Treatment-resistant Depression
Conditions
Keywords
Treatment-resistant Depression, Esketamine, Placebo, Oral Antidepressant
Brief summary
The purpose of this study is to compare the efficacy and safety of switching treatment-resistant depression (TRD) participants from a prior antidepressant treatment (to which they have not responded) to either intranasal esketamine plus a new oral antidepressant or switching to a new oral antidepressant plus intranasal placebo.
Detailed description
This is a randomized, double-blind (neither the researchers nor the participants know what treatment the participant is receiving), active-controlled, multicenter study (more than 1 study site) in participants with TRD to assess the efficacy, safety, and tolerability of fixed doses of intranasal esketamine plus a newly initiated oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus intranasal placebo. The study will consist of 3 phases: Screening/Prospective Observational Phase (4-7 weeks), Double-blind Induction Phase (4-weeks), Follow-up Phase (24-weeks). Participants who rollover into a long-term maintenance study will not participate in the Follow-up Phase. At the start of the screening/prospective observational phase, the participant must have had documented non-response to at least 1 antidepressant treatment (based on Massachusetts General Hospital - Antidepressant Treatment Response Questionnair \[MGH-ATRQ\]) in the current episode of depression, and participant is taking a different oral antidepressant treatment on the MGH-ATRQ for at least the previous 2 weeks at or above the minimum therapeutic dose. This antidepressant treatment, as well as any other ongoing medications being taken for depression at screening (including adjunctive/ augmentation therapies), will continue from the start of Week 1 through the end of Week 4 of the screening/prospective observational phase. Participants will be randomly assigned to receive Intranasal esketamine (56 milligrams \[mg\]), Intranasal esketamine (84 mg), or Intranasal placebo. In addition, each participant will be assigned to receive 1 of 4 oral antidepressant medications from 2 different classes of antidepressant treatments, a Selective Serotonin Reuptake Inhibitor (SSRI) (escitalopram or sertraline) or a Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) (duloxetine or venlafaxine extended release \[XR\]), initiated on Day 1 and continued through the double-blind induction phase. Participants will be primarily evaluated for improvement in depressive symptoms as assessed by change in Montgomery-Asberg Depression Rating Scale (MADRS) total score at Week 4. Participants' safety will be monitored throughout the study.
Interventions
DRUGEsketamine
Participants will self-administer either 84 mg or 56 mg of esketamine, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase.
DRUGPlacebo
Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a fixed dose regimen in Double-Blind Induction Phase.
Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day).
Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be titrated up to a dose of 20 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 10 mg/day.
Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline will be titrated up to a dose of 200 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.
Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release will be titrated up to a dose of 225 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 150 mg/day.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* At the time of signing the informed consent form (ICF), participant must be a man or woman 18 (or older if the minimum legal age of consent in the country in which the study is taking place is greater than \[\>\]18) to 64 years of age, inclusive * At the start of the screening/prospective observational phase, participant must meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) (if single-episode MDD, the duration must be greater than or equal to \[\>=\] 2 years) or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the Mini-International Neuropsychiatric Interview (MINI) * At the start of the screening/prospective observational phase, participant must have an Inventory of Depressive Symptomatology-Clinician rated ( IDS-C30) total score of greater than or equal to (\>=) 34 * At the start of the screening/prospective observational phase, participants must have had non-response (less than or equal to \[\<=25\] percent \[%\] improvement) to \>=1 but less than or equal to (\<=) 5 (if current episode is \>2 years, upper limit is applicable to only the last 2 years) oral antidepressant treatments taken at adequate dosage and for adequate duration, as assessed using the Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and documented by medical history and pharmacy/prescription records, for the current episode of depression. Participant is taking a different oral antidepressant treatment on the MGH-ATRQ for at least the previous 2 weeks at or above the minimum therapeutic dose \- The participant's current major depressive episode, depression symptom severity (Week 1 MADRS total score \>=28 required), and antidepressant treatment response in the current depressive episode, must be confirmed using a Site Independent Qualification Assessment
Exclusion criteria
* Participants who have previously demonstrated nonresponse of depressive symptoms to esketamine or ketamine in the current major depressive episode, to all 4 of the oral antidepressant treatment options available for the double-blind induction phase (i.e, duloxetine, escitalopram, sertraline, and venlafaxine extended release \[XR\]) in the current major depressive episode (based on MGH-ATRQ), or an adequate course of treatment with electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT * Participant has received vagal nerve stimulation (VNS) or has received deep brain stimulation (DBS) in the current episode of depression * Participant 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), 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, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder * Participant has homicidal ideation/intent, per the investigator's clinical judgment, or has suicidal ideation with some intent to act within 6 months prior to the start of the screening/prospective observational phase, per the investigator's clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS) * Participants with history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 of Double- Blind Induction Phase- Mixed- Effects Model Using Repeated Measures (MMRM) Analysis | Baseline up to Day 28 of Double-blind Induction Phase | MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. |
| Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | Baseline up to Double-blind Endpoint (Day 28) | MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using Last Observation Carried Forward (LOCF) method and last post baseline observation during double-blind induction phase was carried forward as End Point for that phase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | Baseline up to Double-blind Endpoint (Day 28) | The SDS is a participant-reported outcome measure and 5 item questionnaire used 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 0 (not at all) to 10 (extremely) rating scale. Score for first 3 items are summed to create total score of 0 (unimpaired) to 30 (highly impaired) where higher score indicates greater impairment. Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as End Point for that phase. |
| Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis | Baseline up to Day 28 of Double-blind Induction phase | PHQ-9 is 9-item, self-reported scale assessing 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria. Each item is rated on 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half days, 3 = Nearly every day). The scores are summed for a total score ranging from 0-27. 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. |
| Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | Baseline up to Double-blind Endpoint (Day 28) | PHQ-9 is 9-item, self-reported scale assessing 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria. Each item is rated on 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half days, 3 = Nearly every day). The scores are summed for a total score ranging from 0-27. 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. Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as End Point for that phase. |
| Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at Day 28 of Double-blind Induction Phase (Observed Data) | At Day 28 of Double-blind Induction phase | A participant was defined as a responder (yes=1 and no=0) at a given time point if the percent reduction from baseline in MADRS total score is at least 50 percent (%). The percentage of participants who achieved at least 50% reduction from baseline were reported. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. |
| Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data) | At Day 28 (Double-blind Endpoint) | A participant was defined as a responder (yes=1 and no=0) at a given time point if the percent reduction from baseline in MADRS total score is at least 50 percent (%). The percentage of participants who achieved at least 50% reduction from baseline were reported. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as End Point for that phase. |
| Percentage of Participants in Remission (MADRS<=12) at Day 28 of Double-blind Induction Phase (Observed Data) | At Day 28 of Double-blind Induction Phase | Participants who had a MADRS total score of less than or equal to (\<=) 12 were considered as remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. |
| Percentage of Participants With Onset of Clinical Response by Day 2 and Day 8 | Day 2 up to Day 28 and Day 8 up to Day 28 | A participant was defined as having a clinical response if there was at least 50% improvement (decrease) from baseline in the MADRS total score with onset by Day 2 and Day 8 that was maintained to Day 28. Participants were allowed one excursion (non-response) on Days 8, 15 or 22, however score must show at least 25% improvement. Participants who did not meet these criteria or discontinued during the study before Day 28 were considered as non-responders and were assigned the value of 0 (that is no). MADRS is clinician-rated scale that consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), for total possible score of 0 to 60. Higher scores represent more severe condition. |
| Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score up to Endpoint (Double-blind Induction Phase [Day 28]) | Baseline up to Double-blind Endpoint (Day 28) | CGI-S provides measure of severity of participant's illness including participant's history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, participant is assessed on severity of mental illness according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among most extremely ill patients (a decrease in score indicates improvement). Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as End Point for that phase. |
| Change From Baseline in Generalized Anxiety Disorder-7 Item (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28]) | Baseline up to Double-blind Endpoint (Day 28) | GAD-7 is a brief and validated 7-item self-reported assessment of overall anxiety. Participants responded to each item using a 4 point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15-21). Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as End Point for that phase. |
| Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Health Status Index | Baseline up to End of Double-blind Induction Phase (Day 28) | EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). The descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each has 5 levels (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). The responses are used to generate Health Status Index (HSI). HSI range is -0.148 to 0.949, is anchored at 0 (dead) and 1 (full health). |
| Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): EQ-VAS | Baseline up to end of Double-blind induction phase (Day 28) | EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). EQ-VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine). |
| Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Sum Score | Baseline up to end of Double-blind Induction phase (Day 28) | EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). The descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each has 5 levels (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). The responses are used to generate Health Status Index (HSI). HSI range is -0.148 to 0.949, is anchored at 0 (dead) and 1 (full health). EQ-VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (the worst health you can imagine) to 100 (the 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. |
| Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis (LOCF Data) | At Day 28 (Double-blind Endpoint) | Participants who had a MADRS total score of less than or equal to (\<=) 12 were considered as remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as End Point for that phase. |
| Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis | Baseline up to Day 28 of Double-blind Induction phase | The SDS is a participant-reported outcome measure and 5 item questionnaire used 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 0 (not at all) to 10 (extremely) rating scale. Score for first 3 items are summed to create total score of 0 (unimpaired) to 30 (highly impaired), where higher score indicates greater impairment. |
Countries
Belgium, Brazil, Canada, Estonia, France, Hungary, Mexico, Slovakia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant Participants self-administered 56 milligram (mg) of intranasal esketamine (Esk) twice per week for 4 weeks in double-blind (DB) induction phase. Also, participants simultaneously initiated new oral antidepressant (AD) with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine extended release (XR) (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) and had received at least 1 dose of intranasal Esk 56 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks. | 115 |
| Intranasal Esketamine 84 mg Plus Oral AD Participants self-administered 56 mg of intranasal esketamine on Day 1 and then 84 mg from Day 4 onwards twice per week for 4 Weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal Esk 84 mg+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks. | 116 |
| Oral AD Plus Intranasal Placebo Participants self-administered intranasal matching placebo, twice per week for 4 weeks in DB induction phase. Also, participants simultaneously initiated new oral AD with one of following: duloxetine (60 mg/day- Weeks 1, 2, 3 and 4), escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2 to 4 with minimum therapeutic dose \[MTD\] of 10 mg/day), sertraline (50 mg/day- Week 1, 100 mg/day- Week 2, 150 mg/day- Week 3 and 200 mg/day- Week 4 with MTD of 50 mg/day) or venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, 225 mg/day- Weeks 3 and 4 with MTD of 150 mg/day) on Day 1 taken daily in DB induction phase. Participants who were not eligible or chose to not participate in maintenance of effect study (ESKETINTRD3003) and had received at least 1 dose of intranasal placebo+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks. | 113 |
| Total | 344 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Induction Phase (4 Weeks) | Adverse Event | 1 | 7 | 2 |
| Double-blind Induction Phase (4 Weeks) | Lack of Efficacy | 1 | 1 | 0 |
| Double-blind Induction Phase (4 Weeks) | Lost to Follow-up | 0 | 1 | 0 |
| Double-blind Induction Phase (4 Weeks) | Other | 1 | 4 | 2 |
| Double-blind Induction Phase (4 Weeks) | Protocol Violation | 2 | 1 | 1 |
| Double-blind Induction Phase (4 Weeks) | Withdrawal by Subject | 1 | 5 | 1 |
| Follow-up Phase (24 Weeks) | Lost to Follow-up | 0 | 2 | 1 |
| Follow-up Phase (24 Weeks) | Other | 2 | 2 | 3 |
| Follow-up Phase (24 Weeks) | PI Decision | 34 | 29 | 44 |
| Follow-up Phase (24 Weeks) | Protocol Violation | 0 | 0 | 1 |
| Follow-up Phase (24 Weeks) | Withdrawal by Subject | 3 | 9 | 2 |
Baseline characteristics
| Characteristic | Intranasal Esketamine 56 mg Plus Oral Antidepressant | Intranasal Esketamine 84 mg Plus Oral AD | Oral AD Plus Intranasal Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 115 Participants | 115 Participants | 112 Participants | 342 Participants |
| Age, Continuous | 46.4 years STANDARD_DEVIATION 11.18 | 45.7 years STANDARD_DEVIATION 11.02 | 46.8 years STANDARD_DEVIATION 11.36 | 46.3 years STANDARD_DEVIATION 11.16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 33 Participants | 27 Participants | 31 Participants | 91 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 74 Participants | 80 Participants | 71 Participants | 225 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 9 Participants | 11 Participants | 28 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 7 Participants | 8 Participants | 5 Participants | 20 Participants |
| Race/Ethnicity, Customized More than one race | 8 Participants | 11 Participants | 11 Participants | 30 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 7 Participants | 9 Participants | 9 Participants | 25 Participants |
| Race/Ethnicity, Customized White | 91 Participants | 86 Participants | 86 Participants | 263 Participants |
| Region of Enrollment Belgium | 8 Participants | 9 Participants | 12 Participants | 29 Participants |
| Region of Enrollment Brazil | 20 Participants | 19 Participants | 18 Participants | 57 Participants |
| Region of Enrollment Canada | 7 Participants | 7 Participants | 6 Participants | 20 Participants |
| Region of Enrollment Estonia | 3 Participants | 4 Participants | 3 Participants | 10 Participants |
| Region of Enrollment France | 11 Participants | 10 Participants | 10 Participants | 31 Participants |
| Region of Enrollment Hungary | 3 Participants | 2 Participants | 1 Participants | 6 Participants |
| Region of Enrollment Mexico | 14 Participants | 16 Participants | 15 Participants | 45 Participants |
| Region of Enrollment Slovakia | 4 Participants | 3 Participants | 3 Participants | 10 Participants |
| Region of Enrollment United States | 45 Participants | 46 Participants | 45 Participants | 136 Participants |
| Sex: Female, Male Female | 81 Participants | 80 Participants | 81 Participants | 242 Participants |
| Sex: Female, Male Male | 34 Participants | 36 Participants | 32 Participants | 102 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 115 | 0 / 116 | 0 / 113 | 0 / 47 | 0 / 52 | 0 / 69 |
| other Total, other adverse events | 93 / 115 | 92 / 116 | 64 / 113 | 7 / 47 | 4 / 52 | 7 / 69 |
| serious Total, serious adverse events | 2 / 115 | 0 / 116 | 0 / 113 | 2 / 47 | 2 / 52 | 1 / 69 |
Outcome results
Primary
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 of Double- Blind Induction Phase- Mixed- Effects Model Using Repeated Measures (MMRM) Analysis
MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Time frame: Baseline up to Day 28 of Double-blind Induction Phase
Population: Full analysis set (FAS): all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 of Double- Blind Induction Phase- Mixed- Effects Model Using Repeated Measures (MMRM) Analysis | -19.0 Units on a scale | Standard Deviation 13.86 |
| Intranasal Esketamine 84 mg Plus Oral AD | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 of Double- Blind Induction Phase- Mixed- Effects Model Using Repeated Measures (MMRM) Analysis | -18.8 Units on a scale | Standard Deviation 14.12 |
| Oral AD Plus Intranasal Placebo | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 of Double- Blind Induction Phase- Mixed- Effects Model Using Repeated Measures (MMRM) Analysis | -14.8 Units on a scale | Standard Deviation 15.07 |
p-value: 0.08895% CI: [-6.88, 0.45]Mixed Model for Repeated Measures
95% CI: [-7.67, -0.49]
Primary
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using Last Observation Carried Forward (LOCF) method and last post baseline observation during double-blind induction phase was carried forward as End Point for that phase.
Time frame: Baseline up to Double-blind Endpoint (Day 28)
Population: Full analysis set (FAS): all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral antidepressant medication during double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | -18.3 Units on a scale | Standard Deviation 14.21 |
| Intranasal Esketamine 84 mg Plus Oral AD | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | -17.4 Units on a scale | Standard Deviation 14.25 |
| Oral AD Plus Intranasal Placebo | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | -14.3 Units on a scale | Standard Deviation 15 |
p-value: =0.2595% CI: [-5.52, 1.42]ANCOVA
95% CI: [-7.53, -0.6]
Secondary
Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score up to Endpoint (Double-blind Induction Phase [Day 28])
CGI-S provides measure of severity of participant's illness including participant's history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, participant is assessed on severity of mental illness according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among most extremely ill patients (a decrease in score indicates improvement). Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as End Point for that phase.
Time frame: Baseline up to Double-blind Endpoint (Day 28)
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score up to Endpoint (Double-blind Induction Phase [Day 28]) | -2.0 Units on a scale |
| Intranasal Esketamine 84 mg Plus Oral AD | Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score up to Endpoint (Double-blind Induction Phase [Day 28]) | -2.0 Units on a scale |
| Oral AD Plus Intranasal Placebo | Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score up to Endpoint (Double-blind Induction Phase [Day 28]) | -1.0 Units on a scale |
Secondary
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): EQ-VAS
EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). EQ-VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine).
Time frame: Baseline up to end of Double-blind induction phase (Day 28)
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): EQ-VAS | 20.9 Units on a scale | Standard Deviation 25.04 |
| Intranasal Esketamine 84 mg Plus Oral AD | Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): EQ-VAS | 19.1 Units on a scale | Standard Deviation 26.86 |
| Oral AD Plus Intranasal Placebo | Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): EQ-VAS | 14.9 Units on a scale | Standard Deviation 27.15 |
Secondary
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Health Status Index
EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). The descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each has 5 levels (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). The responses are used to generate Health Status Index (HSI). HSI range is -0.148 to 0.949, is anchored at 0 (dead) and 1 (full health).
Time frame: Baseline up to End of Double-blind Induction Phase (Day 28)
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Health Status Index | 0.224 Units on a scale | Standard Deviation 0.2481 |
| Intranasal Esketamine 84 mg Plus Oral AD | Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Health Status Index | 0.243 Units on a scale | Standard Deviation 0.2395 |
| Oral AD Plus Intranasal Placebo | Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Health Status Index | 0.181 Units on a scale | Standard Deviation 0.2495 |
Secondary
Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Sum Score
EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). The descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each has 5 levels (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). The responses are used to generate Health Status Index (HSI). HSI range is -0.148 to 0.949, is anchored at 0 (dead) and 1 (full health). EQ-VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) \*5. Higher score indicates worst health state.
Time frame: Baseline up to end of Double-blind Induction phase (Day 28)
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Sum Score | -19.0 Units on a scale | Standard Deviation 18.84 |
| Intranasal Esketamine 84 mg Plus Oral AD | Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Sum Score | -19.4 Units on a scale | Standard Deviation 18.43 |
| Oral AD Plus Intranasal Placebo | Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) up to End of Double-blind Induction Phase (Day 28): Sum Score | -14.6 Units on a scale | Standard Deviation 19.78 |
Secondary
Change From Baseline in Generalized Anxiety Disorder-7 Item (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])
GAD-7 is a brief and validated 7-item self-reported assessment of overall anxiety. Participants responded to each item using a 4 point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15-21). Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as End Point for that phase.
Time frame: Baseline up to Double-blind Endpoint (Day 28)
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Change From Baseline in Generalized Anxiety Disorder-7 Item (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28]) | -7.4 Units on a scale | Standard Deviation 5.94 |
| Intranasal Esketamine 84 mg Plus Oral AD | Change From Baseline in Generalized Anxiety Disorder-7 Item (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28]) | -7.7 Units on a scale | Standard Deviation 5.72 |
| Oral AD Plus Intranasal Placebo | Change From Baseline in Generalized Anxiety Disorder-7 Item (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28]) | -6.0 Units on a scale | Standard Deviation 6.01 |
Secondary
Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
PHQ-9 is 9-item, self-reported scale assessing 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria. Each item is rated on 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half days, 3 = Nearly every day). The scores are summed for a total score ranging from 0-27. 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.
Time frame: Baseline up to Day 28 of Double-blind Induction phase
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis | -11.0 Units on a scale | Standard Deviation 8.07 |
| Intranasal Esketamine 84 mg Plus Oral AD | Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis | -11.7 Units on a scale | Standard Deviation 7.74 |
| Oral AD Plus Intranasal Placebo | Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis | -9.1 Units on a scale | Standard Deviation 8.35 |
Secondary
Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
PHQ-9 is 9-item, self-reported scale assessing 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria. Each item is rated on 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half days, 3 = Nearly every day). The scores are summed for a total score ranging from 0-27. 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. Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as End Point for that phase.
Time frame: Baseline up to Double-blind Endpoint (Day 28)
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | -10.9 Units on a scale | Standard Deviation 8.26 |
| Intranasal Esketamine 84 mg Plus Oral AD | Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | -10.9 Units on a scale | Standard Deviation 7.81 |
| Oral AD Plus Intranasal Placebo | Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | -8.9 Units on a scale | Standard Deviation 8.37 |
Secondary
Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
The SDS is a participant-reported outcome measure and 5 item questionnaire used 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 0 (not at all) to 10 (extremely) rating scale. Score for first 3 items are summed to create total score of 0 (unimpaired) to 30 (highly impaired), where higher score indicates greater impairment.
Time frame: Baseline up to Day 28 of Double-blind Induction phase
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis | -11.0 Units on a scale | Standard Deviation 9.32 |
| Intranasal Esketamine 84 mg Plus Oral AD | Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis | -11.1 Units on a scale | Standard Deviation 10.04 |
| Oral AD Plus Intranasal Placebo | Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis | -8.4 Units on a scale | Standard Deviation 9.7 |
Secondary
Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
The SDS is a participant-reported outcome measure and 5 item questionnaire used 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 0 (not at all) to 10 (extremely) rating scale. Score for first 3 items are summed to create total score of 0 (unimpaired) to 30 (highly impaired) where higher score indicates greater impairment. Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as End Point for that phase.
Time frame: Baseline up to Double-blind Endpoint (Day 28)
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | -10.7 Units on a scale | Standard Deviation 9.39 |
| Intranasal Esketamine 84 mg Plus Oral AD | Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | -10.2 Units on a scale | Standard Deviation 10 |
| Oral AD Plus Intranasal Placebo | Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | -8.1 Units on a scale | Standard Deviation 9.57 |
Secondary
Percentage of Participants in Remission (MADRS<=12) at Day 28 of Double-blind Induction Phase (Observed Data)
Participants who had a MADRS total score of less than or equal to (\<=) 12 were considered as remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Time frame: At Day 28 of Double-blind Induction Phase
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Percentage of Participants in Remission (MADRS<=12) at Day 28 of Double-blind Induction Phase (Observed Data) | 36 Percentage of participants |
| Intranasal Esketamine 84 mg Plus Oral AD | Percentage of Participants in Remission (MADRS<=12) at Day 28 of Double-blind Induction Phase (Observed Data) | 38.8 Percentage of participants |
| Oral AD Plus Intranasal Placebo | Percentage of Participants in Remission (MADRS<=12) at Day 28 of Double-blind Induction Phase (Observed Data) | 30.6 Percentage of participants |
Secondary
Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis (LOCF Data)
Participants who had a MADRS total score of less than or equal to (\<=) 12 were considered as remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as End Point for that phase.
Time frame: At Day 28 (Double-blind Endpoint)
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis (LOCF Data) | 34.8 Percentage of participants |
| Intranasal Esketamine 84 mg Plus Oral AD | Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis (LOCF Data) | 35.4 Percentage of participants |
| Oral AD Plus Intranasal Placebo | Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis (LOCF Data) | 29.2 Percentage of participants |
Secondary
Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at Day 28 of Double-blind Induction Phase (Observed Data)
A participant was defined as a responder (yes=1 and no=0) at a given time point if the percent reduction from baseline in MADRS total score is at least 50 percent (%). The percentage of participants who achieved at least 50% reduction from baseline were reported. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Time frame: At Day 28 of Double-blind Induction phase
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at Day 28 of Double-blind Induction Phase (Observed Data) | 54.1 Percentage of Participants |
| Intranasal Esketamine 84 mg Plus Oral AD | Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at Day 28 of Double-blind Induction Phase (Observed Data) | 53.1 Percentage of Participants |
| Oral AD Plus Intranasal Placebo | Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at Day 28 of Double-blind Induction Phase (Observed Data) | 38.9 Percentage of Participants |
Secondary
Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data)
A participant was defined as a responder (yes=1 and no=0) at a given time point if the percent reduction from baseline in MADRS total score is at least 50 percent (%). The percentage of participants who achieved at least 50% reduction from baseline were reported. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. Missing data was imputed using LOCF method and the last post baseline observation during the double-blind induction phase was carried forward as End Point for that phase.
Time frame: At Day 28 (Double-blind Endpoint)
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data) | 53.0 Percentage of Participants |
| Intranasal Esketamine 84 mg Plus Oral AD | Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data) | 47.8 Percentage of Participants |
| Oral AD Plus Intranasal Placebo | Percentage of Participants Who Achieved at Least 50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28]) (LOCF Data) | 37.2 Percentage of Participants |
Secondary
Percentage of Participants With Onset of Clinical Response by Day 2 and Day 8
A participant was defined as having a clinical response if there was at least 50% improvement (decrease) from baseline in the MADRS total score with onset by Day 2 and Day 8 that was maintained to Day 28. Participants were allowed one excursion (non-response) on Days 8, 15 or 22, however score must show at least 25% improvement. Participants who did not meet these criteria or discontinued during the study before Day 28 were considered as non-responders and were assigned the value of 0 (that is no). MADRS is clinician-rated scale that consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), for total possible score of 0 to 60. Higher scores represent more severe condition.
Time frame: Day 2 up to Day 28 and Day 8 up to Day 28
Population: FAS: all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during the double-blind induction phase.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Percentage of Participants With Onset of Clinical Response by Day 2 and Day 8 | Day 2 up to Day 28 | 10.4 Percentage of Participants |
| Intranasal Esketamine 56 mg Plus Oral Antidepressant | Percentage of Participants With Onset of Clinical Response by Day 2 and Day 8 | Day 8 up to Day 28 | 13.0 Percentage of Participants |
| Intranasal Esketamine 84 mg Plus Oral AD | Percentage of Participants With Onset of Clinical Response by Day 2 and Day 8 | Day 2 up to Day 28 | 8.8 Percentage of Participants |
| Intranasal Esketamine 84 mg Plus Oral AD | Percentage of Participants With Onset of Clinical Response by Day 2 and Day 8 | Day 8 up to Day 28 | 11.4 Percentage of Participants |
| Oral AD Plus Intranasal Placebo | Percentage of Participants With Onset of Clinical Response by Day 2 and Day 8 | Day 2 up to Day 28 | 1.8 Percentage of Participants |
| Oral AD Plus Intranasal Placebo | Percentage of Participants With Onset of Clinical Response by Day 2 and Day 8 | Day 8 up to Day 28 | 3.5 Percentage of Participants |