A Phase 3 interventional study of Esketamine Nasal Spray in Depressive Disorder, Treatment-Resistant, sponsored by Janssen Research & Development, LLC. Completed at 177 sites in 26 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-04-29.
Sponsored by Janssen Research & Development, LLC · Phase 3, Interventional, and Treatment
The purpose of this study is to assess the safety and tolerability of esketamine nasal spray in participants with treatment-resistant depression (TRD).
This is an open-label (the researchers and participants know the treatment the participant is receiving) long-term extension study. The study will consist of 2 open-label Phases: 4-week Induction phase (if applicable) and Open-Label Optimization/Maintenance phase (variable). Participants will enter the study Induction Phase from ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), ESKETINTRD3003 (NCT02493868), ESKETINTRD3005 (NCT02422186) and ESKETINTRD3006 (US sites only). Participants will enter the study Open-Label Optimization/Maintenance phase from ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), ESKETINTRD3003 (NCT02493868) (if appropriate at week 16) or ESKETINTRD3006 (US sites only). In the Open-Label Induction Phase, participants will self-administer flexibly-dosed esketamine nasal spray. During first 4 weeks in Optimization/Maintenance Phase responder participants from the induction phase of study 54135419TRD3008, will continue on the same dose of esketamine nasal spray from the induction phase and have a weekly intranasal treatment session frequency. Participants entering the optimization/maintenance phase from study ESKETINTRD3005 will also have a weekly intranasal treatment session frequency. However, as the ESKETINTRD3005 intranasal study medication is blinded at the time of entry into the current study, the dose of esketamine nasal spray will be administered as outlined in protocol. Participants entering the optimization/maintenance phase from study ESKETINTRD3003 (Direct Entry) or ESKETINTRD3004 who were ongoing in the Optimization, Maintenance, or Optimization/Maintenance phase, respectively, will have the option to have their current intranasal dosing frequency adjusted at the time of entry into 54135419TRD3008 study and should remain on the selected frequency from week 1 to week 4. A one-time dose change will be permitted at study entry. After 4 weeks, esketamine nasal spray treatment sessions will be individualized to either once weekly or once every other week at the fixed 2-week interval (based on clinical global impression - severity [CGI-S] performed at that visit), and every 4 weeks for participants dosed at the 4 week interval. Participants safety will be monitored throughout the study.
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Exclusion Criteria:
Open-Label Induction Phase: Participants will self-administer with esketamine nasal spray twice per week for 4 weeks as a flexible dose regimen (56 milligram \[mg\] or 84 mg for those \< 65 years; 28 mg, 56 mg or 84 mg for those \>= 65 years). Participants \>= 65 years old will start at a dose of 28 mg on Day 1. Optimization/Maintenance Phase: Participants entering from studies ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), ESKETINTRD3003 (NCT02493868), ESKETINTRD3004 (NCT02497287), or ESKETINTRD3006 (US sites only) will self-administer esketamine nasal spray (same dose) once weekly. Participants entering from study ESKETINTRD3005 (NCT02422186) will self-administer esketamine nasal spray (28 mg in week 1; 28 or 56 mg in week 2; and 28, 56 or 84 mg in week 3 and 4) once weekly. After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants can be adjusted based upon efficacy and tolerability.
Drug: Esketamine Nasal Spray
Open-Label Induction Phase: Participants will self-administer with esketamine nasal spray twice per week for 4 weeks as a flexible dose regimen (56 milligram \[mg\] or 84 mg for those \< 65 years; 28 mg, 56 mg or 84 mg for those \>= 65 years). Participants \>= 65 years old will start at a dose of 28 mg on Day 1. Optimization/Maintenance Phase: Participants entering from studies ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585) or ESKETINTRD3006 (US sites only) will self-administer esketamine nasal spray (same dose) once weekly. Participants entering from study ESKETINTRD3005 (NCT02422186) will self-administer esketamine nasal spray (28 mg in week 1; 28 or 56 mg in week 2; and 28, 56 or 84 mg in week 3 and 4) once weekly. After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants can be adjusted based upon efficacy and tolerability.
Also known as: JNJ-54135419
Change From Study Baseline in Computerized Cognitive Battery Domain Score: Detection Test (DET) Score
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. The DET is a measure of psychomotor function and uses a well-validated simple reaction time. In this outcome measure, speed of performance of subjects (calculated as mean of the logarithmic base 10 transformed reaction times) for correct responses was reported. Total score ranged from 2 to 3.3 log 10 milliseconds (msec). Lower score indicated better performance. Higher change from baseline indicated better performance.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Study Baseline in Computerized Cognitive Battery Domain Score: Identification Test (IDN) Score
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. IDN test is a measure of visual attention (choice reaction time) and scored for speed of response (mean of the log10 transformed reaction times for correct responses). Total score ranged from 2 to 3.3 log 10 msec. Lower score indicated better performance. Higher change from baseline indicated better performance.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Study Baseline in Computerized Cognitive Battery Domain Score: One Card Learning Test (OCL) Score
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. OCL test is a measure of visual episodic memory and visual recall test scored using arcsine transformation of the percentage of correct responses (CR). The range for OCL is 0 to 100 percent (%) accuracy; presented as an arcsin transformation, the range is 0 to 1.57. Higher score indicated better performance. Higher change from baseline indicated better performance.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Study Baseline in Computerized Cognitive Battery Domain Score: One Back Test (ONB) Score
The ONB is a measure of working memory and scored for speed of correct response (mean of the log10-transformed reaction times for correct responses). Total score ranged from 2 to 3.54 log10 msec. Lower score indicated better performance. Higher change from baseline indicated better performance.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Study Baseline in Computerized Cognitive Battery Domain Score: Groton Maze Learning Test (GMLT) Score
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. GMLT measures executive function; maze/sequencing test, scored for total number of errors. Total score ranged from 0 to 999 number of errors. Lower score indicated better performance. Higher change from baseline indicated better performance.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Study Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score
The HVLT-R measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0-12); the total number of true-positive errors (0-12); and the range of recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher total recall score indicated higher cognition. The range of the recognition discrimination index is -12 to 12. Higher score indicated better performance and higher change from baseline indicated better performance.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Percentage of Participants Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Score
C-SSRS: interview-based instrument to systematically assess suicidal ideation (SI) and behavior, to assess whether participant experienced any of following: completed suicide, suicide attempt (response of "yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior ("yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("yes" on "wish to be dead", "non-specific active suicidal thoughts", "active SI with methods without intent to act or some intent to act, without or with specific plan and intent), any self-injurious behavior with no suicidal intent ("yes" on "has participant engaged in non-suicidal self-injurious behavior"). Here, percentage of participants with \>=1 positive behavior, participants with \>=1 positive ideations; no event were reported.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. Any AE occurring at or after the initial administration of study intervention up to end of study was considered as treatment-emergent.
Time frame: IND Phase: up to 4 weeks; OP/MA Phase: up to 78 months
Change From Baseline in Heart Rate
Change from baseline (predose) in heart rate were reported.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Baseline in Systolic and Diastolic Blood Pressure
Change from baseline in systolic and diastolic blood pressure were reported.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Baseline in Respiratory Rate
Change from baseline in respiratory rate were reported.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Baseline in Blood Oxygen Saturation
Change from baseline in blood oxygen saturation (predose) were reported.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score
MADRS measures depression severity, detects changes due to AD treatment. It consists of 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe conditions. Negative change in score indicates improvement. Missing data was imputed using last observation carried forward (LOCF) method.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Baseline in Participant-Reported Depressive Symptoms Using the Patient Health Questionnaire - 9 (PHQ-9) Total Score
Change from baseline in PHQ-9 total score were reported. The PHQ-9 was a 9-item, patient-reported outcome measure to assess depressive symptoms. The scale scores each of the 9 symptom domains of the Diagnostic and Statistical Manual of Mental Disorders. Each item was rated on a 4-point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses were summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Baseline in Clinical Global Impression-severity (CGI-S) Score
Change from baseline in clinical global impression-severity (CGI-S) score were reported. The CGI-S provides an overall clinician-determined summary measure of the severity of the participant's illness that takes into account all available information, including knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 1 to 7. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating according to: 1 = normal (not at all ill); 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. Negative change in score indicates improvement.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Baseline in Sheehan Disability Scale (SDS) Total Score
Change from baseline in SDS total score were reported. The SDS, a patient-reported outcome measure, was a 5 item questionnaire which had been widely used and accepted for assessment of functional and associated disability impairment. The first three items assessed disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items were summed to create a total score of 0-30 where a higher score indicated greater impairment.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Baseline in Participant-Reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Valuation Index Score (VAS)
Change from baseline in participant-reported health-related quality of life as assessed by EQ-5D-5L VAS was reported. The EQ-5D-5L is a standardized 2-part instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. It essentially consists of the EQ-5D-5L descriptive system and the EQ-VAS. EQ-VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Positive change in score indicates improvement.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Baseline as Assessed by EQ 5D-5L: Sum Score
EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) \*5. Higher score indicates worst health state.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
Change From Baseline in Participant- Reported Health Related Quality of Life Using the Quality of Life in Depression Scale (QLDS)
Change from baseline in participant- reported health related quality of life using the QLDS. The QLDS is a disease-specific validated patient-reported outcome (PRO) measure which assesses the impact that depression has on a participant's quality of life. It is a 34-item self-rated questionnaire which consists of dichotomous response questions, with the response being either True/Not True. Each statement on the QLDS is given a score of "1" or "0". A score of "1" is indicative of adverse quality of life. All item scores are summed to give a total score that ranges from 0 (good quality of life) to 34 (very poor quality of life). A higher score indicates a more severe condition.
Time frame: IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
| Milestone | Esketamine Nasal Spray |
|---|---|
| Started | 1148 |
| Ind phase | 458 |
| Op/ma phase | 1110 |
| Completed | 680 |
| Not completed | 468 |
| Withdrew: Other | 215 |
| Withdrew: Induction day 28 non responder | 9 |
| Withdrew: Non-compliance with study drug | 2 |
| Withdrew: Death | 8 |
| Withdrew: Pregnancy | 6 |
| Withdrew: Withdrawal by subject | 63 |
| Withdrew: Protocol violation | 7 |
| Withdrew: Lack of efficacy | 61 |
| Withdrew: Lost to follow-up | 23 |
| Withdrew: Adverse event | 74 |
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. The DET is a measure of psychomotor function and uses a well-validated simple reaction time. In this outcome measure, speed of performance of subjects (calculated as mean of the logarithmic base 10 transformed reaction times) for correct responses was reported. Total score ranged from 2 to 3.3 log 10 milliseconds (msec). Lower score indicated better performance. Higher change from baseline indicated better performance.
| log10 msec | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Study Baseline in Computerized Cognitive Battery Domain Score: Detection Test (DET) Score | 0.0218 ± 0.10516 | -0.0065 ± 0.13526 |
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. IDN test is a measure of visual attention (choice reaction time) and scored for speed of response (mean of the log10 transformed reaction times for correct responses). Total score ranged from 2 to 3.3 log 10 msec. Lower score indicated better performance. Higher change from baseline indicated better performance.
| log10 msec | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Study Baseline in Computerized Cognitive Battery Domain Score: Identification Test (IDN) Score | 0.0074 ± 0.07819 | -0.0185 ± 0.09893 |
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. OCL test is a measure of visual episodic memory and visual recall test scored using arcsine transformation of the percentage of correct responses (CR). The range for OCL is 0 to 100 percent (%) accuracy; presented as an arcsin transformation, the range is 0 to 1.57. Higher score indicated better performance. Higher change from baseline indicated better performance.
| Arcsine (sqrt of percentage of CR) | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Study Baseline in Computerized Cognitive Battery Domain Score: One Card Learning Test (OCL) Score | 0.0170 ± 0.12356 | 0.0397 ± 0.15364 |
The ONB is a measure of working memory and scored for speed of correct response (mean of the log10-transformed reaction times for correct responses). Total score ranged from 2 to 3.54 log10 msec. Lower score indicated better performance. Higher change from baseline indicated better performance.
| log10 msec | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Study Baseline in Computerized Cognitive Battery Domain Score: One Back Test (ONB) Score | 0.0086 ± 0.08096 | 0.0198 ± 0.10329 |
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. GMLT measures executive function; maze/sequencing test, scored for total number of errors. Total score ranged from 0 to 999 number of errors. Lower score indicated better performance. Higher change from baseline indicated better performance.
| Number of Errors | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Study Baseline in Computerized Cognitive Battery Domain Score: Groton Maze Learning Test (GMLT) Score | 1.5 ± 17.80 | 5.1 ± 22.52 |
The HVLT-R measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0-12); the total number of true-positive errors (0-12); and the range of recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher total recall score indicated higher cognition. The range of the recognition discrimination index is -12 to 12. Higher score indicated better performance and higher change from baseline indicated better performance.
| score on a scale | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Total Recall | -0.1 ± 4.05 | 0.8 ± 5.05 |
| Delayed Recall | 0.3 ± 3.81 | 0.3 ± 2.03 |
| Total Number of True Positives | 0.1 ± 2.54 | -0.0 ± 2.70 |
| Recognition Discrimination Index | -0.1 ± 2.88 | -0.1 ± 3.10 |
C-SSRS: interview-based instrument to systematically assess suicidal ideation (SI) and behavior, to assess whether participant experienced any of following: completed suicide, suicide attempt (response of "yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior ("yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("yes" on "wish to be dead", "non-specific active suicidal thoughts", "active SI with methods without intent to act or some intent to act, without or with specific plan and intent), any self-injurious behavior with no suicidal intent ("yes" on "has participant engaged in non-suicidal self-injurious behavior"). Here, percentage of participants with \>=1 positive behavior, participants with \>=1 positive ideations; no event were reported.
| Percentage of participants | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Baseline: No Event | 79.8 | 94.8 |
| Baseline: Suicidal ideation | 20.2 | 5.2 |
| Baseline: Suicidal behavior | 0 | 0 |
| Most Severe Post Baseline: No Event | 77.4 | 70.2 |
| Most Severe Post Baseline: Suicidal ideation | 22.6 | 27.8 |
| Most Severe Post Baseline: Suicidal behavior | 0 | 2.0 |
An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. Any AE occurring at or after the initial administration of study intervention up to end of study was considered as treatment-emergent.
| Participants | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 346 | 1052 |
Change from baseline (predose) in heart rate were reported.
| beats per minute | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Baseline in Heart Rate | 0.4 ± 9.52 | 0.8 ± 10.47 |
Change from baseline in systolic and diastolic blood pressure were reported.
| Millimeters of mercury (mmHg) | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Systolic Blood Pressure | 0.4 ± 10.72 | 5.8 ± 12.68 |
| Diastolic Blood Pressure | 0.3 ± 7.47 | 2.7 ± 8.78 |
Change from baseline in respiratory rate were reported.
| breaths per minute | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Baseline in Respiratory Rate | -0.1 ± 2.51 | -0.4 ± 2.83 |
Change from baseline in blood oxygen saturation (predose) were reported.
| percentage of SpO2 | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Baseline in Blood Oxygen Saturation | -0.1 ± 1.54 | -0.1 ± 1.63 |
MADRS measures depression severity, detects changes due to AD treatment. It consists of 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 0 to 60. Higher scores indicate more severe conditions. Negative change in score indicates improvement. Missing data was imputed using last observation carried forward (LOCF) method.
| score on a Scale | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | -12.8 ± 9.73 | 0.2 ± 9.93 |
Change from baseline in PHQ-9 total score were reported. The PHQ-9 was a 9-item, patient-reported outcome measure to assess depressive symptoms. The scale scores each of the 9 symptom domains of the Diagnostic and Statistical Manual of Mental Disorders. Each item was rated on a 4-point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses were summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms.
| score on a scale | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Baseline in Participant-Reported Depressive Symptoms Using the Patient Health Questionnaire - 9 (PHQ-9) Total Score | -5.8 ± 5.84 | 0.6 ± 6.22 |
Change from baseline in clinical global impression-severity (CGI-S) score were reported. The CGI-S provides an overall clinician-determined summary measure of the severity of the participant's illness that takes into account all available information, including knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 1 to 7. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating according to: 1 = normal (not at all ill); 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. Negative change in score indicates improvement.
| score on a scale | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Baseline in Clinical Global Impression-severity (CGI-S) Score | -1.0 (-5.0 to 1) | 0.0 (-5 to 4) |
Change from baseline in SDS total score were reported. The SDS, a patient-reported outcome measure, was a 5 item questionnaire which had been widely used and accepted for assessment of functional and associated disability impairment. The first three items assessed disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items were summed to create a total score of 0-30 where a higher score indicated greater impairment.
| score on a scale | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Baseline in Sheehan Disability Scale (SDS) Total Score | -6.4 ± 7.13 | -0.1 ± 8.35 |
Change from baseline in participant-reported health-related quality of life as assessed by EQ-5D-5L VAS was reported. The EQ-5D-5L is a standardized 2-part instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. It essentially consists of the EQ-5D-5L descriptive system and the EQ-VAS. EQ-VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Positive change in score indicates improvement.
| score on a scale | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Baseline in Participant-Reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Valuation Index Score (VAS) | 13.0 ± 18.05 | 0.7 ± 18.95 |
EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) \*5. Higher score indicates worst health state.
| score on a scale | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Baseline as Assessed by EQ 5D-5L: Sum Score | -10.4 ± 12.81 | 2.9 ± 15.88 |
Change from baseline in participant- reported health related quality of life using the QLDS. The QLDS is a disease-specific validated patient-reported outcome (PRO) measure which assesses the impact that depression has on a participant's quality of life. It is a 34-item self-rated questionnaire which consists of dichotomous response questions, with the response being either True/Not True. Each statement on the QLDS is given a score of "1" or "0". A score of "1" is indicative of adverse quality of life. All item scores are summed to give a total score that ranges from 0 (good quality of life) to 34 (very poor quality of life). A higher score indicates a more severe condition.
| score on a scale | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| Change From Baseline in Participant- Reported Health Related Quality of Life Using the Quality of Life in Depression Scale (QLDS) | -8.2 ± 8.47 | 0.1 ± 9.47 |
Collected over IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Esketamine Nasal Spray (IND Phase) | 1/458 (0.2%) | 5/458 (1.1%) | 318/458 (69.4%) |
| Esketamine Nasal Spray (OP/MA Phase) | 8/1,110 (0.7%) | 212/1,110 (19.1%) | 1,010/1,110 (91%) |
| Event | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| DepressionPsychiatric disorders | 0/458 | 18/1110 |
| Suicide AttemptPsychiatric disorders | 0/458 | 15/1110 |
| Suicidal IdeationPsychiatric disorders | 0/458 | 11/1110 |
| CholelithiasisHepatobiliary disorders | 0/458 | 10/1110 |
| Covid-19Infections and infestations | 0/458 | 9/1110 |
| PneumoniaInfections and infestations | 0/458 | 7/1110 |
| NephrolithiasisRenal and urinary disorders | 0/458 | 6/1110 |
| Atrial FibrillationCardiac disorders | 0/458 | 5/1110 |
| AnxietyPsychiatric disorders | 0/458 | 5/1110 |
| Back PainMusculoskeletal and connective tissue disorders | 2/458 | 2/1110 |
| Event | Esketamine Nasal Spray (IND Phase) | Esketamine Nasal Spray (OP/MA Phase) |
|---|---|---|
| HeadacheNervous system disorders | 70/458 | 401/1110 |
| DizzinessNervous system disorders | 95/458 | 365/1110 |
| NauseaGastrointestinal disorders | 82/458 | 356/1110 |
| DissociationPsychiatric disorders | 100/458 | 272/1110 |
| NasopharyngitisInfections and infestations | 13/458 | 267/1110 |
| SomnolenceNervous system disorders | 43/458 | 253/1110 |
| Back PainMusculoskeletal and connective tissue disorders | 5/458 | 226/1110 |
| DysgeusiaNervous system disorders | 77/458 | 217/1110 |
| VertigoEar and labyrinth disorders | 77/458 | 198/1110 |
| AnxietyPsychiatric disorders | 30/458 | 197/1110 |
| Age, Continuous(years) | Esketamine Nasal Spray |
|---|---|
| Mean | 49.6 ± 12.28 |
| Sex: Female, Male(Participants) | Esketamine Nasal Spray |
|---|---|
| Female | 764 |
| Male | 384 |
| Ethnicity (NIH/OMB)(Participants) | Esketamine Nasal Spray |
|---|---|
| Hispanic or Latino | 200 |
| Not Hispanic or Latino | 922 |
| Unknown or Not Reported | 26 |
| Race/Ethnicity, Customized(Participants) | Esketamine Nasal Spray |
|---|---|
| American Indian or Alaska Native | 1 |
| Asian | 45 |
| Black or African American | 45 |
| Native Hawaiian or Other Pacific Islander | 0 |
| White | 996 |
| More than one race | 10 |
| Unknown or Not Reported | 22 |
| Other | 29 |
| Region of Enrollment(Participants) | Esketamine Nasal Spray |
|---|---|
| ARGENTINA | 71 |
| AUSTRALIA | 16 |
| AUSTRIA | 4 |
| BELGIUM | 18 |
| BRAZIL | 100 |
| BULGARIA | 50 |
| CANADA | 15 |
| CZECH REPUBLIC | 90 |
| ESTONIA | 9 |
| FINLAND | 1 |
| FRANCE | 23 |
| GERMANY | 13 |
| HUNGARY | 20 |
| ITALY | 8 |
| LITHUANIA | 2 |
| MALAYSIA | 9 |
| MEXICO | 46 |
| POLAND | 101 |
| SLOVAKIA | 9 |
| SOUTH AFRICA | 48 |
| SOUTH KOREA | 7 |
| SPAIN | 41 |
| SWEDEN | 65 |
| TAIWAN | 22 |
| TURKEY | 24 |
| UNITED KINGDOM | 8 |
| UNITED STATES | 328 |
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