A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression (TRANSFORM-2)

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ClinicalTrials.gov Identifier: NCT02418585

Recruitment Status : Completed

First Posted : April 16, 2015

Results First Posted : April 19, 2019

Last Update Posted : June 2, 2020

Sponsor:

Information provided by (Responsible Party):

Janssen Research & Development, LLC

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition	Treatment-resistant Depression
Interventions	Drug: Esketamine Drug: Placebo Drug: Duloxetine (Oral Antidepressant) Drug: Escitalopram (Oral antidepressant) Drug: Sertraline (Oral Antidepressant) Drug: Venlafaxine Extended Release (XR) (Oral Antidepressant)
Enrollment	236

Participant Flow

Recruitment Details
Pre-assignment Details	Total 236 participants were enrolled, out of which 227 were randomized and 9 participants were excluded due to Good Clinical Practice (GCP) violations.


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Period Title: Double Blind (DB) Phase (4 Weeks)
Started	116	111
Safety Analysis Set	115	109
Full Analysis Set	114	109
Completed	98	99
Not Completed	18	12
Reason Not Completed
Lost to Follow-up	1	1
Protocol Violation	2	2
Withdrawal by Subject	4	7
Lack of Efficacy	2	0
Adverse Event	9	1
Other	0	1
Period Title: Follow-up Phase (24 Weeks)
Started	34	52
Completed	16	27
Not Completed	18	25
Reason Not Completed
Lost to Follow-up	3	3
Withdrawal by Subject	6	3
Investigator Decision	6	17
Other	3	2

Baseline Characteristics

Arm/Group Title		Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD	Total
Arm/Group Description		Participants self-administered (und...	Participants self-administered (und...	Total of all reporting groups
Arm/Group Description		Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Total of all reporting groups
Overall Number of Baseline Participants		115	109	224
Baseline Analysis Population Description		...
Baseline Analysis Population Description		The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase.
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	115 participants	109 participants	224 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	115 100.0%	109 100.0%	224 100.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	115 participants	109 participants	224 participants
		45 (12.56)	46.4 (11.14)	45.7 (11.89)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	115 participants	109 participants	224 participants
	Female	76 66.1%	63 57.8%	139 62.1%
	Male	39 33.9%	46 42.2%	85 37.9%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	115 participants	109 participants	224 participants
	Hispanic or Latino	5 4.3%	7 6.4%	12 5.4%
	Not Hispanic or Latino	109 94.8%	99 90.8%	208 92.9%
	Unknown or Not Reported	1 0.9%	3 2.8%	4 1.8%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	115 participants	109 participants	224 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	1 0.9%	1 0.9%	2 0.9%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	6 5.2%	5 4.6%	11 4.9%
	White	107 93.0%	102 93.6%	209 93.3%
	More than one race	1 0.9%	1 0.9%	2 0.9%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	115 participants	109 participants	224 participants
CZECH REPUBLIC		30 26.1%	28 25.7%	58 25.9%
GERMANY		10 8.7%	10 9.2%	20 8.9%
POLAND		20 17.4%	18 16.5%	38 17.0%
SPAIN		9 7.8%	9 8.3%	18 8.0%
UNITED STATES		46 40.0%	44 40.4%	90 40.2%

Outcome Measures

1.Primary Outcome


Title	Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 in the Double-blind Induction Phase- Mixed-Effects Model Using Repeated Measures (MMRM) Analysis
Description	MADRS is clinician-rated scale designed to measure depression severity...
Description	MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Time Frame	Baseline up to Day 28 of Double-blind Induction Phase

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) defined as all randomized participants who received at least 1 dose of intranasal study medication, 1 dose of oral antidepressant (AD) medication during double-blind induction phase (D-BIP). Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	101	100
Mean (Standard Deviation) Unit of Measure: Units on a scale
	-21.4 (12.32)	-17.0 (13.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD), Intranasal Placebo Plus Oral AD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	=0.020
	Comments	[Not Specified]
	Method	Mixed Model for Repeated Measures
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference of Least Square (LS) Means
	Estimated Value	-4.0
	Confidence Interval	(2-Sided) 95% -7.31 to -0.64
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.69
	Estimation Comments	[Not Specified]

2.Primary Outcome


Title	Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- Analysis of Covariance (ANCOVA) Analysis
Description	MADRS is clinician-rated scale designed to measure depression severity...
Description	MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description

FAS defined as all randomized participants who received at least 1 dose of intranasal study medication, 1 dose of AD medication during double-blind induction phase (D-BIP). Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	112	109
Mean (Standard Deviation) Unit of Measure: Units on a scale
	-19.6 (13.58)	-16.3 (14.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD), Intranasal Placebo Plus Oral AD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	=0.034
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference of Least Square (LS) Means
	Estimated Value	-3.5
	Confidence Interval	(2-Sided) 95% -6.67 to -0.26
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Percentage of Participants With Onset of Clinical Response on Day 2 and Day 8
Description	A participant was defined as having a clinical response if there is at...
Description	A participant was defined as having a clinical response if there is at least 50 percent (%) improvement from baseline in the MADRS total score with onset by Day 2 and Day 8 that was maintained to Day 28. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Participants who did not meet such criterion or discontinue during the study before Day 28 for any reason were considered as non-responders.
Time Frame	Day 2 up to Day 28 and Day 8 up to Day 28

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase.


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	114	109
Measure Type: Number Unit of Measure: Percentage of participants
Onset of Clinical response on Day 2	7.9	4.6
Onset of Clinical response on Day 8	10.5	6.4

4.Secondary Outcome


Title	Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
Description	The SDS is a participant-reported outcome measure and 5 item questionn...
Description	The SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. First three items assess disruption of 1 work/school, 2 social life, 3 family life/home responsibilities using a 0(no impairment)-10 (most severe impairment). Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment and a negative change in score indicates improvement. It also has one item on days lost from school or work and one item on days when under productive.
Time Frame	Baseline up to Day 28 of Double-blind Induction phase

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	86	85
Mean (Standard Deviation) Unit of Measure: Units on a scale
	-13.6 (8.31)	-9.4 (8.43)

5.Secondary Outcome


Title	Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
Description	The SDS is a participant-reported outcome measure and 5 item questionn...
Description	The SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. First three items assess disruption of 1 work/school, 2 social life, 3 family life/home responsibilities using a 0(no impairment)-10 (most severe impairment). Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment and a negative change in score indicates improvement. It also has one item on days lost from school or work and one item on days when under productive. The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	95	89
Mean (Standard Deviation) Unit of Measure: Units on a scale
	-12.5 (8.85)	-9.3 (8.39)

6.Secondary Outcome


Title	Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
Description	PHQ-9 is 9-item, self-report scale assessing depressive symptoms. Each...
Description	PHQ-9 is 9-item, self-report scale assessing depressive symptoms. Each item is rated on 4-point scale (0=Not at all, 1=Several Days, 2=More than half days, 3=Nearly every day. Scale scores each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria and it has been used both as screening tool and measure of response to treatment for depression. The participant's item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. Severity of PHQ-9 categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19), Severe (20-27).
Time Frame	Baseline up to Day 28 of Double-blind Induction phase

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' signifies overall number of participants who were evaluable for this outcome measure.


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	104	100
Mean (Standard Deviation) Unit of Measure: Units on a scale
	-13.0 (6.42)	-10.2 (7.80)

7.Secondary Outcome


Title	Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
Description	PHQ-9 is 9-item, self-report scale assessing depressive symptoms. Each...
Description	PHQ-9 is 9-item, self-report scale assessing depressive symptoms. Each item is rated on 4-point scale (0=Not at all, 1=Several Days, 2=More than half days, 3=Nearly every day). Scale scores each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria and it has been used both as screening tool and measure of response to treatment for depression. The participant's item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. Severity of PHQ-9 categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19), Severe (20-27). The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' signifies overall number of participants who were evaluable for this outcome measure.


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	111	105
Mean (Standard Deviation) Unit of Measure: Units on a scale
	-12.2 (6.87)	-10.1 (7.87)

8.Secondary Outcome


Title	Percentage of Participants Who Achieved >=50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28])
Description	MADRS is clinician-rated scale designed to measure depression severity...
Description	MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. The percentage of participants with greater than or equal to (>=) 50 % reduction from baseline in MADRS total score was reported. The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	At Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	112	109
Measure Type: Number Unit of Measure: Percentage of participants
	63.4	49.5

9.Secondary Outcome


Title	Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28])
Description	Remission was defined as participants who had a MADRS total score of l...
Description	Remission was defined as participants who had a MADRS total score of less than or equal to (=<) 12. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	At Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	112	109
Measure Type: Number Unit of Measure: Percentage of participants
	48.2	30.3

10.Secondary Outcome


Title	Percentage of Participants in Response (SDS Total Score <=12 and Individual Item Scores Each <=4) at the End of 4-Week Double-blind Induction Phase (Day 28)
Description	Response defined as SDS total score <= 12 and individual item score...
Description	Response defined as SDS total score <= 12 and individual item scores each <= 4. SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. First three items assess disruption of 1 work/school, 2 social life, 3 family life/home responsibilities using a 0(no impairment)-10 (most severe impairment). Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment and a negative change in score indicates improvement. It also has one item on days lost from school or work and one item on days when under productive.
Time Frame	At Day 28 [end of Double-blind Induction Phase]

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	86	86
Measure Type: Number Unit of Measure: Percentage of participants
	57.0	39.5

11.Secondary Outcome


Title	Percentage of Participants in Remission (SDS Total Score <=6 and Individual Item Scores Each <=2) at the End of 4-Week Double-blind Induction Phase (Day 28)
Description	Remission defined as SDS total score <= 6 and individual item score...
Description	Remission defined as SDS total score <= 6 and individual item scores each <= 2. SDS is a participant reported outcome measure and is a 5-item questionnaire which has been widely used and accepted for assessment of functional impairment and associated disability. The first three items assess 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 indicates greater impairment. It also has one item on days lost from school or work and one item on days when under productive.
Time Frame	At Day 28 (End of Double-blind Induction Phase)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	86	86
Measure Type: Number Unit of Measure: Percentage of participants
	39.5	20.9

12.Secondary Outcome


Title	Change From Baseline in Clinical Global Impression-Severity (CGI-S) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])
Description	CGI-S provides measure of severity of participant's illness including ...
Description	CGI-S provides measure of severity of participant's illness including participant's history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, participant is assessed on severity of mental illness according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among most extremely ill patients. CGI-S permits global evaluation of participant's condition at given time. The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description

FAS defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	111	109
Median (Full Range) Unit of Measure: Units on a scale
	-2.0 (-5 to 1)	-2.0 (-5 to 1)

13.Secondary Outcome


Title	Change From Baseline in Generalized Anxiety Disorder (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])
Description	GAD-7 is a brief and validated 7-item self-report assessment of overal...
Description	GAD-7 is a brief and validated 7-item self-report assessment of overall anxiety. Participants respond to each item using a 4-point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15 -21). The last post baseline observation during the phase was carried forward as "End Point" for that phase.
Time Frame	Baseline up to Endpoint (Double-blind Induction Phase [Day 28])

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	110	102
Mean (Standard Deviation) Unit of Measure: Units on a scale
	-7.9 (6.12)	-6.8 (5.75)

14.Secondary Outcome


Title	Change From Baseline in EQ 5D-5L-Health Status Index to End of Double-blind Induction Phase (Day 28)
Description	European Quality of Life Group-5 Dimension-5-Level (EQ-5D-5L) is a 2-p...
Description	European Quality of Life Group-5 Dimension-5-Level (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 Health Status Index (HSI). Health Status Index range is -0.148 - 0.949, is anchored at 0 (dead) and 1 (full health).
Time Frame	Baseline up to End of Double-blind Induction Phase (Day 28)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	111	105
Mean (Standard Deviation) Unit of Measure: Units on a Scale
	0.288 (0.2317)	0.231 (0.2506)

15.Secondary Outcome


Title	Change From Baseline in EQ 5D-5L- European Quality of Life - Visual Analogue Scale (EQ-VAS) to End of Double-blind Induction Phase (Day 28)
Description	EQ-5D-5L is a 2-part instrument for use as a measure of health outcome...
Description	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).
Time Frame	Baseline up to End of Double-blind Induction Phase (Day 28)

Outcome Measure Data

Analysis Population Description

FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	111	105
Mean (Standard Deviation) Unit of Measure: Units on a scale
	29.1 (26.32)	20.9 (26.60)

16.Secondary Outcome


Title	Change From Baseline in EQ 5D-5L- Sum Score to End of Double-blind Induction Phase (Day 28)
Description	EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogu...
Description	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". Responses were used to generate a Health Status Index (HSI). Health Status Index range is -0.148 - 0.949, is anchored at 0 (dead) and 1 (full health). 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). 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.
Time Frame	Baseline up to End of Double-blind Induction Phase (Day 28)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)	Intranasal Placebo Plus Oral AD
Arm/Group Description:	Participants self-administered (und...	Participants self-administered (und...
Arm/Group Description:	Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day-Week 1, 100 mg/day-Week 2, 150 mg/day-Week 3 and 200 mg/day-Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003[NCT02493868]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
Overall Number of Participants Analyzed	111	105
Mean (Standard Deviation) Unit of Measure: Units on a scale
	-23.2 (16.64)	-17.1 (19.66)

Adverse Events

Time Frame	Approximately up to 2.2 Years
Adverse Event Reporting Description	The safety analysis set included all randomized participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication during the double-blind induction phase. The follow-up analysis set included all participants who entered the follow-up phase.

Arm/Group Title	DB Phase: Intranasal Esk + Oral AD	DB Phase: Oral AD + Intranasal Placebo	FU Phase: Intranasal Esk + Oral AD	FU Phase: Oral AD + Intranasal Placebo
Arm/Group Description	Participants self-administered (und...	Participants self-administered (und...	Participants who were not eligible ...	Participants who were not eligible ...
Arm/Group Description	Participants self-administered (under direct supervision by health care professional [HCP]) esketamine either 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1, 4, 8, 11, 15, 18, 22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral antidepressant (AD) with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase.	Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1, 4, 8, 11, 15, 18, 22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: [Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability [MDT] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT of 10 mg/day); Sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase.	Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Esk+ Oral AD in DB induction phase were followed in posttreatment follow-up (FU) phase for up to 24 weeks.	Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 [NCT02493868]) and had received at least 1 dose of intranasal Placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks.
All-Cause Mortality
	DB Phase: Intranasal Esk + Oral AD	DB Phase: Oral AD + Intranasal Placebo	FU Phase: Intranasal Esk + Oral AD	FU Phase: Oral AD + Intranasal Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/115 (0.87%)	0/109 (0.00%)	0/34 (0.00%)	0/52 (0.00%)
Serious Adverse Events Serious Adverse Events
	DB Phase: Intranasal Esk + Oral AD	DB Phase: Oral AD + Intranasal Placebo	FU Phase: Intranasal Esk + Oral AD	FU Phase: Oral AD + Intranasal Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/115 (0.87%)	1/109 (0.92%)	1/34 (2.94%)	0/52 (0.00%)
Ear and labyrinth disorders
Vertigo Positional ^* 1	0/115 (0.00%)	1/109 (0.92%)	0/34 (0.00%)	0/52 (0.00%)
Injury, poisoning and procedural complications
Multiple Injuries ^* 1	1/115 (0.87%)	0/109 (0.00%)	0/34 (0.00%)	0/52 (0.00%)
Road Traffic Accident ^* 1	1/115 (0.87%)	0/109 (0.00%)	0/34 (0.00%)	0/52 (0.00%)
Nervous system disorders
Cerebral Haemorrhage ^* 1	0/115 (0.00%)	0/109 (0.00%)	1/34 (2.94%)	0/52 (0.00%)
1 Term from vocabulary, MedDRA Version 20.0 * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	DB Phase: Intranasal Esk + Oral AD	DB Phase: Oral AD + Intranasal Placebo	FU Phase: Intranasal Esk + Oral AD	FU Phase: Oral AD + Intranasal Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	90/115 (78.26%)	53/109 (48.62%)	7/34 (20.59%)	6/52 (11.54%)
Ear and labyrinth disorders
Vertigo ^* 1	30/115 (26.09%)	3/109 (2.75%)	0/34 (0.00%)	0/52 (0.00%)
Eye disorders
Vision Blurred ^* 1	14/115 (12.17%)	3/109 (2.75%)	0/34 (0.00%)	0/52 (0.00%)
Gastrointestinal disorders
Diarrhoea ^* 1	10/115 (8.70%)	10/109 (9.17%)	1/34 (2.94%)	2/52 (3.85%)
Dry Mouth ^* 1	9/115 (7.83%)	3/109 (2.75%)	1/34 (2.94%)	0/52 (0.00%)
Hypoaesthesia Oral ^* 1	9/115 (7.83%)	1/109 (0.92%)	0/34 (0.00%)	0/52 (0.00%)
Nausea ^* 1	30/115 (26.09%)	7/109 (6.42%)	1/34 (2.94%)	0/52 (0.00%)
Paraesthesia Oral ^* 1	9/115 (7.83%)	1/109 (0.92%)	0/34 (0.00%)	0/52 (0.00%)
Vomiting ^* 1	11/115 (9.57%)	2/109 (1.83%)	0/34 (0.00%)	0/52 (0.00%)
General disorders
Fatigue ^* 1	5/115 (4.35%)	6/109 (5.50%)	0/34 (0.00%)	0/52 (0.00%)
Feeling Drunk ^* 1	9/115 (7.83%)	1/109 (0.92%)	0/34 (0.00%)	0/52 (0.00%)
Infections and infestations
Upper Respiratory Tract Infection ^* 1	0/115 (0.00%)	1/109 (0.92%)	3/34 (8.82%)	0/52 (0.00%)
Investigations
Blood Pressure Increased ^* 1	11/115 (9.57%)	0/109 (0.00%)	0/34 (0.00%)	0/52 (0.00%)
Metabolism and nutrition disorders
Decreased Appetite ^* 1	2/115 (1.74%)	3/109 (2.75%)	2/34 (5.88%)	0/52 (0.00%)
Nervous system disorders
Dizziness ^* 1	24/115 (20.87%)	5/109 (4.59%)	1/34 (2.94%)	2/52 (3.85%)
Dizziness Postural ^* 1	8/115 (6.96%)	1/109 (0.92%)	0/34 (0.00%)	0/52 (0.00%)
Dysgeusia ^* 1	28/115 (24.35%)	13/109 (11.93%)	0/34 (0.00%)	0/52 (0.00%)
Headache ^* 1	23/115 (20.00%)	19/109 (17.43%)	2/34 (5.88%)	1/52 (1.92%)
Hypoaesthesia ^* 1	8/115 (6.96%)	1/109 (0.92%)	0/34 (0.00%)	0/52 (0.00%)
Paraesthesia ^* 1	13/115 (11.30%)	1/109 (0.92%)	1/34 (2.94%)	0/52 (0.00%)
Somnolence ^* 1	15/115 (13.04%)	7/109 (6.42%)	0/34 (0.00%)	0/52 (0.00%)
Psychiatric disorders
Anxiety ^* 1	12/115 (10.43%)	5/109 (4.59%)	1/34 (2.94%)	1/52 (1.92%)
Dissociation ^* 1	30/115 (26.09%)	4/109 (3.67%)	0/34 (0.00%)	0/52 (0.00%)
Insomnia ^* 1	11/115 (9.57%)	5/109 (4.59%)	0/34 (0.00%)	1/52 (1.92%)
Respiratory, thoracic and mediastinal disorders
Nasal Discomfort ^* 1	8/115 (6.96%)	2/109 (1.83%)	0/34 (0.00%)	0/52 (0.00%)
Throat Irritation ^* 1	9/115 (7.83%)	5/109 (4.59%)	0/34 (0.00%)	0/52 (0.00%)
1 Term from vocabulary, MedDRA Version 20.0 * Indicates events were collected by non-systematic assessment

Limitations and Caveats

As this was a flexible-dose study, dose-response relationships could not be evaluated because direct comparisons between dose groups could not be made.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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 in writing, such publication will be withheld for up to an additional 60 days.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Senior Director
Organization:	Janssen Research & Development, LLC
Phone:	844-434-4210
EMail:	ClinicalTrialDisclosure@its.jnj.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Floden L, Hudgens S, Jamieson C, Popova V, Drevets WC, Cooper K, Singh J. Evaluation of Individual Items of the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) in Adults with Treatment-Resistant Depression Treated with Esketamine Nasal Spray Combined with a New Oral Antidepressant. CNS Drugs. 2022 Jun;36(6):649-658. doi: 10.1007/s40263-022-00916-2. Epub 2022 Apr 20.

Chen G, Chen L, Zhang Y, Li X, Lane R, Lim P, Daly EJ, Furey ML, Fedgchin M, Popova V, Singh JB, Drevets WC. Relationship Between Dissociation and Antidepressant Effects of Esketamine Nasal Spray in Patients With Treatment-Resistant Depression. Int J Neuropsychopharmacol. 2022 Apr 19;25(4):269-279. doi: 10.1093/ijnp/pyab084.

Jones RR, Freeman MP, Kornstein SG, Cooper K, Daly EJ, Canuso CM, Nicholson S. Efficacy and safety of esketamine nasal spray by sex in patients with treatment-resistant depression: findings from short-term randomized, controlled trials. Arch Womens Ment Health. 2022 Apr;25(2):313-326. doi: 10.1007/s00737-021-01185-6. Epub 2022 Jan 1.

Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, Marquardt T, Barnes A, Smith R, McShane R, Turner EH, Cipriani A. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database Syst Rev. 2021 Sep 12;9:CD011612. doi: 10.1002/14651858.CD011612.pub3. Review.

Daly EJ, Turkoz I, Salvadore G, Fedgchin M, Ionescu DF, Starr HL, Borentain S, Trivedi MH, Thase ME, Singh JB. The effect of esketamine in patients with treatment-resistant depression with and without comorbid anxiety symptoms or disorder. Depress Anxiety. 2021 Nov;38(11):1120-1130. doi: 10.1002/da.23193. Epub 2021 Jul 22.

Turkoz I, Daly E, Singh J, Lin X, Tymofyeyev Y, Williamson D, Salvadore G, Nash AI, Macaluso M, Wilkinson ST, Nelson JC. Treatment Response With Esketamine Nasal Spray Plus an Oral Antidepressant in Patients With Treatment-Resistant Depression Without Evidence of Early Response: A Pooled Post Hoc Analysis of the TRANSFORM Studies. J Clin Psychiatry. 2021 Jul 20;82(4). pii: 20m13800. doi: 10.4088/JCP.20m13800.

Doty RL, Popova V, Wylie C, Fedgchin M, Daly E, Janik A, Ochs-Ross R, Lane R, Lim P, Cooper K, Melkote R, Jamieson C, Singh J, Drevets WC. Effect of Esketamine Nasal Spray on Olfactory Function and Nasal Tolerability in Patients with Treatment-Resistant Depression: Results from Four Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Studies. CNS Drugs. 2021 Jul;35(7):781-794. doi: 10.1007/s40263-021-00826-9. Epub 2021 Jul 7.

Perez-Ruixo C, Rossenu S, Zannikos P, Nandy P, Singh J, Drevets WC, Perez-Ruixo JJ. Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression. Clin Pharmacokinet. 2021 Apr;60(4):501-516. doi: 10.1007/s40262-020-00953-4. Epub 2020 Oct 31.

Katz EG, Hough D, Doherty T, Lane R, Singh J, Levitan B. Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression. Clin Pharmacol Ther. 2021 Feb;109(2):536-546. doi: 10.1002/cpt.2024. Epub 2020 Oct 13.

Saad Z, Hibar D, Fedgchin M, Popova V, Furey ML, Singh JB, Kolb H, Drevets WC, Chen G. Effects of Mu-Opiate Receptor Gene Polymorphism rs1799971 (A118G) on the Antidepressant and Dissociation Responses in Esketamine Nasal Spray Clinical Trials. Int J Neuropsychopharmacol. 2020 Dec 3;23(9):549-558. doi: 10.1093/ijnp/pyaa030.

Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, Mazzucco C, Hough D, Thase ME, Shelton RC, Molero P, Vieta E, Bajbouj M, Manji H, Drevets WC, Singh JB. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry. 2019 Jun 1;176(6):428-438. doi: 10.1176/appi.ajp.2019.19020172. Epub 2019 May 21. Erratum in: Am J Psychiatry. 2019 Aug 1;176(8):669.

Layout table for additonal information

Responsible Party:	Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:	NCT02418585
Other Study ID Numbers:	CR107147 ESKETINTRD3002 ( Other Identifier: Janssen Research & Development, LLC ) 2014-004585-22 ( EudraCT Number )
First Submitted:	April 13, 2015
First Posted:	April 16, 2015
Results First Submitted:	March 27, 2019
Results First Posted:	April 19, 2019
Last Update Posted:	June 2, 2020

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