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A Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression (SUSTAIN-2)

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ClinicalTrials.gov Identifier: NCT02497287
Recruitment Status : Completed
First Posted : July 14, 2015
Results First Posted : April 29, 2019
Last Update Posted : May 21, 2019
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Treatment-resistant Depression
Interventions Drug: Esketamine (Intranasal Spray)
Drug: Duloxetine (Oral Antidepressant)
Drug: Escitalopram (Oral Antidepressant)
Drug: Sertraline (Oral Antidepressant)
Drug: Venlafaxine Extended Release (XR) (Oral Antidepressant)
Enrollment 802
Recruitment Details In this study participants from study ESKETINTRD3005 (NCT02422186) were enrolled (transferred entry [TE]). ESKETINTRD3005 is referred as TRD3005 in the draft.
Pre-assignment Details Total 802 participants were enrolled (direct-entry [DE]=691 + TE from study ESKETINTRD3005 =111). Among 111 TE participants, 88 participants (non-responders from ESKETINTRD3005) joined induction (IND) phase and 23 participants (responders from ESKETINTRD3005) did not join IND phase and directly entered in optimization/maintenance (OP/MA) phase.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Period Title: Induction Phase (4 Weeks)
Started 779 [1]
Completed 580
Not Completed 199
Reason Not Completed
Did Not Met Criteria for OP/MA Phase             84
Adverse Event             52
Withdrawal by Subject             22
Lack of Efficacy             21
Not specified             13
Lost to Follow-up             5
Protocol Violation             1
Non-Compliance with Study Drug             1
[1]
Included DE participants (691) and non-responders from TRD3005 (88).
Period Title: Optimization/Maintenance (48 Weeks)
Started 603 [1]
Completed 150
Not Completed 453
Reason Not Completed
Study Terminated by Sponsor             331
Withdrawal by Subject             30
Adverse Event             25
Lack of Efficacy             25
Not Specified             21
Lost to Follow-up             10
Protocol Violation             3
Missed Assessment or Treatment Sessions             3
Pregnancy             2
Death             2
Non-Compliance with Study Drug             1
[1]
Included who completed IND phase (580) + responders from TRD3005 (23).
Period Title: Follow-up Phase (4 Week)
Started 357 [1]
Completed 326
Not Completed 31
Reason Not Completed
PI Decision             12
Withdrawal by Subject             10
Lost to Follow-up             5
Adverse Event             3
Not Specified             1
[1]
Included non-responders (IND phase) or discontinued treatment phase or completed OP/MA phase.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Baseline Participants 802
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 802 participants
52.2  (13.69)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 802 participants
Female
502
  62.6%
Male
300
  37.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 802 participants
Hispanic or Latino
149
  18.6%
Not Hispanic or Latino
640
  79.8%
Unknown or Not Reported
13
   1.6%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 802 participants
American Indian or Alaska Native
0
   0.0%
Asian
81
  10.1%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
15
   1.9%
White
686
  85.5%
More than one race
8
   1.0%
Unknown or Not Reported
12
   1.5%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 802 participants
ARGENTINA
106
  13.2%
AUSTRALIA
23
   2.9%
AUSTRIA
16
   2.0%
BELGIUM
5
   0.6%
BRAZIL
52
   6.5%
BULGARIA
94
  11.7%
FINLAND
2
   0.2%
FRANCE
4
   0.5%
GERMANY
13
   1.6%
ITALY
7
   0.9%
MALAYSIA
19
   2.4%
MEXICO
10
   1.2%
POLAND
6
   0.7%
SOUTH AFRICA
64
   8.0%
SOUTH KOREA
26
   3.2%
SPAIN
42
   5.2%
SWEDEN
90
  11.2%
TAIWAN
33
   4.1%
TURKEY
31
   3.9%
UNITED KINGDOM
12
   1.5%
UNITED STATES
147
  18.3%
1.Primary Outcome
Title Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
Hide Description An adverse event is any untoward medical occurrence in a clinical study participants who administered a medicinal (investigational or non-investigational) product and does not necessarily have a causal relationship with the treatment. A TEAE defined as an event that was new in onset or increased in severity following treatment initiation.
Time Frame Up to End of Follow up Phase (Week 56)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 802
Measure Type: Number
Unit of Measure: Percentage of participants
90.1
2.Primary Outcome
Title Percentage of Participants With Cystitis, Urinary Tract Infections, Renal and Urinary Tract Symptoms, Renal and Urinary Disorders
Hide Description Percentage of participants with cystitis, urinary tract infections, renal and urinary tract symptoms, renal and urinary disorders were evaluated. Cystitis and urinary tract infections are selected MedDRA preferred terms, "renal and urinary tract symptoms" refers to any preferred term (PT) in the group of selected PTs; and "renal and urinary disorders" refers to a MedDRA System Organ Class (SOC).
Time Frame Up to End of Follow up Phase (Week 56)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 802
Measure Type: Number
Unit of Measure: Percentage of participants
Cystitis 0.6
Urinary tract infections 8.1
Renal and urinary disorders 10.5
Renal and urinary tract symptoms 17.0
3.Primary Outcome
Title Change From Baseline in Cognitive Test Battery: Detection Test (DET) Score
Hide Description This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. The DET is a measure of psychomotor function and uses a well-validated simple reaction time. In this outcome measure, speed of performance of participants (calculated as mean of the logarithmic base 10 transformed reaction times) for correct responses was reported. Total score ranges from 2 to 3.3 log 10 milliseconds (msec). Lower score indicates better performance. Higher change from baseline indicates better performance.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of Optimization/Maintenance [OP/MA] Phase)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 561
Mean (Standard Deviation)
Unit of Measure: log10 msec
-0.0028  (0.12744)
4.Primary Outcome
Title Change From Baseline in Cognitive Test Battery: Identification Test (IDN) Score
Hide Description This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. IDN test is a measure of visual attention (choice reaction time) and scored for speed of response (mean of the log10 transformed reaction times for correct responses). Total score ranges from 2 to 3.3 log 10 msec. Lower score indicates better performance. Higher change from baseline indicates better performance.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 561
Mean (Standard Deviation)
Unit of Measure: log10 msec
-0.0083  (0.09656)
5.Primary Outcome
Title Change From Baseline in Cognitive Test Battery: One Card Learning Test (OCL) Score
Hide Description This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. OCL test is a measure of visual episodic memory and visual recall test scored using arcsine transformation of the percentage of correct responses (CR). The range for OCL is 0 to 100 percent (%) accuracy; presented as an arcsin transformation, the range is 0 to 1.57. Higher score indicates better performance. Higher change from baseline indicates better performance.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 561
Mean (Standard Deviation)
Unit of Measure: Arcsine ([sqrt] of proportion of [CR])
0.0502  (0.13149)
6.Primary Outcome
Title Change From Baseline in Cognitive Test Battery: One Back Test (ONB) Score
Hide Description The ONB is a measure of working memory and scored for speed of correct response (mean of the log10-transformed reaction times for correct responses). Total score ranges from 2 to 3.54 log10 msec. Lower score indicates better performance. Higher change from baseline indicates better performance.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 563
Mean (Standard Deviation)
Unit of Measure: log10 msec
0.0177  (0.10026)
7.Primary Outcome
Title Change From Baseline in Cognitive Test Battery: Groton Maze Learning Test (GMLT) Score
Hide Description This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. GMLT measures executive function; maze/sequencing test, scored for total number of errors. Total score ranges from 0 to 999 number of errors. Lower score indicates better performance. Higher change from baseline indicates better performance.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 506
Mean (Standard Deviation)
Unit of Measure: Number of Errors
6.9  (25.36)
8.Primary Outcome
Title Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Total Recall
Hide Description Hopkins Verbal Learning Test (HVLT) measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0 -12); the retention (%) score (0-100%) is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3; and the recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score = higher cognition.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 569
Mean (Standard Deviation)
Unit of Measure: Number correct
2.8  (4.74)
9.Primary Outcome
Title Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Delayed Recall
Hide Description HVLT measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0 -12); the retention (%) score (0-100%) is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3; and the recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score = higher cognition.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 569
Mean (Standard Deviation)
Unit of Measure: Number correct
0.8  (2.31)
10.Primary Outcome
Title Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Number of Words Recalled
Hide Description HVLT measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0 -12); the retention (%) score (0-100%) is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3; and the recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score = higher cognition.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 568
Mean (Standard Deviation)
Unit of Measure: Number of words recalled
0.3  (2.83)
11.Primary Outcome
Title Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Recognition Discrimination Index
Hide Description HVLT measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0 -12); the retention (%) score (0-100%) is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3; and the recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score = higher cognition.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 568
Mean (Standard Deviation)
Unit of Measure: Number of words
0.5  (3.16)
12.Secondary Outcome
Title Change From Baseline to Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score During Induction (IND) Phase
Hide Description MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using last observation carried forward (LOCF) method, last post baseline observation during the phase was carried forward as the “Endpoint”.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Hide Outcome Measure Data
Hide Analysis Population Description
The full (IND) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral AD in open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 756
Mean (Standard Deviation)
Unit of Measure: Units on a Scale
-16.4  (8.76)
13.Secondary Outcome
Title Change From Baseline to Endpoint in MADRS Total Score During Optimization/Maintenance (OP/MA) Phase
Hide Description MADRS measure depression severity, detects changes due to AD treatment. It evaluates 10 items: apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores represent a more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “Endpoint”.
Time Frame Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA Phase)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (OP/MA) analysis set: All participants who received at least 1 dose of intranasal study medication or 1 dose of oral AD in the OP/MA phase.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 603
Mean (Standard Deviation)
Unit of Measure: Units on a Scale
0.3  (8.12)
14.Secondary Outcome
Title Change From Baseline to Endpoint in Patient Health Questionnaire - 9 (PHQ-9) Total Score During IND Phase
Hide Description PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. A higher score indicates greater severity of depression. 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 recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “Endpoint”.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (IND) analysis set: All participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 746
Mean (Standard Deviation)
Unit of Measure: Unit on a Scale
-8.9  (6.67)
15.Secondary Outcome
Title Change From Baseline to Endpoint in PHQ-9 Total Score During OP/MA Phase
Hide Description PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. A higher score indicates greater severity of depression. 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 recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “Endpoint”.
Time Frame Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (OP/MA) analysis set: All participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 603
Mean (Standard Deviation)
Unit of Measure: Units on a Scale
-0.2  (5.65)
16.Secondary Outcome
Title Change From Baseline to Endpoint in Clinical Global Impression of Severity (CGI-S) Scale Score During IND Phase
Hide Description CGI-S measures severity of participant’s illness that include knowledge of participant’s history, psychosocial circumstances, symptoms, behavior, impact of symptoms on participant’s ability to function. CGI-S evaluates severity of psychopathology on a scale range from 0 - 7, where 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. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as “Endpoint”.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (IND) analysis set: All participants who received at least 1 dose of intranasal study medication or 1 dose of oral AD in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 763
Median (Full Range)
Unit of Measure: Units on a Scale
-2.0
(-6 to 2)
17.Secondary Outcome
Title Change From Baseline to Endpoint in CGI-S Scale Score During OP/MA Phase
Hide Description The CGI-S measures the severity of the participant’s illness that include 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, where 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. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “Endpoint”.
Time Frame Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Hide Outcome Measure Data
Hide Analysis Population Description
The full (OP/MA) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 603
Median (Full Range)
Unit of Measure: Units on a Scale
0.0
(-3 to 4)
18.Secondary Outcome
Title Change From Baseline to Endpoint in Generalized Anxiety Disorder (GAD-7) Total Score During IND Phase
Hide Description GAD-7 is brief, validated 7-item self-reported assessment of overall anxiety. Participant’s responded to each item using a 4 point scale with response categories: 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield total score ranges from 0 to 21, higher scores indicate more anxiety. Negative change in score indicates improvement. Severity of GAD-7 is categorized as: None (0-4), Mild (5-9), Moderate (10-14), Severe (15 -21). Missing data was imputed using LOCF method, last post baseline observation during the phase was carried forward as “Endpoint”.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Hide Outcome Measure Data
Hide Analysis Population Description
The full (IND) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 724
Mean (Standard Deviation)
Unit of Measure: Units on a Scale
-5.9  (5.85)
19.Secondary Outcome
Title Change From Baseline to Endpoint in GAD-7 Total Score During OP/MA Phase
Hide Description GAD-7 is brief and validated 7-item self-reported assessment of overall anxiety. Participants respond to each item using a 4 point scale with response categories: 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 ranges from 0 to 21, higher scores indicate more anxiety. Negative change in score indicates improvement. Severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14), Severe (15 -21). Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “Endpoint”.
Time Frame Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Hide Outcome Measure Data
Hide Analysis Population Description
Full (OP/MA) analysis set: All participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 574
Mean (Standard Deviation)
Unit of Measure: Units on a Scale
0.2  (4.23)
20.Secondary Outcome
Title Change From Baseline to Endpoint in European Quality of Life (EuroQol) 5-Dimension, 5-Level (EQ 5D-5L) During IND Phase: Sum Score
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 -0.148 to 0.949 and is anchored at 0 (health state value equal to 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 (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Hide Outcome Measure Data
Hide Analysis Population Description
The full (IND) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in the open-label IND phase (direct-entry, transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 745
Mean (Standard Deviation)
Unit of Measure: Units on a Scale
-15.3  (16.26)
21.Secondary Outcome
Title Change From Baseline to Endpoint in EQ-5D-5L Score During IND Phase: EQ-VAS
Hide Description EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ VAS self-rating records the respondent’s own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine).
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Hide Outcome Measure Data
Hide Analysis Population Description
The full (IND) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in the open-label IND phase (direct-entry, transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 746
Mean (Standard Deviation)
Unit of Measure: Units on a Scale
17.0  (21.69)
22.Secondary Outcome
Title Change From Baseline to Endpoint in EQ-5D-5L Scale Score During IND Phase: Health Status Index
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 -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (full health).
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Hide Outcome Measure Data
Hide Analysis Population Description
The full (IND) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in the open-label IND phase (direct-entry, transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 745
Mean (Standard Deviation)
Unit of Measure: Units on a Scale
0.190  (0.2138)
23.Secondary Outcome
Title Change From Baseline to Endpoint in European Quality of Life (EuroQol) 5-Dimension, 5-Level (EQ 5D-5L) During OP/MA Phase: Sum Score
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 Health Status Index (HSI). HSI ranges from -0.148 to 0.949 and is anchored at 0 (health state value equal to 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 (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Hide Outcome Measure Data
Hide Analysis Population Description
The full (OP/MA) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in OP/MA phase.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 603
Mean (Standard Deviation)
Unit of Measure: Units on a Scale
-0.7  (13.19)
24.Secondary Outcome
Title Change From Baseline to Endpoint in EQ-5D-5L Score During OP/MA Phase: EQ-VAS
Hide Description EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ VAS. EQ VAS self-rating records the respondent’s own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine).
Time Frame Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
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Hide Analysis Population Description
The full (OP/MA) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in OP/MA phase.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 603
Mean (Standard Deviation)
Unit of Measure: Units on a Scale
1.6  (18.51)
25.Secondary Outcome
Title Change From Baseline to Endpoint in EQ-5D-5L Scale Score During OP/MA Phase: Health Status Index
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 -0.148 to 0.949 and is anchored at 0 (health state value equal to dead) and 1 (full health).
Time Frame Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Hide Outcome Measure Data
Hide Analysis Population Description
The full (OP/MA) analysis set included all participants who received at least 1 dose of intranasal study drug or 1 dose of oral AD in OP/MA phase.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 603
Mean (Standard Deviation)
Unit of Measure: Units on a Scale
-0.009  (0.1411)
26.Secondary Outcome
Title Change From Baseline in Sheehan Disability Scale (SDS) Total Score During IND Phase
Hide Description SDS was a 5 item questionnaire used for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, (3) family life/home responsibilities using a 0 to 10 rating scale. Score for the first three items are summed to create a total score of 0 to 30, higher score indicates greater impairment and a negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “Endpoint”.
Time Frame Baseline (IND) up to the Endpoint (last post-baseline assessment value during 4 weeks of IND Phase)
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Hide Analysis Population Description
Full (IND) analysis set: All participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 626
Mean (Standard Deviation)
Unit of Measure: Units on a Scale
-9.3  (7.86)
27.Secondary Outcome
Title Change From Baseline in Sheehan Disability Scale Total Score During OP/MA Phase
Hide Description SDS was a participant-reported outcome measure and was a 5 item questionnaire used 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 to 10 rating scale. The score for the first three items are summed to create a total score of 0 to 30 where a higher score indicates greater impairment and a negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “Endpoint”.
Time Frame Baseline (OP/MA) up to the Endpoint (last post-baseline assessment value during 52 weeks of OP/MA phase)
Hide Outcome Measure Data
Hide Analysis Population Description
The full (OP/MA) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 541
Mean (Standard Deviation)
Unit of Measure: Units on a Scale
-1.6  (8.25)
28.Secondary Outcome
Title Percentage of Participants With Response as Assessed by MADRS Total Score During IND Phase
Hide Description Response is defined as greater than or equal to (>=) 50 % reduction from baseline in the MADRS total score. MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “Endpoint”.
Time Frame Days 8, 15, 22 and Endpoint (last post-baseline assessment during 4 weeks of IND phase)
Hide Outcome Measure Data
Hide Analysis Population Description
The full (IND) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'n' signifies those participants who were evaluable at specific time point for this endpoint.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 779
Measure Type: Number
Unit of Measure: Percentage of participants
Day 8 Number Analyzed 739 participants
11.6
Day 15 Number Analyzed 751 participants
25.0
Day 22 Number Analyzed 753 participants
42.8
End point Number Analyzed 756 participants
78.4
29.Secondary Outcome
Title Percentage of Participants With Response as Assessed by PHQ-9 Total Score During IND Phase
Hide Description Response is defined as >= 50 % reduction from baseline (IND phase) in PHQ-9 total score. PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. The scores are summed for a total score ranging from 0-27. A higher score indicates greater severity of depression. 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 recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “Endpoint”.
Time Frame Day 15 and Endpoint (last post-baseline assessment value during 4 Week IND phase)
Hide Outcome Measure Data
Hide Analysis Population Description
The full (IND) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'n' signifies those participants who were evaluable at specific time point for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 779
Measure Type: Number
Unit of Measure: Percentage of participants
Day 15 Number Analyzed 724 participants
37.2
End point Number Analyzed 744 participants
62.0
30.Secondary Outcome
Title Percentage of Participants With Remission as Assessed by MADRS Total Score During IND Phase
Hide Description Remission is defined as MADRS total score less than or equal to (<=) 12. MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “Endpoint”.
Time Frame Days 8, 15, 22 and Endpoint (last post-baseline assessment value during 4 weeks of IND Phase)
Hide Outcome Measure Data
Hide Analysis Population Description
The full (IND) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'n' signifies those participants who were evaluable at specific time point for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 779
Measure Type: Number
Unit of Measure: Percentage of participants
Day 8 Number Analyzed 739 participants
7.3
Day 15 Number Analyzed 751 participants
15.6
Day 22 Number Analyzed 753 participants
27.2
End point Number Analyzed 756 participants
47.2
31.Secondary Outcome
Title Percentage of Participants With Remission as Assessed by PHQ-9 Total Score During IND Phase
Hide Description Remission is defined as PHQ-9 total score <= 4. PHQ-9 is a 9-item, self-reporting scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. The scores are summed for a total score ranging from 0-27. A higher score indicates greater severity of depression. 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 recall period is 2 weeks. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “Endpoint”.
Time Frame Day 15 and Endpoint (last post-baseline assessment value during 4 weeks of IND phase)
Hide Outcome Measure Data
Hide Analysis Population Description
The full (IND) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'n' signifies those participants who were evaluable at specific time point for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 779
Measure Type: Number
Unit of Measure: Percentage of participants
Day 15 Number Analyzed 726 participants
12.7
Endpoint Number Analyzed 746 participants
26.9
32.Secondary Outcome
Title Percentage of Participants With an Increase Score From Predose at Any Time in Clinician-Administered Dissociative States Scale (CADSS) Total Score During IND Phase
Hide Description The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization (with score range from 0 to 28), derealization (with score range from 0 to 52), and amnesia (with score range from 0 to 8). Participants responses are coded on a 5-point scale (0 = “Not at all”, 1 = “Mild”, 2 = “Moderate”, 3 = ‘Severe” and 4 = “Extreme”). The total score is sum of the 23 items and range from 0 to 92, where 0 (best) and 92 (worst). A higher score indicates a more severe condition.
Time Frame Predose, up to 1.5 hours postdose (up to end of IND phase [Week 4])
Hide Outcome Measure Data
Hide Analysis Population Description
The full (IND) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral AD in open-label IND phase (for direct-entry and transferred-entry non-responder participants). Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 775
Measure Type: Number
Unit of Measure: Percentage of participants
92.0
33.Secondary Outcome
Title Percentage of Participants With an Increase Score From Predose at Any Time in CADSS Total Score During OP/MA Phase
Hide Description The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization (with score range from 0 to 28), derealization (with score range from 0 to 52), and amnesia (with score range from 0 to 8). Participants responses are coded on a 5-point scale (0 = “Not at all”, 1 = “Mild”, 2 = “Moderate”, 3 = ‘Severe” and 4 = “Extreme”). The total score is sum of the 23 items and range from 0 to 92, where 0 (best) and 92 (worst). A higher score indicates a more severe condition.
Time Frame Predose, up to 1.5 hours postdose (up to end of OP/MA phase [Week 52])
Hide Outcome Measure Data
Hide Analysis Population Description
The full (OP/MA) analysis set included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 603
Measure Type: Number
Unit of Measure: Percentage of participants
86.1
34.Secondary Outcome
Title Percentage of Participants With Treatment-Emergent Acute Hypertension (Systolic and Diastolic) During IND and OP/MA Phases
Hide Description Percentage of participants with treatment-emergent acute hypertension (Systolic Blood Pressure >=180 millimeters of mercury [mm Hg] or Diastolic Blood Pressure >= 110 mm Hg) during IND and OP/MA Phases were evaluated.
Time Frame Up to End of OP/MA phase (Week 52)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled analysis set included all transferred-entry and direct-entry participants who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant.
Arm/Group Title Intranasal Esketamine + Oral Antidepressant
Hide Arm/Group Description:
Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esketamine (Esk) twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 milligram (mg) (<65 years) and 28, 56 or 84 mg (>=65 years) in IND phase. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal esketamine weekly from week 5-8 of OP/MA phase. From Week 9-52, participants received Esk either weekly or every other week based on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants initiated new oral antidepressant (AD) (1 of: duloxetine/escitalopram/sertraline/venlafaxine extended release [XR]) on Day 1 of IND phase and continued during IND and OP/MA phase. TE participants continued same oral AD from TRD3005. No intranasal Esk was given in follow-up phase and same oral AD was continued at investigator’s clinical judgement.
Overall Number of Participants Analyzed 802
Measure Type: Number
Unit of Measure: Percentage of participants
Systolic BP >=180 2.2
Diastolic BP >=110 2.4
Acute hypertension 4.1
Time Frame Up to follow up phase (Week 56)
Adverse Event Reporting Description Population analyzed included all participants who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the respective phase (Induction, optimization or maintenance) and all participants who entered the follow-up phase.
 
Arm/Group Title IND: Intranasal Esketamine + Oral AD OP/MA: Intranasal Esketamine + Oral AD FU: Intranasal Esketamine + Oral AD
Hide Arm/Group Description Participants enrolled directly or TRD3005 non-responders self-administered intranasal Esk twice a week for 4 weeks as age dependent flexible dose according to titration regimen for 56 or 84 mg (age < 65 years) and 28, 56 or 84 mg (age >=65 years) in IND phase. DE participants initiated new oral AD (1 of: duloxetine/escitalopram/sertraline/venlafaxine XR) on Day 1 of IND phase. TE participants continued same oral AD from TRD3005. Participants who met response criteria at end of IND phase, entered OP/MA phase and received intranasal Esk from Week 5-8 of OP/MA phase at same dose as in IND phase. From Week 9-52, participants received Esk either weekly or every other week depending on MADRS score. TE (TRD3005 responders) joined OP/MA phase and received intranasal Esk 28, 56 or 84 mg weekly until week 8. DE participants continued oral AD (1 of: duloxetine/escitalopram/sertraline/venlafaxine XR) same as in IND phase during OP/MA phase. TE participants continued same oral AD from TRD3005. Participants received no intranasal esketamine and continued same oral AD at the investigator’s clinical judgement during 4-week follow-up (FU) phase.
All-Cause Mortality
IND: Intranasal Esketamine + Oral AD OP/MA: Intranasal Esketamine + Oral AD FU: Intranasal Esketamine + Oral AD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/779 (0.00%)   2/603 (0.33%)   0/357 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
IND: Intranasal Esketamine + Oral AD OP/MA: Intranasal Esketamine + Oral AD FU: Intranasal Esketamine + Oral AD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   17/779 (2.18%)   38/603 (6.30%)   8/357 (2.24%) 
Cardiac disorders       
Cardiac Failure Acute * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Gastrointestinal disorders       
Anal Incontinence * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Colitis Microscopic * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Haemorrhoids * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Large Intestinal Obstruction * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Oesophageal Ulcer * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Pancreatitis * 1  1/779 (0.13%)  0/603 (0.00%)  0/357 (0.00%) 
General disorders       
Pyrexia * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Hepatobiliary disorders       
Hepatitis Alcoholic * 1  0/779 (0.00%)  0/603 (0.00%)  1/357 (0.28%) 
Infections and infestations       
Bronchitis * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Dengue Fever * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Gastroenteritis * 1  0/779 (0.00%)  2/603 (0.33%)  0/357 (0.00%) 
Hepatitis B * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Pyelonephritis * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Pyelonephritis Acute * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Urinary Tract Infection * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Injury, poisoning and procedural complications       
Costochondral Separation * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Fibula Fracture * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Foot Fracture * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Overdose * 1  1/779 (0.13%)  0/603 (0.00%)  0/357 (0.00%) 
Poisoning * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Toxicity to Various Agents * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Investigations       
Transaminases Increased * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Back Pain * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Osteoarthritis * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Synovial Cyst * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Neoplasm Malignant * 1  0/779 (0.00%)  0/603 (0.00%)  1/357 (0.28%) 
Ovarian Cancer * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Nervous system disorders       
Headache * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Psychomotor Hyperactivity * 1  1/779 (0.13%)  0/603 (0.00%)  0/357 (0.00%) 
Pregnancy, puerperium and perinatal conditions       
Abortion Spontaneous * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Psychiatric disorders       
Alcohol Abuse * 1  1/779 (0.13%)  0/603 (0.00%)  0/357 (0.00%) 
Anxiety * 1  2/779 (0.26%)  0/603 (0.00%)  0/357 (0.00%) 
Completed Suicide * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Delirium * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Delusion * 1  1/779 (0.13%)  0/603 (0.00%)  0/357 (0.00%) 
Depression * 1  5/779 (0.64%)  3/603 (0.50%)  5/357 (1.40%) 
Depression Suicidal * 1  1/779 (0.13%)  0/603 (0.00%)  0/357 (0.00%) 
Intentional Self-Injury * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Major Depression * 1  1/779 (0.13%)  0/603 (0.00%)  0/357 (0.00%) 
Suicidal Ideation * 1  2/779 (0.26%)  4/603 (0.66%)  0/357 (0.00%) 
Suicide Attempt * 1  4/779 (0.51%)  2/603 (0.33%)  1/357 (0.28%) 
Renal and urinary disorders       
Stress Urinary Incontinence * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Tubulointerstitial Nephritis * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Vesical Fistula * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Reproductive system and breast disorders       
Menorrhagia * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Acute Respiratory Failure * 1  0/779 (0.00%)  1/603 (0.17%)  0/357 (0.00%) 
1
Term from vocabulary, MedDRA Version 20.0
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
IND: Intranasal Esketamine + Oral AD OP/MA: Intranasal Esketamine + Oral AD FU: Intranasal Esketamine + Oral AD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   587/779 (75.35%)   454/603 (75.29%)   24/357 (6.72%) 
Ear and labyrinth disorders       
Vertigo * 1  68/779 (8.73%)  43/603 (7.13%)  1/357 (0.28%) 
Eye disorders       
Vision Blurred * 1  49/779 (6.29%)  25/603 (4.15%)  0/357 (0.00%) 
Gastrointestinal disorders       
Diarrhoea * 1  27/779 (3.47%)  39/603 (6.47%)  2/357 (0.56%) 
Hypoaesthesia Oral * 1  63/779 (8.09%)  28/603 (4.64%)  0/357 (0.00%) 
Nausea * 1  157/779 (20.15%)  84/603 (13.93%)  2/357 (0.56%) 
Vomiting * 1  56/779 (7.19%)  45/603 (7.46%)  2/357 (0.56%) 
General disorders       
Fatigue * 1  40/779 (5.13%)  28/603 (4.64%)  1/357 (0.28%) 
Infections and infestations       
Influenza * 1  4/779 (0.51%)  40/603 (6.63%)  0/357 (0.00%) 
Upper Respiratory Tract Infection * 1  8/779 (1.03%)  35/603 (5.80%)  3/357 (0.84%) 
Urinary Tract Infection * 1  26/779 (3.34%)  48/603 (7.96%)  7/357 (1.96%) 
Viral Upper Respiratory Tract Infection * 1  19/779 (2.44%)  70/603 (11.61%)  1/357 (0.28%) 
Investigations       
Blood Pressure Increased * 1  53/779 (6.80%)  46/603 (7.63%)  0/357 (0.00%) 
Musculoskeletal and connective tissue disorders       
Back Pain * 1  14/779 (1.80%)  33/603 (5.47%)  1/357 (0.28%) 
Nervous system disorders       
Dizziness * 1  228/779 (29.27%)  135/603 (22.39%)  1/357 (0.28%) 
Dizziness Postural * 1  54/779 (6.93%)  41/603 (6.80%)  1/357 (0.28%) 
Dysgeusia * 1  77/779 (9.88%)  54/603 (8.96%)  0/357 (0.00%) 
Headache * 1  137/779 (17.59%)  114/603 (18.91%)  4/357 (1.12%) 
Hypoaesthesia * 1  79/779 (10.14%)  40/603 (6.63%)  0/357 (0.00%) 
Paraesthesia * 1  46/779 (5.91%)  26/603 (4.31%)  1/357 (0.28%) 
Sedation * 1  51/779 (6.55%)  29/603 (4.81%)  0/357 (0.00%) 
Somnolence * 1  94/779 (12.07%)  85/603 (14.10%)  0/357 (0.00%) 
Psychiatric disorders       
Anxiety * 1  49/779 (6.29%)  26/603 (4.31%)  1/357 (0.28%) 
Dissociation * 1  182/779 (23.36%)  113/603 (18.74%)  1/357 (0.28%) 
Insomnia * 1  40/779 (5.13%)  34/603 (5.64%)  1/357 (0.28%) 
1
Term from vocabulary, MedDRA Version 20.0
*
Indicates events were collected by non-systematic assessment
Protocol defined study will be completed when at least 300 participants reach 26 weeks and 100 reach 52 weeks of treatment with esketamine. Discontinuation due to "Study terminated by sponsor" reflects reaching these prespecified completion criteria.
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
Layout table for additonal information
Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT02497287     History of Changes
Other Study ID Numbers: CR107148
ESKETINTRD3004 ( Other Identifier: Janssen Research & Development, LLC )
2014-004587-38 ( EudraCT Number )
First Submitted: May 18, 2015
First Posted: July 14, 2015
Results First Submitted: April 3, 2019
Results First Posted: April 29, 2019
Last Update Posted: May 21, 2019