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A Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Adult Participants With Treatment-resistant Depression (SUSTAIN-1)

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ClinicalTrials.gov Identifier: NCT02493868
Recruitment Status : Completed
First Posted : July 10, 2015
Results First Posted : May 21, 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 Depressive Disorder, Treatment-Resistant
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 719
Recruitment Details Total of 719 participants were enrolled out of which 705 were included in the analysis. 14 participants were excluded due to premature closure of a site due to quality and data integrity issues.
Pre-assignment Details Out of 705 participants, 437 (direct entry [DE] participants) entered in induction (IND) phase and 268 participants (150 transferred-entry [TE] participants from study ESKETINTRD3001 [NCT02417064] and 118 participants from study ESKETINTRD3002 [NCT02418585]) entered in this study in optimization (OP) phase.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD + Intranasal Placebo
Hide Arm/Group Description Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase. Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance (MA) phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Period Title: Induction Phase: DE Participants
Started 437 0
Completed 273 [1] 0
Not Completed 164 0
Reason Not Completed
Adverse Event             22             0
Lost to Follow-up             1             0
Lack of Efficacy             2             0
Protocol Violation             2             0
Withdrawal by Subject             15             0
Not meet criteria to continue next phase             114             0
Other             8             0
[1]
Participants who completed and met predefined response criteria continued to OP phase.
Period Title: Optimization Phase: DE+TE Participants
Started 455 [1] 86 [2]
Completed 297 [3] 54 [4]
Not Completed 158 32
Reason Not Completed
Adverse Event             5             0
Lost to Follow-up             2             1
Lack of Efficacy             8             0
Protocol Violation             4             1
Withdrawal by Subject             8             3
MADRS >= 22 for 2 Consecutive Visit             14             5
Not meet criteria to continue next phase             107             20
Other             10             2
[1]
Total participants: direct-entry (273) + esketamine-treated transferred-entry participants (182).
[2]
Placebo treated transferred-entry participant.
[3]
Participants who completed and met predefined remission/response criteria randomized to MA phase
[4]
Participants who completed and met predefined remission/response criteria continued to MA phase.
Period Title: Maintenance Phase: DE+TE Participants
Started 152 [1] 199 [2]
Stable Remitters 90 86
Stable Responders 62 59
Completed 139 177
Not Completed 13 22
Reason Not Completed
Adverse Event             1             4
Lost to Follow-up             1             0
Protocol Violation             1             1
Withdrawal by Subject             5             7
Pregnancy             1             0
Non Compliance with Study Drug             0             1
Other             4             9
[1]
152 participants randomized from intranasal esketamine arm after OP phase: DE (90) + TE (62)
[2]
145 participants randomized from intranasal esketamine arm after OP phase+54 continued from OP phase
Period Title: Follow-up Phase
Started 481 64
Completed 470 62
Not Completed 11 2
Reason Not Completed
Lost to Follow-up             1             0
Withdrawal by Subject             3             0
Investigator Decision             5             1
Other             2             1
Arm/Group Title All Participants
Hide Arm/Group Description All Participants (direct entry and transferred entry) who were enrolled in this study and received intranasal esketamine, matching placebo and oral antidepressant as per the assigned treatment.
Overall Number of Baseline Participants 705
Hide Baseline Analysis Population Description
The baseline characteristics are reported for the all enrolled population. Not all participants enrolled were actually randomized to one of 2 treatments in the Maintenance phase as they had to meet specific criteria to be randomized.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 705 participants
46.1  (11.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 705 participants
Female
457
  64.8%
Male
248
  35.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 705 participants
Hispanic or Latino
94
  13.3%
Not Hispanic or Latino
600
  85.1%
Unknown or Not Reported
11
   1.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 705 participants
Asian
3
   0.4%
Black or African American
31
   4.4%
Hispanic or Latino
71
  10.1%
Other
38
   5.4%
White Non-Hispanic
562
  79.7%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 705 participants
BELGIUM
14
   2.0%
BRAZIL
64
   9.1%
CANADA
5
   0.7%
CZECH REPUBLIC
99
  14.0%
ESTONIA
1
   0.1%
FRANCE
10
   1.4%
GERMANY
7
   1.0%
HUNGARY
35
   5.0%
ITALY
21
   3.0%
MEXICO
35
   5.0%
POLAND
132
  18.7%
SLOVAKIA
7
   1.0%
SPAIN
16
   2.3%
SWEDEN
16
   2.3%
TURKEY
53
   7.5%
UNITED STATES
190
  27.0%
1.Primary Outcome
Title Time to Relapse in Participants With Stable Remission (Maintenance Phase)
Hide Description Relapse is defined as any of following: Montgomery-asberg depression rating scale (MADRS) total score greater than or equal to (>=) 22 for 2 consecutive assessments separated by 5-15 days and/or hospitalization for worsening depression or any other clinically relevant event to be suggestive of a relapse of depressive illness such as suicide attempt/completed suicide/hospitalization for suicide prevention; If hospitalized, start date of hospitalization will be date of relapse, if not hospitalized date of event will be used. MADRS: clinician-rated scale to measure depression severity and to detect changes due to antidepressant treatment. It has 10 items, scored from 0-6 (not present/normal-severe/continuous symptoms), with total score of 60. Higher scores mean more severe condition. Stable remission: MADRS total score less than or equal to (<=) 12 for at least 3 of last 4 weeks of OP phase, with 1 excursion total score greater than (>) 12 or one missing assessment at OP week 13 or 14.
Time Frame Time from randomization to the first relapse during the maintenance phase (up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable remitters) analysis set included all the randomized participants who were in stable remission at the end of the optimization phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during the maintenance phase.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 90 86
Median (95% Confidence Interval)
Unit of Measure: Days
NA [1] 
(NA to NA)
273.0 [2] 
(97.0 to NA)
[1]
Here NA signifies that median and 95%CI was not estimable due to not having sufficient events to meet the threshold for 50% on the Kaplan-Meier curve.
[2]
Here NA signifies that upper limit of CI could not be estimated due to insufficient data.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Intranasal Esketamine + Oral AD, Oral AD+ Intranasal Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.003
Comments [Not Specified]
Method Weighted Log-rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.49
Confidence Interval (2-Sided) 95%
0.29 to 0.84
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Time to Relapse in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
Hide Description Relapse is defined as any of following: MADRS total score >= 22 for 2 consecutive assessments separated by 5-15 days and/or hospitalization for worsening depression or any other clinically relevant event to be suggestive of a relapse of depressive illness such as suicide attempt/completed suicide/hospitalization for suicide prevention; If hospitalized, start date of hospitalization will be date of relapse, if not hospitalized date of event will be used. MADRS: clinician-rated scale to measure depression severity and to detect changes due to antidepressant treatment. It has 10 items, scored from 0-6 (not present/normal-severe/continuous symptoms), with total score of 60. Higher scores mean more severe condition. Stable response is defined as >= 50 percent (%) reduction in MADRS total score from baseline (Day 1 of induction phase, prior to first intranasal dose) in each of the last 2 weeks of the OP phase, but without meeting criteria for stable remission.
Time Frame Time from randomization to the first relapse during the maintenance phase (up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable responders) analysis set included all randomized participants who were stable responders (who were not stable remitters) at the end of the optimization phase and who received at least 1 dose of intranasal study drug and 1 dose of oral antidepressant during the maintenance phase.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 62 59
Median (95% Confidence Interval)
Unit of Measure: Days
635.0
(264.0 to 635.0)
88.0
(46.0 to 196.0)
3.Secondary Outcome
Title Change From Baseline in MADRS Total Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
Hide Description MADRS: clinician-rated scale to measure depression severity and to detect changes due to antidepressant treatment. It has 10 items, scored from 0-6 (not present/normal - severe/continuous symptoms), with total score of 60. Higher scores mean more severe condition. The change from baseline in MADRS total score (last observation carried forward [LOCF] data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint.
Time Frame Baseline and Endpoint (Up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable remitters) analysis set included all randomized participants who were in stable remission at end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure (OM).
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 89 86
Mean (Standard Deviation)
Unit of Measure: Units on a scale
7.5  (11.59) 12.5  (13.63)
4.Secondary Outcome
Title Change From Baseline in MADRS Total Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
Hide Description MADRS: clinician-rated scale to measure depression severity and to detect changes due to antidepressant treatment. It has 10 items, scored from 0-6 (not present/normal - severe/continuous symptoms), with total score of 60. Higher scores mean more severe condition. The change from baseline in MADRS total score (LOCF data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint.
Time Frame Baseline and Endpoint (Up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable responders) analysis set included all randomized participants who were stable responders (who were not stable remitters) at the end of the optimization phase and who received at least 1 dose of intranasal study drug and 1 dose of oral antidepressant during the maintenance phase.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 62 59
Mean (Standard Deviation)
Unit of Measure: Units on a scale
4.4  (11.38) 11.4  (12.00)
5.Secondary Outcome
Title Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
Hide Description PHQ-9 is a 9-item, self-report scale assessing depressive symptoms. Each item is 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 are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: None-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19) and severe (20-27). The change from baseline in PHQ-9 total score, (LOCF data) at endpoint was reported. The last post baseline observation was carried forward as the endpoint.
Time Frame Baseline and Endpoint (Up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable remitters) analysis set included all randomized participants who were in stable remission at the end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 89 86
Mean (Standard Deviation)
Unit of Measure: Units on a scale
3.3  (5.58) 5.9  (7.09)
6.Secondary Outcome
Title Change From Baseline in PHQ-9 Total Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
Hide Description PHQ-9 is a 9-item, self-report scale assessing depressive symptoms. Each item is 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 are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: None-minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19) and severe (20-27). The change from baseline in PHQ-9 total score, (LOCF data) at endpoint was reported. The last post baseline observation was carried forward as the endpoint.
Time Frame Baseline and Endpoint (Up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable responders) analysis set: all randomized participants who were stable responders (not stable remitters) at end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 61 58
Mean (Standard Deviation)
Unit of Measure: Units on a scale
1.7  (5.02) 4.7  (5.48)
7.Secondary Outcome
Title Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
Hide Description 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 0 to 7. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating 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 the most extremely ill patients. The change from baseline in CGI-S score, (LOCF data) at endpoint was reported. The last post baseline observation was carried forward as the endpoint.
Time Frame Baseline and Endpoint (Up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable remitters) analysis set included all randomized participants who were in stable remission at the end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 89 86
Median (Full Range)
Unit of Measure: Units on a scale
0.0
(-3 to 4)
1.0
(-2 to 5)
8.Secondary Outcome
Title Change From Baseline in Clinical Global Impression-Severity Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
Hide Description 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 0 to 7. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating 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 the most extremely ill patients. The change from baseline in CGI-S score, (LOCF data) at endpoint was reported. The last post baseline observation was carried forward as the endpoint.
Time Frame Baseline and Endpoint (Up to 92 Weeks)
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Hide Analysis Population Description
Full (stable responders) analysis set: all randomized participants who were stable responders (not stable remitters) at end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 62 58
Median (Full Range)
Unit of Measure: Units on a scale
0.0
(-2 to 4)
1.0
(-3 to 5)
9.Secondary Outcome
Title Change From Baseline in Generalized Anxiety Disorder-7 Items (GAD-7) Total Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
Hide 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). Item responses are summed to yield a total score (range of 0 to 21), with higher scores indicating more anxiety. The change from baseline in GAD-7 total score, (LOCF data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint.
Time Frame Baseline and Endpoint (Up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable remitters) analysis set included all randomized participants who were in stable remission at the end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 89 86
Mean (Standard Deviation)
Unit of Measure: Units on a scale
2.2  (4.45) 4.0  (5.93)
10.Secondary Outcome
Title Change From Baseline in Generalized Anxiety Disorder-7 Items Total Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
Hide 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). Item responses are summed to yield a total score (range of 0 to 21), with higher scores indicating more anxiety. The change from baseline in GAD-7 total score, (LOCF data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint.
Time Frame Baseline and Endpoint (Up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable responders) analysis set: all randomized participants who were stable responders (not stable remitters) at end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 61 58
Mean (Standard Deviation)
Unit of Measure: Units on a scale
1.4  (3.76) 2.6  (4.26)
11.Secondary Outcome
Title Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Sum Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
Hide 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). HSI ranges from 0 (dead) to 1.00 (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 and Endpoint (Up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable remitters) analysis set included all randomized participants who were in stable remission at the end of optimization phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 88 86
Mean (Standard Deviation)
Unit of Measure: Units on a scale
7.5  (11.87) 10.9  (14.74)
12.Secondary Outcome
Title Change From Baseline in EQ Visual Analogue Scale Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
Hide 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 and Endpoint (Up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable remitters) analysis set included all randomized participants who were in stable remission at the end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 88 86
Mean (Standard Deviation)
Unit of Measure: Units on a scale
-10.4  (20.29) -16.1  (21.80)
13.Secondary Outcome
Title Change From Baseline in EQ-5D-5L Health Status Index at Endpoint in Participants With Stable Remission (Maintenance Phase)
Hide 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. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a HSI. HSI ranges from 0 (dead) to 1.00 (full health).
Time Frame Baseline and Endpoint (Up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable remitters) analysis set included all randomized participants who were in stable remission at the end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 88 86
Mean (Standard Deviation)
Unit of Measure: Units on a scale
-0.067  (0.1180) -0.096  (0.1484)
14.Secondary Outcome
Title Change From Baseline in EuroQol-5 Dimension-5 Level Sum Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
Hide Description EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a HSI. HSI ranges from 0 (dead) to 1.00 (full health). 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 and Endpoint (Up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable responders) analysis set: all randomized participants who were stable responders (not stable remitters) at end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 61 58
Mean (Standard Deviation)
Unit of Measure: Units on a scale
3.0  (8.13) 8.4  (13.55)
15.Secondary Outcome
Title Change From Baseline in EQ-5D-5L EQ Visual Analogue Scale Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
Hide 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 and Endpoint (Up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable responders) analysis set: all randomized participants who were stable responders (not stable remitters) at end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 61 59
Mean (Standard Deviation)
Unit of Measure: Units on a scale
-1.3  (15.55) -13.8  (19.81)
16.Secondary Outcome
Title Change From Baseline in EQ-5D-5L Health Status Index at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
Hide 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. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses were used to generate a HSI. HSI ranges from 0 (dead) to 1.00 (full health).
Time Frame Baseline and Endpoint (Up to 92 Weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (stable responders) analysis set: all randomized participants who were stable responders (not stable remitters) at end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 61 58
Mean (Standard Deviation)
Unit of Measure: Units on a scale
-0.023  (0.0753) -0.073  (0.1383)
17.Secondary Outcome
Title Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Endpoint in Participants With Stable Remission (Maintenance Phase)
Hide Description The SDS is a participant-reported outcome measure and is a 5-item questionnaire used and accepted for assessment of functional impairment and associated disability. The first 3 items assess disruption of 1: work/school 2: social life 3: family life/home responsibilities using a 0-10 rating scale. It also has one item on days lost from school or work and one item on days when underproductive. The score for the first 3 items are summed to create a total score of 0-30 where a higher score indicates greater impairment. The recall period is 7 days. Scores <= 4 for each item and <= 12 for the total score are considered response. Scores <= 2 for each item and <= 6 for the total score are considered remission. The change from baseline in SDS total Score, (LOCF data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint.
Time Frame Baseline and Endpoint (Up to 92 Weeks)
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Hide Analysis Population Description
Full (stable remitters) analysis set included all randomized participants who were in stable remission at the end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
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Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 82 77
Mean (Standard Deviation)
Unit of Measure: Units on a scale
4.7  (7.34) 7.2  (10.44)
18.Secondary Outcome
Title Change From Baseline in Sheehan Disability Total Score at Endpoint in Participants With Stable Response (But Not in Stable Remission) (Maintenance Phase)
Hide Description The SDS is a participant-reported outcome measure and is a 5-item questionnaire used and accepted for assessment of functional impairment and associated disability. The first 3 items assess disruption of 1: work/school 2: social life 3: family life/home responsibilities using a 0-10 rating scale. It also has one item on days lost from school or work and one item on days when underproductive. The score for the first 3 items are summed to create a total score of 0-30 where a higher score indicates greater impairment. The recall period is 7 days. Scores <= 4 for each item and <= 12 for the total score are considered response. Scores <= 2 for each item and <= 6 for the total score are considered remission. The change from baseline in SDS total Score, (LOCF data), at endpoint was reported. The last post baseline observation was carried forward as the endpoint.
Time Frame Baseline and Endpoint (Up to 92 Weeks)
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Hide Analysis Population Description
Full (stable responders) analysis set: all randomized participants who were stable responders (not stable remitters) at end of OP phase and received at least 1 dose of intranasal study drug and 1 dose of oral AD during MA phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this OM.
Arm/Group Title Intranasal Esketamine + Oral AD Oral AD+ Intranasal Placebo
Hide Arm/Group Description:
Open-label induction (IND) phase (DE): received 56 or 84 milligram intranasal esketamine solution twice weekly with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. OP phase (DE+TE): received intranasal esketamine (same dose) solution once per week for first 4 weeks, then once per week/once every other week based on severity of depressive symptoms, and continued same oral AD from IND phase for 12 weeks. MA phase (DE+TE): Participants were randomized (at end of OP phase) to receive intranasal esketamine (same dose) once weekly/once every other week based on depressive symptoms and continued same oral AD from IND phase. Follow-up (FU) phase: participants received no intranasal esketamine but continued oral AD for 2 weeks unless determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Open-label induction phase: No intervention was administered. Optimization phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (DE+TE participants): Participants were randomized (at the end of optimization phase) to receive intranasal esketamine placebo with oral AD from optimization phase. Follow-up Phase: Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants who were non-responders at end of IND phase or who were early terminated at any phase proceeded directly to FU phase.
Overall Number of Participants Analyzed 58 53
Mean (Standard Deviation)
Unit of Measure: Units on a scale
2.2  (6.63) 6.8  (7.64)
Time Frame Up to 2 years
Adverse Event Reporting Description Safety analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in respective phase (Induction, Optimization, Maintenance). Follow-up analysis set included all participants who entered the follow-up phase.
 
Arm/Group Title IND: Intranasal Esketamine + Oral AD OP: Intranasal Esketamine + Oral AD MA: Intranasal Esketamine + Oral AD MA: Oral AD + Intranasal Placebo FU: Intranasal Esketamine + Oral AD FU: Oral AD + Intranasal Placebo OP_TEP: Oral AD + Intranasal Placebo MA_TEP: Oral AD + Intranasal Placebo
Hide Arm/Group Description Open-label induction (IND) phase (direct-entry participants only): received 56 milligram (mg) or 84 mg intranasal esketamine solution twice weekly with open-label oral antidepressant (AD) (one of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]), once daily for 4 weeks. Optimization (OP) phase (both direct-entry and transferred-entry participants): received 56 mg or 84 mg intranasal esketamine solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance (MA) phase (both direct-entry and transferred-entry participants): received 56 mg or 84 mg intranasal esketamine solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily until relapse or study termination. Maintenance phase (transferred-entry participants): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), until relapse or study termination. Participants (who were non-responders in IND phase and who were in OP and MA phase at study termination) who received at least 1 dose of 56 mg or 84 mg intranasal esketamine participated in the follow-up (FU) phase. No intranasal esketamine was administered during FU phase. Participants received oral AD for 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. Participants (who were non-responders in IND phase and who were in OP and MA phase at study termination) who received intranasal esketamine matching placebo with oral AD participated in the FU phase. Participants received oral AD for at least the 2 weeks of the follow-up phase unless it was determined to not be clinically appropriate. OP phase (transferred-entry participants [TEP]): received intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine XR), once daily for 12 weeks. Maintenance phase (transferred-entry participants): Participants were randomized (at the end of optimization phase) to intranasal esketamine matching placebo solution once per week for the first 4 weeks, then once per week or once every other week depending on severity of depressive symptoms with open-label oral AD (one of: duloxetine/escitalopram/sertraline/venlafaxine XR).
All-Cause Mortality
IND: Intranasal Esketamine + Oral AD OP: Intranasal Esketamine + Oral AD MA: Intranasal Esketamine + Oral AD MA: Oral AD + Intranasal Placebo FU: Intranasal Esketamine + Oral AD FU: Oral AD + Intranasal Placebo OP_TEP: Oral AD + Intranasal Placebo MA_TEP: Oral AD + Intranasal Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/437 (0.00%)   0/455 (0.00%)   0/152 (0.00%)   0/145 (0.00%)   0/481 (0.00%)   0/64 (0.00%)   0/86 (0.00%)   0/54 (0.00%) 
Hide Serious Adverse Events
IND: Intranasal Esketamine + Oral AD OP: Intranasal Esketamine + Oral AD MA: Intranasal Esketamine + Oral AD MA: Oral AD + Intranasal Placebo FU: Intranasal Esketamine + Oral AD FU: Oral AD + Intranasal Placebo OP_TEP: Oral AD + Intranasal Placebo MA_TEP: Oral AD + Intranasal Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   13/437 (2.97%)   11/455 (2.42%)   4/152 (2.63%)   1/145 (0.69%)   3/481 (0.62%)   0/64 (0.00%)   0/86 (0.00%)   1/54 (1.85%) 
Cardiac disorders                 
Sinus Tachycardia * 1  0/437 (0.00%)  1/455 (0.22%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Gastrointestinal disorders                 
Anal Fissure * 1  0/437 (0.00%)  1/455 (0.22%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
General disorders                 
Chest Pain * 1  0/437 (0.00%)  1/455 (0.22%)  0/152 (0.00%)  0/145 (0.00%)  1/481 (0.21%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Hypothermia * 1  1/437 (0.23%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Hepatobiliary disorders                 
Cholecystitis Acute * 1  0/437 (0.00%)  1/455 (0.22%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Infections and infestations                 
Pneumonia * 1  0/437 (0.00%)  1/455 (0.22%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Sepsis * 1  0/437 (0.00%)  1/455 (0.22%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Injury, poisoning and procedural complications                 
Procedural Pain * 1  1/437 (0.23%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Clavicle Fracture * 1  0/437 (0.00%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  1/54 (1.85%) 
Musculoskeletal and connective tissue disorders                 
Intervertebral Disc Protrusion * 1  0/437 (0.00%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  1/481 (0.21%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Pain in Extremity * 1  0/437 (0.00%)  1/455 (0.22%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Nervous system disorders                 
Autonomic Nervous System Imbalance * 1  1/437 (0.23%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Headache * 1  0/437 (0.00%)  1/455 (0.22%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Lacunar Stroke * 1  1/437 (0.23%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Migraine * 1  0/437 (0.00%)  1/455 (0.22%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Paraesthesia * 1  0/437 (0.00%)  1/455 (0.22%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Sedation * 1  1/437 (0.23%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Simple Partial Seizures * 1  1/437 (0.23%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Pregnancy, puerperium and perinatal conditions                 
Ectopic Pregnancy * 1  0/437 (0.00%)  0/455 (0.00%)  1/152 (0.66%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Psychiatric disorders                 
Anxiety * 1  2/437 (0.46%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Depression * 1  3/437 (0.69%)  1/455 (0.22%)  2/152 (1.32%)  1/145 (0.69%)  1/481 (0.21%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Disorientation * 1  1/437 (0.23%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Major Depression * 1  0/437 (0.00%)  0/455 (0.00%)  1/152 (0.66%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Mania * 1  0/437 (0.00%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  1/481 (0.21%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Panic Attack * 1  0/437 (0.00%)  1/455 (0.22%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Suicidal Ideation * 1  1/437 (0.23%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Renal and urinary disorders                 
Nephrolithiasis * 1  1/437 (0.23%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Vascular disorders                 
Hypertensive Crisis * 1  0/437 (0.00%)  1/455 (0.22%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Orthostatic Hypotension * 1  1/437 (0.23%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
1
Term from vocabulary, MedDRA Version 20.0
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
IND: Intranasal Esketamine + Oral AD OP: Intranasal Esketamine + Oral AD MA: Intranasal Esketamine + Oral AD MA: Oral AD + Intranasal Placebo FU: Intranasal Esketamine + Oral AD FU: Oral AD + Intranasal Placebo OP_TEP: Oral AD + Intranasal Placebo MA_TEP: Oral AD + Intranasal Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   306/437 (70.02%)   279/455 (61.32%)   114/152 (75.00%)   45/145 (31.03%)   14/481 (2.91%)   1/64 (1.56%)   40/86 (46.51%)   37/54 (68.52%) 
Ear and labyrinth disorders                 
Vertigo * 1  99/437 (22.65%)  91/455 (20.00%)  38/152 (25.00%)  8/145 (5.52%)  2/481 (0.42%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Eye disorders                 
Diplopia * 1  16/437 (3.66%)  10/455 (2.20%)  9/152 (5.92%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Vision Blurred * 1  45/437 (10.30%)  30/455 (6.59%)  24/152 (15.79%)  1/145 (0.69%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Gastrointestinal disorders                 
Hypoaesthesia Oral * 1  32/437 (7.32%)  34/455 (7.47%)  20/152 (13.16%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Nausea * 1  94/437 (21.51%)  48/455 (10.55%)  25/152 (16.45%)  1/145 (0.69%)  2/481 (0.42%)  1/64 (1.56%)  0/86 (0.00%)  3/54 (5.56%) 
Paraesthesia Oral * 1  16/437 (3.66%)  13/455 (2.86%)  8/152 (5.26%)  1/145 (0.69%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Vomiting * 1  29/437 (6.64%)  17/455 (3.74%)  10/152 (6.58%)  1/145 (0.69%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Diarrhoea * 1  0/437 (0.00%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  4/54 (7.41%) 
Infections and infestations                 
Viral Upper Respiratory Tract Infection * 1  5/437 (1.14%)  22/455 (4.84%)  11/152 (7.24%)  12/145 (8.28%)  1/481 (0.21%)  0/64 (0.00%)  0/86 (0.00%)  13/54 (24.07%) 
Urinary Tract Infection * 1  0/437 (0.00%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  3/54 (5.56%) 
Investigations                 
Blood Pressure Increased * 1  34/437 (7.78%)  26/455 (5.71%)  10/152 (6.58%)  5/145 (3.45%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Musculoskeletal and connective tissue disorders                 
Musculoskeletal Pain * 1  0/437 (0.00%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  3/54 (5.56%) 
Spinal Pain * 1  0/437 (0.00%)  0/455 (0.00%)  0/152 (0.00%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  3/54 (5.56%) 
Nervous system disorders                 
Dizziness * 1  97/437 (22.20%)  61/455 (13.41%)  31/152 (20.39%)  7/145 (4.83%)  0/481 (0.00%)  1/64 (1.56%)  6/86 (6.98%)  0/54 (0.00%) 
Dizziness Postural * 1  33/437 (7.55%)  26/455 (5.71%)  10/152 (6.58%)  3/145 (2.07%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Dysgeusia * 1  90/437 (20.59%)  79/455 (17.36%)  41/152 (26.97%)  10/145 (6.90%)  0/481 (0.00%)  0/64 (0.00%)  8/86 (9.30%)  8/54 (14.81%) 
Headache * 1  60/437 (13.73%)  57/455 (12.53%)  27/152 (17.76%)  14/145 (9.66%)  8/481 (1.66%)  0/64 (0.00%)  16/86 (18.60%)  12/54 (22.22%) 
Hypoaesthesia * 1  30/437 (6.86%)  24/455 (5.27%)  9/152 (5.92%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Paraesthesia * 1  48/437 (10.98%)  23/455 (5.05%)  11/152 (7.24%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Sedation * 1  43/437 (9.84%)  19/455 (4.18%)  10/152 (6.58%)  1/145 (0.69%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Somnolence * 1  65/437 (14.87%)  63/455 (13.85%)  32/152 (21.05%)  3/145 (2.07%)  0/481 (0.00%)  0/64 (0.00%)  5/86 (5.81%)  4/54 (7.41%) 
Psychiatric disorders                 
Anxiety * 1  31/437 (7.09%)  11/455 (2.42%)  12/152 (7.89%)  5/145 (3.45%)  2/481 (0.42%)  0/64 (0.00%)  5/86 (5.81%)  0/54 (0.00%) 
Confusional State * 1  13/437 (2.97%)  9/455 (1.98%)  9/152 (5.92%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Dissociation * 1  82/437 (18.76%)  73/455 (16.04%)  35/152 (23.03%)  0/145 (0.00%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Respiratory, thoracic and mediastinal disorders                 
Nasal Discomfort * 1  29/437 (6.64%)  26/455 (5.71%)  11/152 (7.24%)  4/145 (2.76%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
Throat Irritation * 1  26/437 (5.95%)  16/455 (3.52%)  8/152 (5.26%)  1/145 (0.69%)  0/481 (0.00%)  0/64 (0.00%)  0/86 (0.00%)  0/54 (0.00%) 
1
Term from vocabulary, MedDRA Version 20.0
*
Indicates events were collected by non-systematic assessment
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.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Senior Director, Clinical Research
Organization: Janssen Research & Development, LLC
Phone: 844-434-4210
EMail: ClinicalTrialDisclosure@its.jnj.com
Layout table for additonal information
Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT02493868    
Other Study ID Numbers: CR107128
ESKETINTRD3003 ( Other Identifier: Janssen Research & Development, LLC )
2014-004586-24 ( EudraCT Number )
First Submitted: May 13, 2015
First Posted: July 10, 2015
Results First Submitted: March 29, 2019
Results First Posted: May 21, 2019
Last Update Posted: June 2, 2020