Depression
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy of fixed dosed intranasal esketamine compared to intranasal placebo, as an add-on to an oral antidepressant in Japanese participants with treatment-resistant depression (TRD), in improving depressive symptoms.
Interventions
DRUGPlacebo
Participant will receive 1 spray of placebo to each nostril at 0 minute, 5 minutes and 10 minutes.
DRUGIntranasal esketamine (28 mg)
Participant will receive 1 spray of Esketamine to each nostril at 0 minute and placebo at 5 minutes and 10 minutes.
DRUGIntranasal esketamine (56 mg)
Participant will receive 1 spray of Esketamine to each nostril at 0 minute, 5 minutes and placebo at 10 minutes.
DRUGIntranasal esketamine (84 mg)
Participant will receive 1 spray of Esketamine to each nostril at 0 minute, 5 minutes and 10 minutes.
Sponsors
Janssen Pharmaceutical K.K.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* At the start of the screening phase, participant must meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) or recurrent major depressive disorder (MDD), without psychotic features, based upon clinical assessment and confirmed by the Mini International Neuropsychiatric Interview (MINI). In the case of single-episode MDD, the participant must be diagnosed with persistent depressive disorder, which meets criteria of major depressive episode for a continuous duration of greater than or equal to (\>=)2 years, and the same physician from the site must be examining the participant for \>=2 years continuously as a primary care physician of the participant * The participant's current major depressive episode, depression symptom severity (MADRS total score greater than or equal to \[\>=\] 28 required), and antidepressant treatment response in the current depressive episode, must be confirmed using the SAFER interview * Participant must be medically stable on the basis of clinical laboratory tests, physical examination, medical history, vital signs (including blood pressure), pulse oximetry, and 12-lead electrocardiogram (ECG) performed in the screening phase * A woman of childbearing potential must have a negative highly sensitive serum Beta (β) human chorionic gonadotropin \[β-hCG\] test at the start of the screening phase and a negative urine pregnancy test must be obtained before the first dose of study drug on Day 1 of the double-blind induction phase prior to randomization * Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for participant participating in clinical studies
Exclusion criteria
* Participant has received vagal nerve stimulation or has received deep brain stimulation in the current episode of depression * Participant previously received esketamine or ketamine as treatment for their MDD * 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 phase * Participant has a history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria, except nicotine or caffeine, within 6 months before the start of the screening phase * Participant has a current or past history of seizure disorder (uncomplicated childhood febrile seizures with no sequelae are not exclusionary)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Double-Blind (DB) Induction Phase: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 | Baseline (Day 1) up to Day 28 (DB phase) induction | 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. Negative change in score indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Days 2, 8, 15, 22 and 28 (DB induction phase) | A participant was considered in remission at a given time point if the MADRS total score \<=12. 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. |
| DB Induction Phase: Percentage of Participants Showing Onset of Clinical Response | Day 2 up to Day 28 (DB induction phase) | A participant was defined as having a clinical response if there was at least 50% improvement from baseline in the MADRS total score with onset by Day 2 that was maintained to Day 28 in DB induction phase. Participants were allowed one excursion (non-response) on Days 8, 15 or 22, provided the score is at least 25% improvement. 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. |
| DB Induction Phase: Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score up to Day 28 | Baseline (Day 1) up to Day 28 (DB induction pahse) | 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. Values of 0 (not assessed) were excluded from analysis. CGI-S permits global evaluation of participant's condition at given time. |
| DB Induction Phase: Change From Baseline in Generalized Anxiety Disorder 7-Item Scale (GAD-7) up to Day 28 | Baseline (Day 1) up to Day 28 (DB induction phase) | GAD-7 was a brief and validated 7-item self-report assessment of overall anxiety. Participants respond to each item using a 4-point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15 -21). |
| DB Induction Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 | Baseline (Day 1) to Day 28 (DB induction phase) | SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. First three items assess disruption of 1 work/school, 2 social life, 3 family life/home responsibilities using a 0(no impairment)-10 (most severe impairment). Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment and a negative change in score indicates improvement. It also has one item on days lost from school or work and one item on days when under productive. |
| DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Days 2, 8, 15, 22 and 28 (DB induction phase) | A participant is defined as responder (yes=1 and no=0) at a given time point if the percent improvement from baseline in MADRS is greater than or equal to (\>=) 50 percent (%). 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. |
| Posttreatment Phase: Time to Relapse in Participants With Response (>=50% Reduction From Baseline in MADRS Total Score) But Who Are Not in Remission | From EndPoint (last post baseline assessment value during the DB induction phase [up to Day 28]) up to 24 weeks (posttreatment phase) | Time to relapse in participants with response (\>=50% reduction from baseline in MADRS total score) but who are not in remission was reported. Relapse is defined as any of the following: 1) MADRS total score \>= 22 for 2 consecutive assessments. The date of the second MADRS assessment was used for the date of relapse. 2)Hospitalization for worsening depression or any other clinically relevant event determined per clinical judgment to be suggestive of relapse of depressive illness like suicide attempt, completed suicide, or hospitalization for suicide prevention. If hospitalized for any of these events, start date of hospitalization was used as relapse date. If participant was not hospitalized, event date was used. 3) If both relapse criteria were met, earlier date was defined as date of relapse. Remission was defined as MADRS total score \<=12. |
| Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Baseline (DB induction phase), Weeks 2, 4, 6, 8, 12, 16, 20 and 24 (posttreatment phase) | SDS is a participant-reported outcome measure and is a 5-item questionnaire which has been widely used and accepted for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items are summed to create a total score of 0-30, where a higher score indicates greater impairment. It also has one item on days lost from school or work and one item on days when under productive. FAS (responders): All randomized participants who received at least 1 dose of intranasal study medication during DB induction phase and who were responders at the end of DB induction phase and entered posttreatment phase |
| OL Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Days 8, 15, 22 and 28 (OL induction phase) | A participant was considered in remission at a given time point if the MADRS total score \<=12. 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. |
| OL Induction Phase: Change From Baseline (Prior to the First Dose of OL Induction Phase) in MADRS Total Score up to Endpoint OL Induction Phase (Last Post Baseline Assessment Value During the OL Induction Phase [OL: up to Day 28]) | Baseline (Prior to first Dose of OL induction phase on Day 1) up to endpoint of OL induction phase (last post baseline assessment value during OL induction phase [OL: up to 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. |
| OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Baseline (Prior to first dose of OL induction phase on Day 1), endpoint of OL induction phase (last post baseline assessment value during the OL induction phase [OL: up to 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. CGI-S permits global evaluation of participant's condition at given time. |
| Posttreatment Phase: Time to Relapse in Participants With Remission (MADRS Total Score <=12) | From EndPoint (last post baseline assessment value during the DB induction phase [up to Day 28]) up to 24 weeks (posttreatment phase) | Time to relapse in participants with remission at the end of the double-blind phase was defined as the time between induction phase and the first documentation of a relapse event during the posttreatment phase. Relapse was defined as any of the following: 1) MADRS total score \>= 22 for 2 consecutive assessments. The date of the second MADRS assessment was used for the date of relapse; 2) Hospitalization for worsening depression or any other clinically relevant event determined per clinical judgment to be suggestive of relapse of depressive illness like suicide attempt, completed suicide, or hospitalization for suicide prevention. If hospitalized for any of these events, start date of hospitalization was used as relapse date. If participant was not hospitalized, event date was used. 3) If both relapse criteria were met, earlier date was defined as date of relapse. Remission was defined as MADRS total score \<=12. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Esketamine 28 Milligrams (mg) Double-blind (DB) induction phase: Participants received intranasal esketamine (Esk) 28 mg twice a week add-on to an oral antidepressant (AD) for 4 weeks. Responders (participants who had \>=50% reduction from baseline in MADRS total score) at the end of the DB induction phase were eligible to proceed to the posttreatment. DB Follow-up Phase: Participants who did not respond (non-responders) in DB induction phase proceeded to the 4-week DB follow-up and received only oral AD. Posttreatment phase: Participants who were responders at the end of DB induction phase entered in posttreatment phase and received oral AD once daily for up to 24 weeks. | 41 |
| Esketamine 56 mg DB induction phase: Participants received intranasal Esk 56 mg twice a week add-on to a AD for 4 weeks. Responders (participants who had \>=50% reduction from baseline in MADRS total score) at the end of the DB induction phase were eligible to proceed to the posttreatment. DB Follow-up Phase: Participants who did not respond (non-responders) in DB induction phase proceeded to the 4-week DB follow-up and received only oral AD. Posttreatment phase: Participants who were responders at the end of DB induction phase entered in posttreatment phase and received oral AD once daily for up to 24 weeks. | 40 |
| Esketamine 84 mg DB induction phase: Participants received intranasal Esk 84 mg twice a week add-on to AD for 4 weeks. Responders (participants who had \>=50% reduction from baseline in MADRS total score) at the end of the DB induction phase were eligible to proceed to the posttreatment. DB Follow-up Phase: Participants who did not respond (non-responders) in DB induction phase proceeded to the 4-week DB follow-up and received only oral AD. Posttreatment phase: Participants who were responders at the end of DB induction phase entered in posttreatment phase and received oral AD once daily for up to 24 weeks. | 41 |
| Placebo DB induction phase: Participants received intranasal Esk placebo twice a week add-on to AD for 4 weeks. Responders (participants who had \>=50% reduction from baseline in MADRS total score) at the end of the DB induction phase were eligible to proceed to the posttreatment. DB Follow-up Phase: Participants who did not respond (non-responders) in DB induction phase proceeded to the 4-week DB follow-up and received only oral AD. Posttreatment phase: Participants who were responders at the end of DB induction phase entered in posttreatment phase and received oral AD once daily for 24 weeks. | 80 |
| Total | 202 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Double-blind Follow-up Phase: 4 Weeks | Adverse Event | 1 | 0 | 1 | 1 | 0 |
| Double-blind Follow-up Phase: 4 Weeks | Withdrawal by Subject | 0 | 0 | 0 | 2 | 0 |
| Double-blind Induction Phase: 4 Weeks | Adverse Event | 1 | 4 | 2 | 3 | 0 |
| Double-blind Induction Phase: 4 Weeks | Lack of Efficacy | 0 | 0 | 0 | 2 | 0 |
| Double-blind Induction Phase: 4 Weeks | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 |
| Double-blind Induction Phase: 4 Weeks | Non-compliance | 0 | 0 | 0 | 1 | 0 |
| Double-blind Induction Phase: 4 Weeks | Other | 0 | 2 | 0 | 1 | 0 |
| Double-blind Induction Phase: 4 Weeks | Withdrawal by Subject | 1 | 1 | 0 | 0 | 0 |
| Open Label Follow-up Phase: 4 Weeks | Adverse Event | 0 | 0 | 0 | 0 | 1 |
| Open Label Treatment Phase: 4 Weeks | Adverse Event | 0 | 0 | 0 | 0 | 1 |
| Posttreatment Phase: Up to 24 Weeks | Other | 0 | 3 | 1 | 1 | 0 |
| Posttreatment Phase: Up to 24 Weeks | Withdrawal by Subject | 1 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Esketamine 28 Milligrams (mg) | Esketamine 56 mg | Esketamine 84 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 45.9 years STANDARD_DEVIATION 9.97 | 42.5 years STANDARD_DEVIATION 8.36 | 41.9 years STANDARD_DEVIATION 10.26 | 43.3 years STANDARD_DEVIATION 11.4 | 43.4 years STANDARD_DEVIATION 10.35 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 40 Participants | 41 Participants | 80 Participants | 202 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 41 Participants | 40 Participants | 41 Participants | 80 Participants | 202 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment JAPAN | 41 Participants | 40 Participants | 41 Participants | 80 Participants | 202 Participants |
| Sex: Female, Male Female | 23 Participants | 16 Participants | 18 Participants | 39 Participants | 96 Participants |
| Sex: Female, Male Male | 18 Participants | 24 Participants | 23 Participants | 41 Participants | 106 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 41 | 0 / 40 | 0 / 80 | 0 / 27 | 0 / 29 | 0 / 23 | 0 / 53 | 0 / 13 | 0 / 11 | 0 / 17 | 0 / 27 | 0 / 48 | 0 / 48 |
| other Total, other adverse events | 33 / 41 | 39 / 41 | 39 / 40 | 34 / 80 | 3 / 27 | 3 / 29 | 3 / 23 | 7 / 53 | 6 / 13 | 4 / 11 | 6 / 17 | 7 / 27 | 47 / 48 | 3 / 48 |
| serious Total, serious adverse events | 1 / 41 | 0 / 41 | 1 / 40 | 1 / 80 | 0 / 27 | 0 / 29 | 1 / 23 | 2 / 53 | 0 / 13 | 0 / 11 | 0 / 17 | 0 / 27 | 1 / 48 | 2 / 48 |
Outcome results
Primary
Double-Blind (DB) Induction Phase: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to 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. Negative change in score indicates improvement.
Time frame: Baseline (Day 1) up to Day 28 (DB phase) induction
Population: Full analysis set (FAS \[DB\]) included all randomized participants who received at least 1 dose of intranasal study agent during the DB induction phase. Here, N (Number of participants analyzed) signifies those participants who were evaluable for this outcome measure (OM).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esketamine 28 Milligrams (mg) | Double-Blind (DB) Induction Phase: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 | -15.2 Units on a scale | Standard Deviation 13.07 |
| Esketamine 56 mg | Double-Blind (DB) Induction Phase: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 | -14.5 Units on a scale | Standard Deviation 10.53 |
| Esketamine 84 mg | Double-Blind (DB) Induction Phase: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 | -15.1 Units on a scale | Standard Deviation 12.21 |
| Placebo | Double-Blind (DB) Induction Phase: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 | -15.3 Units on a scale | Standard Deviation 11.68 |
p-value: 0.47590% CI: [-5.77, 3.7]Dunnett adjustment
p-value: 0.50490% CI: [-4.32, 5.47]Dunnett adjustment
p-value: 0.48290% CI: [-5.66, 3.83]Dunnett adjustment
Secondary
DB Induction Phase: Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score up to 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. Values of 0 (not assessed) were excluded from analysis. CGI-S permits global evaluation of participant's condition at given time.
Time frame: Baseline (Day 1) up to Day 28 (DB induction pahse)
Population: FAS (DB) included all randomized participants who received at least 1 dose of intranasal study agent during the DB induction phase. Here, 'N' (number of participants analyzed) signifies participants who were evaluable for this OM.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score up to Day 28 | -1.0 Units on a scale |
| Esketamine 56 mg | DB Induction Phase: Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score up to Day 28 | -1.0 Units on a scale |
| Esketamine 84 mg | DB Induction Phase: Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score up to Day 28 | -1.0 Units on a scale |
| Placebo | DB Induction Phase: Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score up to Day 28 | -1.0 Units on a scale |
Secondary
DB Induction Phase: Change From Baseline in Generalized Anxiety Disorder 7-Item Scale (GAD-7) up to Day 28
GAD-7 was a brief and validated 7-item self-report assessment of overall anxiety. Participants respond to each item using a 4-point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15 -21).
Time frame: Baseline (Day 1) up to Day 28 (DB induction phase)
Population: FAS included all randomized participants who received at least 1 dose of intranasal study agent during the DB induction phase. Here, 'N' (number of participants analyzed) signifies participants who were evaluable for this OM.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Change From Baseline in Generalized Anxiety Disorder 7-Item Scale (GAD-7) up to Day 28 | -8.2 Units on a scale | Standard Deviation 4.94 |
| Esketamine 56 mg | DB Induction Phase: Change From Baseline in Generalized Anxiety Disorder 7-Item Scale (GAD-7) up to Day 28 | -7.8 Units on a scale | Standard Deviation 5.05 |
| Esketamine 84 mg | DB Induction Phase: Change From Baseline in Generalized Anxiety Disorder 7-Item Scale (GAD-7) up to Day 28 | -8.1 Units on a scale | Standard Deviation 5.67 |
| Placebo | DB Induction Phase: Change From Baseline in Generalized Anxiety Disorder 7-Item Scale (GAD-7) up to Day 28 | -7.7 Units on a scale | Standard Deviation 5.05 |
Secondary
DB Induction Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28
SDS is a participant-reported outcome measure and 5 item questionnaire used for assessment of functional impairment and associated disability. First three items assess disruption of 1 work/school, 2 social life, 3 family life/home responsibilities using a 0(no impairment)-10 (most severe impairment). Score for first 3 items are summed to create total score of 0-30 where higher score indicates greater impairment and a negative change in score indicates improvement. It also has one item on days lost from school or work and one item on days when under productive.
Time frame: Baseline (Day 1) to Day 28 (DB induction phase)
Population: FAS (DB) included all randomized participants who received at least 1 dose of intranasal study agent during the DB induction phase. Here, 'N' (number of participants analyzed) signifies participants who were evaluable for this OM.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 | -8.6 Units on a scale | Standard Deviation 8.68 |
| Esketamine 56 mg | DB Induction Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 | -7.9 Units on a scale | Standard Deviation 7.94 |
| Esketamine 84 mg | DB Induction Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 | -9.5 Units on a scale | Standard Deviation 8.93 |
| Placebo | DB Induction Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 | -7.0 Units on a scale | Standard Deviation 7.39 |
Secondary
DB Induction Phase: Percentage of Participants Showing Onset of Clinical Response
A participant was defined as having a clinical response if there was at least 50% improvement from baseline in the MADRS total score with onset by Day 2 that was maintained to Day 28 in DB induction phase. Participants were allowed one excursion (non-response) on Days 8, 15 or 22, provided the score is at least 25% improvement. 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: Day 2 up to Day 28 (DB induction phase)
Population: FAS (DB) included all randomized participants who received at least 1 dose of intranasal study agent during DB induction phase. Participants with missed assessments or discontinued early were not considered to have onset of clinical response. Here, 'N' (number of participants analyzed) signifies participants who were evaluable for this OM.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Percentage of Participants Showing Onset of Clinical Response | Onset of clinical response: Yes | 2.4 Percentage of participants |
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Percentage of Participants Showing Onset of Clinical Response | Onset of clinical response: No | 97.6 Percentage of participants |
| Esketamine 56 mg | DB Induction Phase: Percentage of Participants Showing Onset of Clinical Response | Onset of clinical response: No | 97.4 Percentage of participants |
| Esketamine 56 mg | DB Induction Phase: Percentage of Participants Showing Onset of Clinical Response | Onset of clinical response: Yes | 2.6 Percentage of participants |
| Esketamine 84 mg | DB Induction Phase: Percentage of Participants Showing Onset of Clinical Response | Onset of clinical response: Yes | 7.3 Percentage of participants |
| Esketamine 84 mg | DB Induction Phase: Percentage of Participants Showing Onset of Clinical Response | Onset of clinical response: No | 92.7 Percentage of participants |
| Placebo | DB Induction Phase: Percentage of Participants Showing Onset of Clinical Response | Onset of clinical response: Yes | 6.3 Percentage of participants |
| Placebo | DB Induction Phase: Percentage of Participants Showing Onset of Clinical Response | Onset of clinical response: No | 93.7 Percentage of participants |
Secondary
DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score
A participant was considered in remission at a given time point if the MADRS total score \<=12. 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: Days 2, 8, 15, 22 and 28 (DB induction phase)
Population: FAS (DB) included all randomized defined as all participants who received at least 1 dose of intranasal study agent during the DB induction phase. Here 'n' (number analyzed) signifies number of participants who were evaluable for this OM at specified timepoints.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 22 | 10.3 Percentage of participants |
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 8 | 2.4 Percentage of participants |
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 28 | 23.1 Percentage of participants |
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 15 | 7.5 Percentage of participants |
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 2 | 9.8 Percentage of participants |
| Esketamine 56 mg | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 15 | 2.8 Percentage of participants |
| Esketamine 56 mg | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 22 | 5.6 Percentage of participants |
| Esketamine 56 mg | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 28 | 11.8 Percentage of participants |
| Esketamine 56 mg | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 8 | 0 Percentage of participants |
| Esketamine 56 mg | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 2 | 0 Percentage of participants |
| Esketamine 84 mg | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 15 | 10.0 Percentage of participants |
| Esketamine 84 mg | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 2 | 7.5 Percentage of participants |
| Esketamine 84 mg | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 8 | 4.9 Percentage of participants |
| Esketamine 84 mg | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 22 | 7.7 Percentage of participants |
| Esketamine 84 mg | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 28 | 23.1 Percentage of participants |
| Placebo | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 22 | 14.9 Percentage of participants |
| Placebo | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 8 | 1.3 Percentage of participants |
| Placebo | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 2 | 3.8 Percentage of participants |
| Placebo | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 15 | 3.9 Percentage of participants |
| Placebo | DB Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 28 | 20.8 Percentage of participants |
Secondary
DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score
A participant is defined as responder (yes=1 and no=0) at a given time point if the percent improvement from baseline in MADRS is greater than or equal to (\>=) 50 percent (%). 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: Days 2, 8, 15, 22 and 28 (DB induction phase)
Population: FAS (DB) included all randomized participants who received at least 1 dose of intranasal study agent during the DB induction phase. Here 'n' (number analyzed) signifies number of participants who were evaluable for this OM at specified timepoints.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 15 | 17.5 Percentage of participants |
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 2 | 22.0 Percentage of participants |
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 22 | 23.1 Percentage of participants |
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 8 | 2.4 Percentage of participants |
| Esketamine 28 Milligrams (mg) | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 28 | 33.3 Percentage of participants |
| Esketamine 56 mg | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 15 | 8.3 Percentage of participants |
| Esketamine 56 mg | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 8 | 2.6 Percentage of participants |
| Esketamine 56 mg | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 22 | 13.9 Percentage of participants |
| Esketamine 56 mg | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 2 | 13.2 Percentage of participants |
| Esketamine 56 mg | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 28 | 35.3 Percentage of participants |
| Esketamine 84 mg | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 28 | 43.6 Percentage of participants |
| Esketamine 84 mg | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 2 | 10.0 Percentage of participants |
| Esketamine 84 mg | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 8 | 9.8 Percentage of participants |
| Esketamine 84 mg | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 15 | 15.0 Percentage of participants |
| Esketamine 84 mg | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 22 | 20.5 Percentage of participants |
| Placebo | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 28 | 37.5 Percentage of participants |
| Placebo | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 22 | 29.7 Percentage of participants |
| Placebo | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 8 | 3.8 Percentage of participants |
| Placebo | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 2 | 9.0 Percentage of participants |
| Placebo | DB Induction Phase: Percentage of Participants With Response Based on MADRS Total Score | Day 15 | 18.2 Percentage of participants |
Secondary
OL Induction Phase: Change From Baseline (Prior to the First Dose of OL Induction Phase) in MADRS Total Score up to Endpoint OL Induction Phase (Last Post Baseline Assessment Value During the OL Induction Phase [OL: up to 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.
Time frame: Baseline (Prior to first Dose of OL induction phase on Day 1) up to endpoint of OL induction phase (last post baseline assessment value during OL induction phase [OL: up to Day 28])
Population: FAS (OL) included all participants who received at least 1 dose of intranasal study agent during the OL induction phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Change From Baseline (Prior to the First Dose of OL Induction Phase) in MADRS Total Score up to Endpoint OL Induction Phase (Last Post Baseline Assessment Value During the OL Induction Phase [OL: up to Day 28]) | Baseline | 16.1 Units on a scale | Standard Deviation 9.47 |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Change From Baseline (Prior to the First Dose of OL Induction Phase) in MADRS Total Score up to Endpoint OL Induction Phase (Last Post Baseline Assessment Value During the OL Induction Phase [OL: up to Day 28]) | Change from baseline | -14.5 Units on a scale | Standard Deviation 11.06 |
Secondary
OL Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score
A participant was considered in remission at a given time point if the MADRS total score \<=12. 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: Days 8, 15, 22 and 28 (OL induction phase)
Population: FAS (OL) included all randomized participants who received at least 1 dose of intranasal study agent during the OL induction phase. Here 'n' (Number analyzed) signifies number of participants who were evaluable for this OM at specified timepoints.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 8 | 14.6 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 15 | 23.4 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 22 | 31.9 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Remission Based on MADRS Total Score | Day 28 | 42.6 Percentage of participants |
Secondary
OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale
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. CGI-S permits global evaluation of participant's condition at given time.
Time frame: Baseline (Prior to first dose of OL induction phase on Day 1), endpoint of OL induction phase (last post baseline assessment value during the OL induction phase [OL: up to Day 28])
Population: FAS (OL) included all participants who received at least 1 dose of intranasal study agent during the OL induction phase.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Normal, not at all ill:Baseline | 0 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Normal, not at all ill:Endpoint | 14.6 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Borderline mentally ill:Baseline | 0 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Borderline mentally ill:Endpoint | 16.7 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Mildly ill:Baseline | 4.2 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Mildly ill:Endpoint | 43.8 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Moderately ill:Baseline | 75.0 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Moderately ill:Endpoint | 20.8 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Markedly ill:Baseline | 14.6 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Markedly ill:Endpoint | 4.2 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Severely ill:Baseline | 4.2 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Severely ill:Endpoint | 0 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Among the most extremely ill patients:Baseline | 2.1 Percentage of participants |
| Esketamine 28 Milligrams (mg) | OL Induction Phase: Percentage of Participants With Severity of Psychopathology on the CGI-S Scale | Among the most extremely ill patients:Endpoint | 0 Percentage of participants |
Secondary
Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24
SDS is a participant-reported outcome measure and is a 5-item questionnaire which has been widely used and accepted for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items are summed to create a total score of 0-30, where a higher score indicates greater impairment. It also has one item on days lost from school or work and one item on days when under productive. FAS (responders): All randomized participants who received at least 1 dose of intranasal study medication during DB induction phase and who were responders at the end of DB induction phase and entered posttreatment phase
Time frame: Baseline (DB induction phase), Weeks 2, 4, 6, 8, 12, 16, 20 and 24 (posttreatment phase)
Population: Here, 'N' (number of participants analyzed) signifies participants who were evaluable for this OM. Here, 'n' (number analyzed) signifies number of participants who were evaluable for this OM at specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Esketamine 28 Milligrams (mg) | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 20 | -22.0 Units on a scale | Standard Deviation 7.07 |
| Esketamine 28 Milligrams (mg) | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 4 | -12.9 Units on a scale | Standard Deviation 5.69 |
| Esketamine 28 Milligrams (mg) | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 24 | -21.5 Units on a scale | Standard Deviation 4.95 |
| Esketamine 28 Milligrams (mg) | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 6 | -17.7 Units on a scale | Standard Deviation 8.5 |
| Esketamine 28 Milligrams (mg) | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 8 | -12.0 Units on a scale | Standard Deviation 14.42 |
| Esketamine 28 Milligrams (mg) | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 12 | -20.5 Units on a scale | Standard Deviation 3.54 |
| Esketamine 28 Milligrams (mg) | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 16 | -21.5 Units on a scale | Standard Deviation 6.36 |
| Esketamine 28 Milligrams (mg) | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 2 | -14.6 Units on a scale | Standard Deviation 7.82 |
| Esketamine 56 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 4 | -8.3 Units on a scale | Standard Deviation 2.75 |
| Esketamine 56 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 6 | -11.0 Units on a scale | Standard Deviation 3.61 |
| Esketamine 56 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 2 | -8.1 Units on a scale | Standard Deviation 6.15 |
| Esketamine 56 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 8 | -13.3 Units on a scale | Standard Deviation 1.53 |
| Esketamine 56 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 16 | -17.5 Units on a scale | Standard Deviation 0.71 |
| Esketamine 56 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 20 | -18.0 Units on a scale | — |
| Esketamine 56 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 12 | -13.0 Units on a scale | Standard Deviation 7.21 |
| Esketamine 56 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 24 | -16.0 Units on a scale | — |
| Esketamine 84 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 12 | -18.3 Units on a scale | Standard Deviation 7.76 |
| Esketamine 84 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 2 | -13.1 Units on a scale | Standard Deviation 7.65 |
| Esketamine 84 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 4 | -13.6 Units on a scale | Standard Deviation 7.34 |
| Esketamine 84 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 6 | -14.6 Units on a scale | Standard Deviation 5.53 |
| Esketamine 84 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 20 | -28.0 Units on a scale | — |
| Esketamine 84 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 16 | -12.5 Units on a scale | Standard Deviation 21.92 |
| Esketamine 84 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 24 | -28.0 Units on a scale | — |
| Esketamine 84 mg | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 8 | -15.3 Units on a scale | Standard Deviation 7.15 |
| Placebo | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 24 | -14.8 Units on a scale | Standard Deviation 3.59 |
| Placebo | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 8 | -11.4 Units on a scale | Standard Deviation 6.02 |
| Placebo | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 2 | -11.2 Units on a scale | Standard Deviation 6.83 |
| Placebo | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 6 | -12.0 Units on a scale | Standard Deviation 4.39 |
| Placebo | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 12 | -14.8 Units on a scale | Standard Deviation 4.88 |
| Placebo | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 16 | -15.8 Units on a scale | Standard Deviation 1.89 |
| Placebo | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 20 | -14.0 Units on a scale | Standard Deviation 3.65 |
| Placebo | Posttreatment Phase: Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 | Week 4 | -9.8 Units on a scale | Standard Deviation 5.84 |
Secondary
Posttreatment Phase: Time to Relapse in Participants With Remission (MADRS Total Score <=12)
Time to relapse in participants with remission at the end of the double-blind phase was defined as the time between induction phase and the first documentation of a relapse event during the posttreatment phase. Relapse was defined as any of the following: 1) MADRS total score \>= 22 for 2 consecutive assessments. The date of the second MADRS assessment was used for the date of relapse; 2) Hospitalization for worsening depression or any other clinically relevant event determined per clinical judgment to be suggestive of relapse of depressive illness like suicide attempt, completed suicide, or hospitalization for suicide prevention. If hospitalized for any of these events, start date of hospitalization was used as relapse date. If participant was not hospitalized, event date was used. 3) If both relapse criteria were met, earlier date was defined as date of relapse. Remission was defined as MADRS total score \<=12.
Time frame: From EndPoint (last post baseline assessment value during the DB induction phase [up to Day 28]) up to 24 weeks (posttreatment phase)
Population: Population included participants with remit at the end of DB.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Esketamine 28 Milligrams (mg) | Posttreatment Phase: Time to Relapse in Participants With Remission (MADRS Total Score <=12) | 34.0 Days |
| Esketamine 56 mg | Posttreatment Phase: Time to Relapse in Participants With Remission (MADRS Total Score <=12) | 52.0 Days |
| Esketamine 84 mg | Posttreatment Phase: Time to Relapse in Participants With Remission (MADRS Total Score <=12) | 37.0 Days |
| Placebo | Posttreatment Phase: Time to Relapse in Participants With Remission (MADRS Total Score <=12) | 30.0 Days |
Secondary
Posttreatment Phase: Time to Relapse in Participants With Response (>=50% Reduction From Baseline in MADRS Total Score) But Who Are Not in Remission
Time to relapse in participants with response (\>=50% reduction from baseline in MADRS total score) but who are not in remission was reported. Relapse is defined as any of the following: 1) MADRS total score \>= 22 for 2 consecutive assessments. The date of the second MADRS assessment was used for the date of relapse. 2)Hospitalization for worsening depression or any other clinically relevant event determined per clinical judgment to be suggestive of relapse of depressive illness like suicide attempt, completed suicide, or hospitalization for suicide prevention. If hospitalized for any of these events, start date of hospitalization was used as relapse date. If participant was not hospitalized, event date was used. 3) If both relapse criteria were met, earlier date was defined as date of relapse. Remission was defined as MADRS total score \<=12.
Time frame: From EndPoint (last post baseline assessment value during the DB induction phase [up to Day 28]) up to 24 weeks (posttreatment phase)
Population: Population included participants with response (not remit) at the end of DB.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Esketamine 28 Milligrams (mg) | Posttreatment Phase: Time to Relapse in Participants With Response (>=50% Reduction From Baseline in MADRS Total Score) But Who Are Not in Remission | 32.0 Days |
| Esketamine 56 mg | Posttreatment Phase: Time to Relapse in Participants With Response (>=50% Reduction From Baseline in MADRS Total Score) But Who Are Not in Remission | 26.0 Days |
| Esketamine 84 mg | Posttreatment Phase: Time to Relapse in Participants With Response (>=50% Reduction From Baseline in MADRS Total Score) But Who Are Not in Remission | 79.5 Days |
| Placebo | Posttreatment Phase: Time to Relapse in Participants With Response (>=50% Reduction From Baseline in MADRS Total Score) But Who Are Not in Remission | 91.0 Days |