregnancy	6
Overall Study Withdrawal by Subject	63
Overall Study Protocol Violation	7
Overall Study Lack of Efficacy	61
Overall Study Lost to Follow-up	23
Overall Study Adverse Event	74

Baseline Characteristics

A Long-term Safety Study of Esketamine Nasal Spray in Treatment-resistant Depression

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Esketamine Nasal Spray n=1148 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years). Participants who entered the optimization and maintenance phase (OP/MA) from the IND phase of study NCT02782104 continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or ESKETINTRD3006 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered from study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in OP/MP.
Age, Continuous	49.6 years STANDARD_DEVIATION 12.28 • n=5 Participants
Sex: Female, Male Female	764 Participants n=5 Participants
Sex: Female, Male Male	384 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	200 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	922 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	26 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian	45 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	45 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race/Ethnicity, Customized White	996 Participants n=5 Participants
Race/Ethnicity, Customized More than one race	10 Participants n=5 Participants
Race/Ethnicity, Customized Unknown or Not Reported	22 Participants n=5 Participants
Race/Ethnicity, Customized Other	29 Participants n=5 Participants
Region of Enrollment ARGENTINA	71 Participants n=5 Participants
Region of Enrollment AUSTRALIA	16 Participants n=5 Participants
Region of Enrollment AUSTRIA	4 Participants n=5 Participants
Region of Enrollment BELGIUM	18 Participants n=5 Participants
Region of Enrollment BRAZIL	100 Participants n=5 Participants
Region of Enrollment BULGARIA	50 Participants n=5 Participants
Region of Enrollment CANADA	15 Participants n=5 Participants
Region of Enrollment CZECH REPUBLIC	90 Participants n=5 Participants
Region of Enrollment ESTONIA	9 Participants n=5 Participants
Region of Enrollment FINLAND	1 Participants n=5 Participants
Region of Enrollment FRANCE	23 Participants n=5 Participants
Region of Enrollment GERMANY	13 Participants n=5 Participants
Region of Enrollment HUNGARY	20 Participants n=5 Participants
Region of Enrollment ITALY	8 Participants n=5 Participants
Region of Enrollment LITHUANIA	2 Participants n=5 Participants
Region of Enrollment MALAYSIA	9 Participants n=5 Participants
Region of Enrollment MEXICO	46 Participants n=5 Participants
Region of Enrollment POLAND	101 Participants n=5 Participants
Region of Enrollment SLOVAKIA	9 Participants n=5 Participants
Region of Enrollment SOUTH AFRICA	48 Participants n=5 Participants
Region of Enrollment SOUTH KOREA	7 Participants n=5 Participants
Region of Enrollment SPAIN	41 Participants n=5 Participants
Region of Enrollment SWEDEN	65 Participants n=5 Participants
Region of Enrollment TAIWAN	22 Participants n=5 Participants
Region of Enrollment TURKEY	24 Participants n=5 Participants
Region of Enrollment UNITED KINGDOM	8 Participants n=5 Participants
Region of Enrollment UNITED STATES	328 Participants n=5 Participants

PRIMARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

Population: All enrolled analysis set included all participants who were eligible to enter this study and received at least 1 dose of intranasal study medication. Here, 'N' (number analyzed) signifies number of participants analyzed for this outcome measure.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=420 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1085 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Study Baseline in Computerized Cognitive Battery Domain Score: Detection Test (DET) Score	0.0218 log10 msec Standard Deviation 0.10516	-0.0065 log10 msec Standard Deviation 0.13526

PRIMARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. IDN test is a measure of visual attention (choice reaction time) and scored for speed of response (mean of the log10 transformed reaction times for correct responses). Total score ranged from 2 to 3.3 log 10 msec. Lower score indicated better performance. Higher change from baseline indicated better performance.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=422 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1084 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Study Baseline in Computerized Cognitive Battery Domain Score: Identification Test (IDN) Score	0.0074 log10 msec Standard Deviation 0.07819	-0.0185 log10 msec Standard Deviation 0.09893

PRIMARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. OCL test is a measure of visual episodic memory and visual recall test scored using arcsine transformation of the percentage of correct responses (CR). The range for OCL is 0 to 100 percent (%) accuracy; presented as an arcsin transformation, the range is 0 to 1.57. Higher score indicated better performance. Higher change from baseline indicated better performance.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=429 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1084 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Study Baseline in Computerized Cognitive Battery Domain Score: One Card Learning Test (OCL) Score	0.0170 Arcsine (sqrt of percentage of CR) Standard Deviation 0.12356	0.0397 Arcsine (sqrt of percentage of CR) Standard Deviation 0.15364

PRIMARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

The ONB is a measure of working memory and scored for speed of correct response (mean of the log10-transformed reaction times for correct responses). Total score ranged from 2 to 3.54 log10 msec. Lower score indicated better performance. Higher change from baseline indicated better performance.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=429 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1084 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Study Baseline in Computerized Cognitive Battery Domain Score: One Back Test (ONB) Score	0.0086 log10 msec Standard Deviation 0.08096	0.0198 log10 msec Standard Deviation 0.10329

PRIMARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. GMLT measures executive function; maze/sequencing test, scored for total number of errors. Total score ranged from 0 to 999 number of errors. Lower score indicated better performance. Higher change from baseline indicated better performance.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=415 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1072 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Study Baseline in Computerized Cognitive Battery Domain Score: Groton Maze Learning Test (GMLT) Score	1.5 Number of Errors Standard Deviation 17.80	5.1 Number of Errors Standard Deviation 22.52

PRIMARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

The HVLT-R measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0-12); the total number of true-positive errors (0-12); and the range of recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher total recall score indicated higher cognition. The range of the recognition discrimination index is -12 to 12. Higher score indicated better performance and higher change from baseline indicated better performance.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=444 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1091 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Study Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score Total Recall	-0.1 score on a scale Standard Deviation 4.05	0.8 score on a scale Standard Deviation 5.05
Change From Study Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score Delayed Recall	0.3 score on a scale Standard Deviation 3.81	0.3 score on a scale Standard Deviation 2.03
Change From Study Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score Total Number of True Positives	0.1 score on a scale Standard Deviation 2.54	-0.0 score on a scale Standard Deviation 2.70
Change From Study Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score Recognition Discrimination Index	-0.1 score on a scale Standard Deviation 2.88	-0.1 score on a scale Standard Deviation 3.10

PRIMARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

C-SSRS: interview-based instrument to systematically assess suicidal ideation (SI) and behavior, to assess whether participant experienced any of following: completed suicide, suicide attempt (response of "yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior ("yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("yes" on "wish to be dead", "non-specific active suicidal thoughts", "active SI with methods without intent to act or some intent to act, without or with specific plan and intent), any self-injurious behavior with no suicidal intent ("yes" on "has participant engaged in non-suicidal self-injurious behavior"). Here, percentage of participants with \>=1 positive behavior, participants with \>=1 positive ideations; no event were reported.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=456 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1109 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Percentage of Participants Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Score Baseline: No Event	79.8 Percentage of participants	94.8 Percentage of participants
Percentage of Participants Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Score Baseline: Suicidal ideation	20.2 Percentage of participants	5.2 Percentage of participants
Percentage of Participants Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Score Baseline: Suicidal behavior	0 Percentage of participants	0 Percentage of participants
Percentage of Participants Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Score Most Severe Post Baseline: No Event	77.4 Percentage of participants	70.2 Percentage of participants
Percentage of Participants Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Score Most Severe Post Baseline: Suicidal ideation	22.6 Percentage of participants	27.8 Percentage of participants
Percentage of Participants Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Score Most Severe Post Baseline: Suicidal behavior	0 Percentage of participants	2.0 Percentage of participants

PRIMARY outcome

Timeframe: IND Phase: up to 4 weeks; OP/MA Phase: up to 78 months

Population: All enrolled analysis set included all participants who were eligible to enter this study and received at least 1 dose of intranasal study medication.

An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. Any AE occurring at or after the initial administration of study intervention up to end of study was considered as treatment-emergent.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=458 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1110 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	346 Participants	1052 Participants

PRIMARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

Population: Full analysis set included participants who received at least 1 dose of intranasal study medication in this study.

Change from baseline (predose) in heart rate were reported.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=458 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1110 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Baseline in Heart Rate	0.4 beats per minute Standard Deviation 9.52	0.8 beats per minute Standard Deviation 10.47

PRIMARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

Population: Full analysis set included participants who received at least 1 dose of intranasal study medication in this study.

Change from baseline in systolic and diastolic blood pressure were reported.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=458 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1110 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Baseline in Systolic and Diastolic Blood Pressure Systolic Blood Pressure	0.4 Millimeters of mercury (mmHg) Standard Deviation 10.72	5.8 Millimeters of mercury (mmHg) Standard Deviation 12.68
Change From Baseline in Systolic and Diastolic Blood Pressure Diastolic Blood Pressure	0.3 Millimeters of mercury (mmHg) Standard Deviation 7.47	2.7 Millimeters of mercury (mmHg) Standard Deviation 8.78

PRIMARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

Population: Full analysis set included participants who received at least 1 dose of intranasal study medication in this study.

Change from baseline in respiratory rate were reported.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=458 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1110 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Baseline in Respiratory Rate	-0.1 breaths per minute Standard Deviation 2.51	-0.4 breaths per minute Standard Deviation 2.83

PRIMARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

Population: Full analysis set included participants who received at least 1 dose of intranasal study medication in this study.

Change from baseline in blood oxygen saturation (predose) were reported.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=458 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1110 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Baseline in Blood Oxygen Saturation	-0.1 percentage of SpO2 Standard Deviation 1.54	-0.1 percentage of SpO2 Standard Deviation 1.63

SECONDARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

Population: Full analysis set included all participants who received at least 1 dose of intranasal study medication in this study. Here, 'N' (number analyzed) signifies number of participants analyzed for this outcome measure.

MADRS measures depression severity, detects changes due to AD treatment. It consists of 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe conditions. Negative change in score indicates improvement. Missing data was imputed using last observation carried forward (LOCF) method.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=455 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1110 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score	-12.8 score on a Scale Standard Deviation 9.73	0.2 score on a Scale Standard Deviation 9.93

SECONDARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

Change from baseline in PHQ-9 total score were reported. The PHQ-9 was a 9-item, patient-reported outcome measure to assess depressive symptoms. The scale scores each of the 9 symptom domains of the Diagnostic and Statistical Manual of Mental Disorders. Each item was rated on a 4-point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses were summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=453 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1109 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Baseline in Participant-Reported Depressive Symptoms Using the Patient Health Questionnaire - 9 (PHQ-9) Total Score	-5.8 score on a scale Standard Deviation 5.84	0.6 score on a scale Standard Deviation 6.22

SECONDARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

Change from baseline in clinical global impression-severity (CGI-S) score were reported. The CGI-S provides an overall clinician-determined summary measure of the severity of the participant's illness that takes into account all available information, including knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 1 to 7. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating according to: 1 = normal (not at all ill); 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. Negative change in score indicates improvement.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=456 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1110 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Baseline in Clinical Global Impression-severity (CGI-S) Score	-1.0 score on a scale Interval -5.0 to 1.0	0.0 score on a scale Interval -5.0 to 4.0

SECONDARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

Change from baseline in SDS total score were reported. The SDS, a patient-reported outcome measure, was a 5 item questionnaire which had been widely used and accepted for assessment of functional and associated disability impairment. The first three items assessed disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items were summed to create a total score of 0-30 where a higher score indicated greater impairment.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=384 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1067 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Baseline in Sheehan Disability Scale (SDS) Total Score	-6.4 score on a scale Standard Deviation 7.13	-0.1 score on a scale Standard Deviation 8.35

SECONDARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

Population: Full analysis set included who received at least 1 dose of intranasal study medication in this study. Here, 'N' (number analyzed) signifies number of participants analyzed for this outcome measure.

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

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=454 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1110 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Baseline in Participant-Reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Valuation Index Score (VAS)	13.0 score on a scale Standard Deviation 18.05	0.7 score on a scale Standard Deviation 18.95

SECONDARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (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". Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) \*5. Higher score indicates worst health state.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=454 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=1110 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Baseline as Assessed by EQ 5D-5L: Sum Score	-10.4 score on a scale Standard Deviation 12.81	2.9 score on a scale Standard Deviation 15.88

SECONDARY outcome

Timeframe: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months

Change from baseline in participant- reported health related quality of life using the QLDS. The QLDS is a disease-specific validated patient-reported outcome (PRO) measure which assesses the impact that depression has on a participant's quality of life. It is a 34-item self-rated questionnaire which consists of dichotomous response questions, with the response being either True/Not True. Each statement on the QLDS is given a score of "1" or "0". A score of "1" is indicative of adverse quality of life. All item scores are summed to give a total score that ranges from 0 (good quality of life) to 34 (very poor quality of life). A higher score indicates a more severe condition.

Outcome measures

Outcome measures
Measure	Esketamine Nasal Spray (IND Phase) n=293 Participants Participants who entered induction phase (IND) from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, NCT02422186, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams \[mg\] or 84 mg for participants less than \[\<\] 65 years; 28 mg, 56 mg or 84 mg for participants greater than or equal to \[\>=\] 65 years).	Esketamine Nasal Spray (OP/MA Phase) n=537 Participants Participants who entered the OP/MA phase from the IND phase of study NCT02782104, continued on the same dose of esketamine from the IND phase, weekly. Participants who entered from studies NCT02417064, NCT02418585, NCT02493868, NCT02497287, or NCT02782104 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Participants who entered study NCT02422186 received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants was adjusted based upon efficacy and tolerability.
Change From Baseline in Participant- Reported Health Related Quality of Life Using the Quality of Life in Depression Scale (QLDS)	-8.2 score on a scale Standard Deviation 8.47	0.1 score on a scale Standard Deviation 9.47

Adverse Events

Esketamine Nasal Spray (IND Phase)

Serious events: 5 serious events

Other events: 318 other events

Deaths: 1 deaths

Esketamine Nasal Spray (OP/MA Phase)

Serious events: 212 serious events

Other events: 1010 other events

Deaths: 8 deaths

Serious adverse events

Other adverse events

Additional Information

Global Medical Head

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