A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive Disorder (ESCAPE-TRD)

• ClinicalTrials.gov Identifier: NCT04338321
• Recruitment Status: Completed
• First Posted: April 8, 2020
• Results First Posted: February 15, 2023
• Last Update Posted: October 24, 2023
• Sponsor: Janssen-Cilag International NV
• Information provided by (Responsible Party): Janssen-Cilag International NV

Study Description

Brief Summary:

The primary purpose of this study is to evaluate the efficacy of flexibly dosed esketamine nasal spray compared with quetiapine extended-release (XR), both in combination with a continuing selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI), in achieving remission in participants who have treatment-resistant major depressive disorder (MDD) with a current moderate to severe depressive episode.

Condition or disease	Intervention/treatment	Phase
Depressive Disorder, Major	Drug: Esketamine 28 mg; Drug: Esketamine 56 mg; Drug: Esketamine 84 mg; Drug: Quetiapine XR 50 mg; Drug: Quetiapine XR 100 mg; Drug: Quetiapine XR 150 mg; Drug: SSRI/SNRI	Phase 3

Detailed Description:

A depressive state with classical symptoms such as low (depressive/sad) mood, markedly diminished interest in activities, significant weight loss/gain, insomnia or hypersomnia, psychomotor agitation/retardation, excessive fatigue, inappropriate guilt, diminished concentration, and recurrent thoughts of death, persisting for more than 2 weeks is classified as major depressive disorder (MDD). The mechanism of action of ketamine is distinct from conventional antidepressants (ADs), which target the monoamines (serotonin, norepinephrine, and/or dopamine). Esketamine, the S-enantiomer of ketamine, is approved and widely used for the induction and maintenance of anesthesia via intramuscular or intravenous (IV) administration. There is a significant unmet need to develop novel AD treatments based on the relevant psychophysiological pathways underlying MDD. The goal of any novel treatment would be the rapid and long-lasting relief of depressive symptoms, especially in participants with treatment-resistant depression (TRD), who lack a sufficient response to the currently available treatment strategies. The study consists of a Screening Phase (up to 14 days), an Acute Phase (8 Weeks), a Maintenance Phase (24 Weeks) and a Safety Follow-up Phase (2 Weeks). Safety assessment includes adverse event, serious adverse events, physical examination, vital signs, electrocardiogram, clinical safety laboratory assessments, suicidal risk monitoring. The total duration of the study is approximately 36 Weeks for all participants.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 676 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-label, Rater-Blinded, Active-Controlled, International, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Flexibly Dosed Esketamine Nasal Spray Compared With Quetiapine Extended-Release in Adult and Elderly Participants With Treatment-Resistant Major Depressive Disorder Who Are Continuing a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor
• Actual Study Start Date: August 21, 2020
• Actual Primary Completion Date: January 20, 2022
• Actual Study Completion Date: July 15, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Esketamine Arm; Participants will receive treatment with esketamine nasal spray (28 milligram [mg] [initial dose for elderly participants 65 to 74 years of age and adults of Japanese ancestry; may be used throughout the study in these populations; may be uptitrated in 28 mg increments], 56 mg [initial dose for adult participants aged 18 to 64 years and may be used for all age groups throughout the study], or 84 mg [maximum dose esketamine nasal spray may be uptitrated to]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI).	Drug: Esketamine 28 mg; Esketamine will be self-administered at a dose of 28 mg as nasal spray.; Drug: Esketamine 56 mg; Esketamine will be self-administered at a dose of 56 mg as nasal spray.; Drug: Esketamine 84 mg; Esketamine will be self-administered at a dose of 84 mg (maximum uptitrated dose) as nasal spray.; Drug: SSRI/SNRI; Participants will continue to take SSRI/SNRI that is approved for use in depression in their country of participation; off-label use of any SSRI/SNRI is not permitted. The continuing SSRI/SNRI dosage may be optimized throughout the study, at the investigator's discretion and based on the SmPC (or local equivalent, if applicable).
Active Comparator: Comparator Arm; Participants will continue to take their current SSRI/SNRI augmented with quetiapine extended release (XR) as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable). In adult participants aged 18 to 64 years, the initial dose is 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 [lowest effective dose]; a further dose increase to 300 mg/day on Day 5 and onward will be based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose is 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day will be based on individual participant evaluation no earlier than Day 22.	Drug: Quetiapine XR 50 mg; Quetiapine XR will be administered at an initial dose of 50 mg/day and may be further increased to 300 mg/day based on individual participant evaluation.; Drug: Quetiapine XR 100 mg; Quetiapine XR will be administered at a dose of 100 mg/day and may be further increased to 300 mg/day based on individual participant evaluation.; Drug: Quetiapine XR 150 mg; Quetiapine XR will be administered at a dose of 150 mg/day and may be further increased to 300 mg/day based on individual participant evaluation.; Drug: SSRI/SNRI; Participants will continue to take SSRI/SNRI that is approved for use in depression in their country of participation; off-label use of any SSRI/SNRI is not permitted. The continuing SSRI/SNRI dosage may be optimized throughout the study, at the investigator's discretion and based on the SmPC (or local equivalent, if applicable).

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Remission as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) Score at Week 8 [ Time Frame: Week 8 ]
   Percentage of participants with remission as assessed by the MADRS at Week 8 was reported. The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts. A participant was defined as being in remission if the MADRS total score was less than or equal to (<=)10 and no treatment or study discontinuation before Week 8.

Secondary Outcome Measures :

1. Percentage of Participants With Both Remission at Week 8 and Relapse-free Until Week 32 [ Time Frame: Week 32 ]
   Percentage of participants with both remission at Week 8 and relapse-free until Week 32 were reported. A participant was defined as being in remission if the MADRS total score was <= 10 and no treatment or study discontinuation before Week 8. A relapse was defined by any of following: a) Worsening of depressive symptoms as indicated by MADRS total score greater than or equal to (>=) 22 confirmed by 1 additional assessment of MADRS total score >= 22 within the next 5 to 15 days. The date of the second MADRS assessment was used for the date of relapse; b) Any psychiatric hospitalization for: worsening of depression, suicide prevention or suicide attempt, the start date of hospitalization was the date of relapse; c) Suicide attempt, completed suicide, or any other clinically relevant event determined by investigator's judgment to be indicative of a relapse of depressive illness, but without hospitalized. The onset of the event was used for the date of relapse.
2. Change From Baseline in Clinician-rated Overall MADRS Score [ Time Frame: Baseline, Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 ]
   Change from baseline in clinician-rated overall MADRS score was reported. The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), summed up for a total possible score range of 0 to 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts.
3. Change From Baseline in Clinician-rated Overall MADRS Score at Last Observation Carried Forward (LOCF) [ Time Frame: Baseline, LOCF at Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 ]
   Change from baseline in clinician-rated overall MADRS score at LOCF was reported. The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), summed up for a total possible score range of 0 to 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.
4. Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Severity (CGI-S) Scale Score [ Time Frame: Baseline, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32 ]
   Change from baseline in clinician-rated overall severity of depressive illness as assessed by CGI-S scale score was 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.
5. Change From Baseline in Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-S Scale Score at LOCF [ Time Frame: Baseline, LOCF at Weeks 2, 3, 4, 8, 12, 16, 20, 24, 28, 32 ]
   Change from Baseline in clinician-rated overall severity of depressive illness as assessed by CGI-S scale score at LOCF was 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. 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. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.
6. Clinician-rated Overall Severity of Depressive Illness as Assessed by Clinical Global Impression - Change (CGI-C) Scale Score [ Time Frame: Baseline, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32 ]
   Clinician-rated overall severity of depressive illness as assessed by CGI-C scale score was reported. The CGI-C evaluates the total improvement whether or not entirely due to drug treatment on a scale of 1 to 7. Compared to the condition at baseline, a participant is assessed on how much he/she has changed, according to: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse. Higher scores indicate more severity.
7. Number of Participants With Clinician-rated Overall Severity of Depressive Illness as Assessed by CGI-C Scale Score at LOCF [ Time Frame: Baseline, LOCF at Weeks 2, 3, 4, 8, 12, 16, 20, 24, 28, 32 ]
   Number of participants with clinician-rated overall severity of depressive illness as assessed by CGI-C scale score at LOCF was reported. The CGI-C evaluates the total improvement whether or not entirely due to drug treatment on a scale of 1 to 7. Compared to the condition at baseline, a participant is assessed on how much he/she has changed, according to: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse. Higher scores indicate more severity. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.
8. Change From Baseline in Participant-reported Depressive Symptoms as Assessed by Patient Health Questionnaire (PHQ) 9-item Total Score [ Time Frame: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 ]
   Change from baseline in participant-reported depressive symptoms as assessed by PHQ 9-item total score was reported. The PHQ-9 is a validated 9-item, patient-reported outcome (PRO) measure to assess depressive symptoms. Each item is rated on a 4-point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses are summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19) and Severe (20-27).
9. Change From Baseline in Participant-reported Depressive Symptoms as Assessed by PHQ 9-item Total Score at LOCF [ Time Frame: Baseline, LOCF at Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 ]
   Change from baseline in participant-reported depressive symptoms as assessed by PHQ 9-item total score at LOCF was reported. The PHQ-9 is a validated 9-item, PRO measure to assess depressive symptoms. Each item is rated on a 4-point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses are summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19) and Severe (20-27). LOCF is defined as participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.
10. Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by Sheehan Disability Scale (SDS) Total Score [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32 ]
    Change from baseline in participant-reported functional impairment and associated disability as assessed by SDS total score was reported. The SDS is a validated PRO measure consisting of a 5-item questionnaire that has been widely used and accepted for assessment of functional impairment and associated disability. The first 3 items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a rating scale from 0 to 10. It also has 1 item assessing days lost from school or work and 1 item assessing days of underproductivity. The scores for the first 3 items are summed to create a total score of 0 to 30, where higher score indicates greater impairment. Scores <=2 for each item and <= 6 for the total score are considered functional remission.
11. Change From Baseline in Participant-reported Functional Impairment and Associated Disability as Assessed by SDS Total Score at LOCF [ Time Frame: Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32 ]
    Change from baseline in participant-reported functional impairment and associated disability as assessed by SDS total score at LOCF was reported. The SDS is a validated PRO measure consisting of a 5-item questionnaire for assessment of functional impairment and associated disability. The first 3 items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a rating scale from 0 to 10. It also has 1 item assessing days lost from school or work and 1 item assessing days of underproductivity. The scores for the first 3 items are summed to create a total score of 0 to 30, where higher score indicates greater impairment. Scores <=2 for each item and <= 6 for the total score are considered functional remission. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.
12. Change From Baseline in Participant-reported Health-related Quality of Life (HRQoL) and Health Status as Assessed by 36-item Short-Form Health Survey (SF-36) Scale Score [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32 ]
    Change from baseline in participant-reported HRQoL and health status as assessed by SF-36 scale score was reported. The SF-36 consists of 8 subscales (physical function, role limitations due to physical problems, pain, general health perception, vitality, social function, role limitations due to emotional problems, and mental health). Participants self-report on items in a subscale that have between 2-6 choices per item using likert-type responses (for example: none of the time, some of the time, etc.). Summations of item scores of the same subscale give the subscale scores, which are transformed into a range from 0 to 100; 0= worst HRQoL, 100=best HRQoL. Higher scores indicate better health status.
13. Change From Baseline in Participant-reported HRQoL and Health Status as Assessed by SF-36 Scale Score at LOCF [ Time Frame: Baseline, LOCF at Weeks 8, 12, 16, 20, 24, 28, 32 ]
    Change from baseline in participant-reported HRQoL and health status as assessed by SF-36 domain scores at LOCF was reported. The SF-36 consists of 8 subscales (physical function, role limitations due to physical problems, pain, general health perception, vitality, social function, role limitations due to emotional problems, and mental health). Participants self-report on items in a subscale that have between 2-6 choices per item using likert-type responses (for example: none of the time, some of the time, etc.). Summations of item scores of the same subscale give the subscale scores, which are transformed into a range from 0 to 100; 0= worst HRQoL, 100=best HRQoL. Higher scores indicate better health status. LOCF is defined as participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.
14. Change From Baseline in Participant-reported Quality of Life as Assessed by Quality of Life in Depression Scale (QLDS) Total Score [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32 ]
    Change from baseline in participant-reported quality of life as assessed by QLDS total score was reported. The QLDS is a disease-specific validated 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.
15. Change From Baseline in Participant-reported Quality of Life as Assessed by QLDS Total Score at LOCF [ Time Frame: Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32 ]
    Change from baseline in participant-reported quality of life as assessed by QLDS total score at LOCF was reported. The QLDS is a disease-specific validated 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. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.
16. Change From Baseline in Participant-reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Score: Health Status Index [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32 ]
    Change from baseline in participant-reported health-related quality of Life as assessed by EQ-5D-5L score: health status index was reported. The EQ-5D-5L is a standardized 2-part instrument used to measure health outcomes, primarily designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and the EQ Visual Analogue Scale (EQ-VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems (level 1 = no problem, level 2 = slight problems, level 3 = moderate problems, level 4 = severe problems, level 5 = extreme problems). The participant selects an answer for each of the 5 dimensions considering the response that best matches his or her health "today." Responses were used to generate health status index which ranges from 0 (dead) and 1 (full health), a lower score indicates worse health.
17. Change From Baseline in Participant-reported Health-related Quality of Life Group, as Assessed by EQ-5D-5L Score: Health Status Index at LOCF [ Time Frame: Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32 ]
    Change from baseline in participant-reported health-related quality of Life as assessed by EQ-5D-5L score: health status index at LOCF was reported. The EQ-5D-5L is a standardized 2-part instrument used to measure health outcomes, primarily designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and the EQ-VAS. The EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems (level 1 = no problem, level 2 = slight problems, level 3 = moderate problems, level 4 = severe problems, level 5 = extreme problems). The participant selects an answer for each of the 5 dimensions considering the response that best matches his or her health "today." LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.
18. Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32 ]
    Change from baseline in participant-reported health status as assessed by EQ-5D-5L Score: 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.
19. Change From Baseline in Participant-reported Health Status as Assessed by EQ-5D-5L Score: VAS at LOCF [ Time Frame: Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32 ]
    Change from baseline in participant-reported health status as assessed by EQ-5D-5L score: VAS at LOCF 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. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.
20. Change From Baseline in Participant-reported Work Productivity as Assessed by Work Productivity and Activity Impairment (WPAI): Depression Questionnaire [ Time Frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32 ]
    Change from baseline in participant-reported work productivity as assessed by WPAI: depression questionnaire was reported. The WPAI-D questionnaire is a validated short instrument that assesses impairment in work and other regular activities over the past 7 days. The WPAI yields four types of scores: (a) Absenteeism (work time missed); (b) Presenteeism (impairment at work / reduced on-the-job effectiveness); (c) Work productivity loss (overall work impairment / absenteeism plus presenteeism); (d) Activity Impairment. The first three scores were derived only for respondents who were working (should be missing for non-working), but the last score was applicable for all respondents. Each score ranges from 0 to 100 with higher scores indicating greater impairment and less productivity.
21. Change From Baseline in Participant-reported Work Productivity as Assessed by WPAI: Depression Questionnaire at LOCF [ Time Frame: Baseline, LOCF at Weeks 4, 8, 12, 16, 20, 24, 28, 32 ]
    Change from baseline in participant-reported work productivity as assessed by WPAI: depression questionnaire at LOCF was reported. The WPAI-D questionnaire is a validated short instrument that assesses impairment in work and other regular activities over the past 7 days. The WPAI yields four types of scores: (a) Absenteeism (work time missed); (b) Presenteeism (impairment at work / reduced on-the-job effectiveness); (c) Work productivity loss (overall work impairment / absenteeism plus presenteeism); (d) Activity Impairment. The first three scores were derived only for respondents who were working (should be missing for non-working), but the last score was applicable for all respondents. Each score ranges from 0 to 100 with higher scores indicating greater impairment and less productivity. LOCF is defined as the participants who had a missing value or who stopped treatment at a specific time point had their last non-missing value carried forward.
22. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to Week 35 ]
    An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. TEAEs were those events if they started after administration of the first dose until 14 days after the last dose of study medication for other TEAEs except serious; and first dose until 30 days after the last dose of study medication for serious TEAEs.
23. Number of Participants With TEAEs of Special Interest [ Time Frame: Up to Week 35 ]
    Number of participants with TEAEs of special interest were reported. It included significant TEAEs that were judged to be of special interest because of clinical importance, known or suspected class effects, or based on nonclinical signals. Events such as sedation, depersonalization/derealization disorder, depression suicidal, aggression, allergic cystitis, cholestasis and jaundice of hepatic origin, and many more were considered as TEAEs of special interest.
24. Number of Participants With Suicidal Ideation or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score [ Time Frame: Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32 ]
    Number of participants with suicidal ideation or behavior as assessed by C-SSRS score was reported. The C-SSRS is an assessment tool that evaluates suicidal ideation and behavior. Suicidal ideation consists of 5 items: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intention to act, active suicidal ideation with some intent to act without specific plan, and active suicidal ideation with specific plan and intent. Suicidal behavior consists of 5 items: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt (non-fatal), and completed suicide. The maximum score (from the 10 categories) assigned for each participant was summarized into one of three broad categories: No suicidal ideation or behavior (0), Suicidal ideation (1 - 5), Suicidal behavior (6 - 10). Total score ranges from 1 to 10. Higher scores indicate more severe suicidal ideation and behavior.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 74 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• At screening, each participant must meet Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) or recurrent MDD, without psychotic features, based on clinical assessment and confirmed by the Mini International Neuropsychiatric Interview (MINI)
• At screening and baseline, each participant must have an Inventory of Depressive Symptomatology - Clinician-rated, 30 item (IDS-C30) total score of greater than or equal to (>=) 34
• Must be on a current antidepressive treatment that includes an selective serotonin reuptake inhibitor (SSRI)/ serotonin-norepinephrine reuptake inhibitor (SNRI) at screening that resulted in nonresponse (less than 25% improvement of symptoms) after having been given at an adequate dosage (based on antidepressive dosages from SmPC [or local equivalent, if applicable]) for an adequate duration of at least 6 weeks and having been uptitrated to the maximum tolerated dose; however, at screening the participant must show signs of minimal clinical improvement to be eligible for the study. Clinical improvement of a participant on their current AD treatment will be retrospectively evaluated in a qualified psychiatric interview performed by an experienced clinician. At baseline (Day 1) prior to randomization, the investigator will evaluate any changes in the participant's signs/symptoms of depression since the screening assessment and confirm that the inclusion criteria for the current AD treatment are still met (that is nonresponse and minimal clinical improvement)
• The current antidepressive treatment, was immediately preceded by nonresponse to at least 1 but not more than 5 different, consecutive treatments (all within the current moderate to severe antidepressive episode) with anti-depressants (ADs) taken at an adequate dosage for an adequate duration of at least 6 weeks and must be documented
• Must have been treated with at least 2 different antidepressive substance classes among the treatments taken at an adequate dosage for an adequate duration of at least 6 weeks resulting in nonresponse in the current moderate to severe depressive episode (including the current treatment with an selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor [SSRI/SNRI])
• Must be on a single oral SSRI/SNRI on Day 1 prior to randomization

Exclusion Criteria:

• Received treatment with esketamine or ketamine in the current moderate to severe depressive episode
• Received treatment with quetiapine extended- or immediate-release in the current moderate to severe depressive episode of a dose higher than 50 milligram per day (mg/day)
• Had depressive symptoms in the current moderate to severe depressive episode that previously did not respond to an adequate course of treatment with electroconvulsive therapy (ECT), defined as at least 7 treatments with unilateral/bilateral ECT
• Has no signs of clinical improvement at all or with a significant improvement on their current AD treatment that includes an SSRI/SNRI as determined at screening by an experienced clinician during the qualified psychiatric interview
• Received vagal nerve stimulation or has received deep brain stimulation in the current episode of depression
• has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders (confirmed by the Mini International Neuropsychiatric Interview [MINI]), obsessive compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, borderline personality disorder, or antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder
• age at onset of first episode of MDD was more than or equal to (>=) 55 years
• has homicidal ideation or intent, per the investigator's clinical judgment; or has suicidal ideation with some intent to act within 1 month prior to screening, per the investigator's clinical judgment; or based on the Columbia-Suicide Severity Rating Scale (C-SSRS), corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation, or a history of suicidal behavior within the past year prior to screening. Participants reporting suicidal ideation with intent to act or suicidal behavior prior to the start of the acute phase should also be excluded

Contacts and Locations

Locations

Argentina

FunDaMos

Ciudad Autonoma de Buenos Aires, Argentina, C1405BOA

Fundacion para el Estudio y Tratamiento de las Enfermedades Mentales

Ciudad Autónoma De Buenos Aires, Argentina, C1133AAH

CEN-Consultorios Especializados en Neurociencias

Cordoba, Argentina, 5000FJF

Fundacion Lennox

Cordoba, Argentina, 5000

Instituto Médico DAMIC

Cordoba, Argentina, X5003DCE

Sanatorio Prof. Leon S. Morra S.A

Cordoba, Argentina, X5009BIN

Instituto de Neurociencias San Agustín

La Plata, Argentina, 1900

C.I.A.P. (Centro de investigación y Asistencia en Psiquiatría)

Rosario, Argentina, 2000

Austria

Medical University Graz

Graz, Austria, 8036

Schmitz and Schmitz

Vienna, Austria, 1010

Medical University Vienna, MUV

Vienna, Austria, 1090

Belgium

Anima

Alken, Belgium, 3570

Pz Duffel

Duffel, Belgium, 2570

Clinique Psychiatrique des Frères Alexiens

Henri-Chapelle, Belgium, 4841

Sint-Franciskusziekenhuis

Heusden-Zolder, Belgium, 3550

ARIADNE

Lede, Belgium, 9340

CHU de Liège

Liege, Belgium, 4000

Brazil

CPN - Centro de Pesquisa em Neurociências Ltda

Belo Horizonte, Brazil, 30150-270

Trial Tech Tecnologia em Pesquisas com Medicamentos

Curitiba, Brazil, 80240-280

Ruschel Medicina e Pesquisa Clínica Ltda

Rio de Janeiro, Brazil, 22270-060

C.J.S. Carvalho & Carvalho LTDA (Viver - Centro De Desospitalizacao Humana)

São Paulo, Brazil, 04020-060

BR Trials

São Paulo, Brazil, 05003-090

Bulgaria

State Psychiatric Hospital Kardzhali

Kardzhali, Bulgaria, 6600

UMHAT 'Dr. Georgi Stranski', EAD

Pleven, Bulgaria, 5800

Mental Health Center - Plovdiv

Plovdiv, Bulgaria, 4002

Mental Health Center - Rousse

Rousse, Bulgaria, 7003

Multiprofile Hospital for Active Treatment in Neurology and Psychiatry Sveti Naum

Sofia, Bulgaria, 1113

MHC - Sofia, EOOD

Sofia, Bulgaria, 1202

Centre for Mental Health Prof.N.Shipkovenski EOOD

Sofia, Bulgaria, 1377

University Multiprofile Hospital for Active Treatment - UMHAT Alexandrovska EAD

Sofia, Bulgaria, 1431

Czechia

Psychiatricka ambulance Saint Anne s.r.o.

Brno, Czechia, 60200

Psychiatricka ambulance, MUDr. Marta Holanova

Brno, Czechia, 61500

NeuropsychiatrieHK, s.r.o.

Hradec Kralove-Vekose, Czechia, 50341

A-Shine s.r.o.

Plzen, Czechia, 31200

Institut Neuropsychiatricke pece

Prague, Czechia, 18600

Clintrial s.r.o.

Praha 10, Czechia, 10000

AD71 s.r.o.

Praha 10, Czechia, 109 00

Medical Services Prague s.r.o.

Praha 6, Czechia, 16000

Denmark

Aalborg University Hospital

Aalborg, Denmark, 9000

Psykiatrien i Region Syddanmark

Esbjerg N, Denmark, 6715

Finland

Mederon LTD at ARTES

Helsinki, Finland, 00270

Psykiatrinen Palvelukeskus Solvum Oy

Helsinki, Finland, 120

Savon Psykiatripalvelu

Kuopio, Finland, 70110

Germany

Universitaetsklinikum der RWTH Aachen

Aachen, Germany, 52074

Rheinhessen Fachklinik Alzey

Alzey, Germany, 55232

Emovis GmbH

Berlin, Germany, 10629

Charite Campus Benjamin Franklin

Berlin, Germany, 12203

Medizinisches Versorgungszentrum LiO GmbH

Berlin, Germany, 12209

Alexander Schulze - Germany

Berlin, Germany, 13156

Praxis Dr. med. Kirsten Hahn

Berlin, Germany, 13187

Vivantes Klinikum Spandau

Berlin, Germany, 13585

Universitatsklinikum Bonn

Bonn, Germany, 53105

Klinikum Chemnitz gGmbH

Chemnitz, Germany, 09131

Carl-Thiem-Klinikum Cottbus gGmbH

Cottbus, Germany, 3048

Klinikum Dortmund gGmbH

Dortmund, Germany, 44287

Universitatsklinikum Carl Gustav Carcus Dresden

Dresden, Germany, 01307

Universitatsklinikum Frankfurt

Frankfurt Am Main, Germany, 60528

Universitätsklinikum Freiburg - Abteilung für Psychiatrie u. Psychotherapie mit Poliklinik

Freiburg, Germany, 79104

SRH Waldklinikum Gera GmbH

Gera, Germany, 7548

Georg-August Universität, Universitätsmedizin Göttingen

Gottingen, Germany, 37075

Evangelisches Krankenhaus Bethanien gGmbH

Greifswald, Germany, 17489

Universitaetsklinik Hamburg-Eppendorf

Hamburg, Germany, 20251

Klinische Forschung Hamburg

Hamburg, Germany, 20253

Klinische Forschung Hannover-Mitte GmbH

Hannover, Germany, 30159

Medizinische Hochschule Hannover

Hannover, Germany, 30625

Universität Heidelberg

Heidelberg, Germany, 69115

Oberhavel Kliniken GmbH

Hennigsdorf, Germany, 16761

Universitätsklinikum des Saarlandes

Homburg, Germany, 66421

Universitätsklinikum Jena

Jena, Germany, 7743

Panakeia - Arzneimittelforschung GmbH

Leipzig, Germany, 04275

Universitaetsklinikum Magdeburg A.oe.R

Magdeburg, Germany, 39120

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

Mainz, Germany, 55131

Pharmakologisches Studienzentrum Chemnitz GmbH

Mittweida, Germany, 09648

Universitätsklinikum Münster

Munster, Germany, 48147

Ruppiner Kliniken

Neuruppin, Germany, 16816

Praxis Prof. Steinwachs

Nurnberg, Germany, 90402

Johanniter Krankenhaus Oberhausen

Oberhausen, Germany, 46145

Danuvius Klinik Pfaffenhofen Fachklinik für Psychiatrie, Psychotherapie und Psychosomatik

Pfaffenhofen, Germany, 85276

Somni Bene GmbH

Schwerin, Germany, 19053

Klinische Forschung Schwerin GmbH

Schwerin, Germany, 19055

Klinikum der Hansestadt Stralsund GmbH-Ambulanz-Klinik für Psychiatrie und Psychotherapie - Germany

Stralsund, Germany, 18437

Greece

Aiginition Hospital of Athens

Athens, Greece, 11528

'Dafni' Psychiatric Hospital of Attica

Athens, Greece, 124 62

Venizeleio General Hospital

Crete, Greece, 71409

Psychiatric Clinic 'Agios Charalampos'

Heraklion, Greece, 71305

University General Hospital of Ioannina

Ioannina, Greece, 45110

University General Hospital of Rio Patras

Patras, Greece, 26504

424 Military Hospital of Thessaloniki

Thessaloniki, Greece, 54636

Psychiatric Hospital of Thessaloniki

Thessaloniki, Greece, 56430

'G. Papanikolaou' Hospital of Thessaloniki

Thessaloniki, Greece, 57010

Hungary

Semmelweis Egyetem

Budapest, Hungary, 1083

Észak-Közép-budai Centrum, Új Szent János Kórház és Szakrendelő Budai Családközpontú

Budapest, Hungary, 1125

Processus Kft.

Budapest, Hungary, 1137

Debreceni Egyetem, Kenézy Gyula Egyetemi Oktatókórház

Debrecen, Hungary, 4031

Bugat Pal Korhaz

Gyongyos, Hungary, 3200

Petz Aladar Megyei Oktato Korhaz

Gyor, Hungary, H-9024

Bács-Kiskun Megyei Kórház a Szegedi Tudományegyetem Általános Orvostudományi Kar Oktató Kórháza

Kalocsa, Hungary, 6300

Szabolcs-Szatmar-Bereg Megyei Korhazak es Egyetemi Oktatokorhaz

Nyiregyhaza, Hungary, 4400

Pecsi Tudomanyegyetem Klinikai Kozpont

Pecs, Hungary, 7623

Israel

Rambam Medical Center

Haifa, Israel, 3109601

Shalvata Mental Health Center

Hod Hasharon, Israel, 45100

Beer Yaakov Mental Health Center

Lod, Israel, 7129434

Geha Mental Health Center

Petach Tikva, Israel, 4910002

Sheba Medical Center

Ramat Gan, Israel, 52621

Tel Aviv Sourasky Medical Center

Telaviv, Israel, 6423914

Kazakhstan

Republican Scientific and Practical Center of Mental Health

Almaty, Kazakhstan, 50012

Medical Center for Psychological Healt SME

Nur-Sultan, Kazakhstan

East-Kazakhstan Regional Centre of Mental Health

Ust'-Kamenogorsk, Kazakhstan, 70016

Korea, Republic of

Chonnam National University Hospital

Gwangju, Korea, Republic of, 61469

Wonkwang University Hospital

Iksan, Korea, Republic of, 570-711

KyungHee University Hospital

Seoul, Korea, Republic of, 02447

Korea University Anam Hospital

Seoul, Korea, Republic of, 02841

Severance Hospital, Yonsei University Health System

Seoul, Korea, Republic of, 03722

Samsung Medical Center

Seoul, Korea, Republic of, 06351

Malaysia

Hospital Raja Permaisuri Bainun

Ipoh, Malaysia, 30990

Hospital Kuala Lumpur

Kuala Lumpur, Malaysia, 50586

University Malaya Medical Centre

Kuala Lumpur, Malaysia, 59100

Hospital Pengajar Universiti Putra Malaysia

Serdang, Malaysia, 43400

Hospital Tuanku Jaafar

Seremban, Malaysia, 70300

Netherlands

Brain Research Center

Amsterdam, Netherlands, 1081 GN

AMC

Amsterdam, Netherlands, 1105 AZ

LUMC

Leiden, Netherlands, 2300 RC

Norway

Haukeland University Hospital

Hordaland, Norway, 5021

Sykehuset Ostfold

Moss, Norway, 1535

St Olav University Hospital

Trondheim, Norway, 7000

Poland

Mlynowamed Specjalistyczny Psychiatryczny Gabinet Lekarski Joanna Lazarczyk

Bialystok, Poland, 15-404

Osrodek Badan Klinicznych CLINSANTE S.C.

Bydgoszcz, Poland, 85-794

Uniwersyteckie Centrum Kliniczne

Gdansk, Poland, 80-214

Centrum Badań Klinicznych PI-House sp. z o.o.

Gdansk, Poland, 80-546

Centrum Medyczne Care Clinic Katowice

Katowice, Poland, 40-568

Niepubliczny Zaklad Opieki Psychiatrycznej MENTIS

Leszno, Poland, 64-100

Specjalistyczny Psychiatryczny Zespol Opieki Zdrowotnej w Lodzi Szpital im. J. Babinskiego

Lodz, Poland, 91-229

SPZOZ CSK UM w Lodzi Klinika Zaburzen Afektywnych i Psychotycznych

Lodz, Poland, 92-216

Centrum Medyczne Luxmed Sp z o o

Lublin, Poland, 20-109

Osrodek Badan Klinicznych CLINSANTE S.C.

Torun, Poland, 87-100

Portugal

Hospital de Braga

Braga, Portugal, 4710-243

Centro Hospitalar do Tâmega e Sousa, EPE - Hospital Padre Americo, Vale do Sousa

Guilhufe - Penafiel, Portugal, 4564-007

Fundação Champalimaud

Lisboa, Portugal, 1400-038

Centro Hospitalar de Lisboa Norte - Hospital Santa Maria

Lisboa, Portugal, 1649-035

Hospital CUF Tejo

Lisbon, Portugal, 1350-352

Hospital Beatriz Angelo

Loures, Portugal, 2674-514

South Africa

Cape Town Clinical Research Centre

Cape Town, South Africa, 7530

Flexivest 14 Research

Cape Town, South Africa, 7550

Gert Bosch - Pretoria South Africa

Garsfontein, South Africa, 00 45

Sweden

Psykiatriska kliniken

Goteborg, Sweden, 41717

Affecta Pskyiatrimottagning

Halmstad, Sweden, SE-30248

Psykiatriska kliniken

Lulea, Sweden, 97180

ProbarE i Lund AB

Lund, Sweden, 22222

ONE LIFETIME Läkarmottagning

Skovde, Sweden, SE-54150

ProbarE i Stockholm AB

Stockholm, Sweden, 113 29

Taiwan

Changhua Christian Hospital

ChangHua, Taiwan, 500

Hualien Tzu Chi Hospital

Hualien, Taiwan, 970

Kai-Syuan Psychiatric Hospital

Kaohsiung, Taiwan, 80276

Chang Gung Memorial Hospital

Kaohsiung, Taiwan, 83342

National Cheng Kung University Hospital

Tainan, Taiwan, 70403

Taipei Medical University

Taipei City, Taiwan, 110

National Taiwan University Hospital

Taipei, Taiwan, 10002

Mackay Memorial Hospital

Taipei, Taiwan, 10449

Taipei Veterans General Hospital

Taipei, Taiwan, 11217

Chang Gung Memorial Hospital

Taoyuan, Taiwan, 333

Turkey

Hacettepe University Medical Faculty

Ankara, Turkey, 6100

Bursa Yuksek Ihtisas Training and Research Hospital

Bursa, Turkey, 16285

Uludag University Medical Faculty

Bursa, Turkey, 16285

Bakirkoy Mental Health Training and Research Hospital

Istanbul, Turkey, 34147

Erenkoy Mental Health Hospital

Istanbul, Turkey, 34736

Uskudar University Neuropsychiatry Hospital

Istanbul, Turkey, 34768

Ege Universitesi Tip Fakultesi

Izmir, Turkey, 34371

Selcuk University Medical Faculty

Konya, Turkey, 42130

Liv Hospital

Samsun, Turkey, 55020

Namik Kemal University

Tekirdag, Turkey, 59030

United Arab Emirates

American Center for Psychiatry and Neurology

Abu Dhabi, United Arab Emirates, 51133

Sponsors and Collaborators

Janssen-Cilag International NV

Investigators

• Study Director: Janssen-Cilag International NV Clinical Trials; Janssen-Cilag International NV

  Study Documents (Full-Text)

Documents provided by Janssen-Cilag International NV:

Study Protocol  [PDF] October 8, 2020

Statistical Analysis Plan  [PDF] September 12, 2022

More Information

• Responsible Party: Janssen-Cilag International NV
• ClinicalTrials.gov Identifier: NCT04338321
• Other Study ID Numbers: CR108787; 2019-002992-33 ( EudraCT Number ); 54135419TRD3013 ( Other Identifier: Janssen-Cilag International NV )
• First Posted: April 8, 2020
• Results First Posted: February 15, 2023
• Last Update Posted: October 24, 2023
• Last Verified: October 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale open Data Access (YODA) Project site at yoda.yale.edu
• URL: https://www.janssen.com/clinical-trials/transparency

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Depressive Disorder; Depression; Depressive Disorder, Major; Mood Disorders; Mental Disorders; Behavioral Symptoms; Quetiapine Fumarate; Esketamine; Antidepressive Agents; Psychotropic Drugs; Antipsychotic Agents; Tranquilizing Agents; Central Nervous System Depressants; Physiological Effects of Drugs