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) subjects 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 subjects know what treatment the subject is receiving), active-controlled, multicenter study (more than 1 study site) in subjects with TRD to assess the efficacy, safety, and tolerability of flexible 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). Subjects who rollover into a long-term maintenance study will not participate in the Follow-up Phase. The antidepressant treatment, as well as any other ongoing medications being taken for depression at screening (including adjunctive/ augmentation therapies), will continue unchanged, at the same dosage, from the start of Week 1 through the end of Week 4 of the screening/prospective observational phase. Subjects' safety will be monitored throughout the study.
Interventions
DRUGEsketamine
Participants will self-administer either 56 mg or 84 mg of esketamine, intranasally, twice per week as a flexible dose regimen in the Double-Blind Induction Phase.
DRUGPlacebo
Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a flexible dose regimen in the 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 upto 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 upto a dose of 150 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 upto 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, participant must have had non-response (greater 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 in the current episode of depression, 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. In addition, the 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 (ie, 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 psychosis, bipolar or related disorders (confirmed by the MINI), comorbid obsessive compulsive disorder, intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), 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 in the 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])- Analysis of Covariance (ANCOVA) Analysis | Baseline up to Endpoint (Double-blind Induction Phase [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. The last post baseline observation during the 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 Endpoint (Double-blind Induction Phase [Day 28]) | The 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. The last post baseline observation during the phase was carried forward as End Point for that phase. |
| Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (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-report scale assessing depressive symptoms. Each item is rated on 4-point scale (0=Not at all, 1=Several Days, 2=More than half days, 3=Nearly every day. Scale scores each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria and it has been used both as screening tool and measure of response to treatment for depression. The participant's item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. Severity of PHQ-9 categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19), Severe (20-27). |
| Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | Baseline up to Endpoint (Double-blind Induction Phase [Day 28]) | PHQ-9 is 9-item, self-report scale assessing depressive symptoms. Each item is rated on 4-point scale (0=Not at all, 1=Several Days, 2=More than half days, 3=Nearly every day). Scale scores each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria and it has been used both as screening tool and measure of response to treatment for depression. The participant's item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. 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 last post baseline observation during the phase was carried forward as End Point for that phase. |
| Percentage of Participants Who Achieved >=50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28]) | At Endpoint (Double-blind Induction Phase [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. The percentage of participants with greater than or equal to (\>=) 50 % reduction from baseline in MADRS total score was reported. The last post baseline observation during the phase was carried forward as End Point for that phase. |
| Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28]) | At Endpoint (Double-blind Induction Phase [Day 28]) | Remission was defined as participants who had a MADRS total score of less than or equal to (=\<) 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. The last post baseline observation during the phase was carried forward as End Point for that phase. |
| Percentage of Participants in Response (SDS Total Score <=12 and Individual Item Scores Each <=4) at the End of 4-Week Double-blind Induction Phase (Day 28) | At Day 28 [end of Double-blind Induction Phase] | Response defined as SDS total score \<= 12 and individual item scores each \<= 4. 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. |
| Percentage of Participants With Onset of Clinical Response on 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 is at least 50 percent (%) improvement from baseline in the MADRS total score with onset by Day 2 and Day 8 that was maintained 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. Participants who did not meet such criterion or discontinue during the study before Day 28 for any reason were considered as non-responders. |
| Change From Baseline in Clinical Global Impression-Severity (CGI-S) Total Score up to Endpoint (Double-blind Induction Phase [Day 28]) | Baseline 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. CGI-S permits global evaluation of participant's condition at given time. The last post baseline observation during the phase was carried forward as End Point for that phase. |
| Change From Baseline in Generalized Anxiety Disorder (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28]) | Baseline up to Endpoint (Double-blind Induction Phase [Day 28]) | GAD-7 is 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). The last post baseline observation during the phase was carried forward as End Point for that phase. |
| Change From Baseline in EQ 5D-5L-Health Status Index to End of Double-blind Induction Phase (Day 28) | Baseline up to End of Double-blind Induction Phase (Day 28) | European Quality of Life Group-5 Dimension-5-Level (EQ-5D-5L) is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a Health Status Index (HSI). Health Status Index range is -0.148 - 0.949, is anchored at 0 (dead) and 1 (full health). |
| Change From Baseline in EQ 5D-5L- European Quality of Life - Visual Analogue Scale (EQ-VAS) to End of Double-blind Induction Phase (Day 28) | Baseline up to End of Double-blind Induction Phase (Day 28) | EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. The EQ VAS self-rating records the respondent's own assessment of his or her overall health status at the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine). |
| Change From Baseline in EQ 5D-5L- Sum Score to End of Double-blind Induction Phase (Day 28) | Baseline up to End of Double-blind Induction Phase (Day 28) | EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ VAS). EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a Health Status Index (HSI). Health Status Index range is -0.148 - 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 a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) \*5. Higher score indicates worst health state. |
| Percentage of Participants in Remission (SDS Total Score <=6 and Individual Item Scores Each <=2) at the End of 4-Week Double-blind Induction Phase (Day 28) | At Day 28 (End of Double-blind Induction Phase) | Remission defined as SDS total score \<= 6 and individual item scores each \<= 2. 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 were 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. |
| 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. 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. |
Countries
Czechia, Germany, Poland, Spain, United States
Participant flow
Pre-assignment details
Total 236 participants were enrolled, out of which 227 were randomized and 9 participants were excluded due to Good Clinical Practice (GCP) violations.
Participants by arm
| Arm | Count |
|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) Participants self-administered (under direct supervision by HCP) esketamine 56 milligram (mg) or 84 mg intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22,25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day-Week 1 and 20 mg/day- Weeks 2-4 with MDT 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 MDT of 50 mg/day) or Venlafaxine XR (75 mg/day-Week 1, 150 mg/day-Week 2, and 225 mg/day-Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003\[NCT02493868\]) and had received at least 1 dose of intranasal Esketamine+ Oral AD in DB induction phase were followed in posttreatment follow-up phase for up to 24 weeks. | 115 |
| Intranasal Placebo Plus Oral AD Participants self-administered (under direct supervision by HCP) esketamine matched placebo intranasally twice weekly for 4 weeks (on Day 1,4,8,11,15,18,22 and 25). Simultaneously, participants initiated per fixed titration scheme a new open-label oral AD with one of following: \[Duloxetine (60 milligram (mg)/day- Weeks 1-4 with minimum dose for tolerability \[MDT\] of 60 mg/day); Escitalopram (10 mg/day- Week 1 and 20 mg/day- Weeks 2-4 with MDT 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 MDT of 50 mg/day) or Venlafaxine XR (75 mg/day- Week 1, 150 mg/day- Week 2, and 225 mg/day- Weeks 3 and 4 with MDT of 150 mg/day) during DB Induction Phase. Participants who were not eligible or who chose to not participate in maintenance of effect study (ESKETINTRD3003 \[NCT02493868\]) 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. | 109 |
| Total | 224 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind (DB) Phase (4 Weeks) | Adverse Event | 9 | 1 |
| Double Blind (DB) Phase (4 Weeks) | Lack of Efficacy | 2 | 0 |
| Double Blind (DB) Phase (4 Weeks) | Lost to Follow-up | 1 | 1 |
| Double Blind (DB) Phase (4 Weeks) | Other | 0 | 1 |
| Double Blind (DB) Phase (4 Weeks) | Protocol Violation | 2 | 2 |
| Double Blind (DB) Phase (4 Weeks) | Withdrawal by Subject | 4 | 7 |
| Follow-up Phase (24 Weeks) | Investigator Decision | 6 | 17 |
| Follow-up Phase (24 Weeks) | Lost to Follow-up | 3 | 3 |
| Follow-up Phase (24 Weeks) | Other | 3 | 2 |
| Follow-up Phase (24 Weeks) | Withdrawal by Subject | 6 | 3 |
Baseline characteristics
| Characteristic | Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Intranasal Placebo Plus Oral AD | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 115 Participants | 109 Participants | 224 Participants |
| Age, Continuous | 45 years STANDARD_DEVIATION 12.56 | 46.4 years STANDARD_DEVIATION 11.14 | 45.7 years STANDARD_DEVIATION 11.89 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 7 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 109 Participants | 99 Participants | 208 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 5 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 107 Participants | 102 Participants | 209 Participants |
| Region of Enrollment CZECH REPUBLIC | 30 Participants | 28 Participants | 58 Participants |
| Region of Enrollment GERMANY | 10 Participants | 10 Participants | 20 Participants |
| Region of Enrollment POLAND | 20 Participants | 18 Participants | 38 Participants |
| Region of Enrollment SPAIN | 9 Participants | 9 Participants | 18 Participants |
| Region of Enrollment UNITED STATES | 46 Participants | 44 Participants | 90 Participants |
| Sex: Female, Male Female | 76 Participants | 63 Participants | 139 Participants |
| Sex: Female, Male Male | 39 Participants | 46 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 115 | 0 / 109 | 0 / 34 | 0 / 52 |
| other Total, other adverse events | 90 / 115 | 53 / 109 | 7 / 34 | 6 / 52 |
| serious Total, serious adverse events | 1 / 115 | 1 / 109 | 1 / 34 | 0 / 52 |
Outcome results
Primary
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 in the 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) defined as all randomized participants who received at least 1 dose of intranasal study medication, 1 dose of oral antidepressant (AD) medication during double-blind induction phase (D-BIP). Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 in the Double-blind Induction Phase- Mixed-Effects Model Using Repeated Measures (MMRM) Analysis | -21.4 Units on a scale | Standard Deviation 12.32 |
| Intranasal Placebo Plus Oral AD | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Day 28 in the Double-blind Induction Phase- Mixed-Effects Model Using Repeated Measures (MMRM) Analysis | -17.0 Units on a scale | Standard Deviation 13.88 |
p-value: =0.0295% CI: [-7.31, -0.64]Mixed Model for Repeated Measures
Primary
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- Analysis of Covariance (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. The last post baseline observation during the phase was carried forward as End Point for that phase.
Time frame: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])
Population: FAS defined as all randomized participants who received at least 1 dose of intranasal study medication, 1 dose of AD medication during double-blind induction phase (D-BIP). Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- Analysis of Covariance (ANCOVA) Analysis | -19.6 Units on a scale | Standard Deviation 13.58 |
| Intranasal Placebo Plus Oral AD | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- Analysis of Covariance (ANCOVA) Analysis | -16.3 Units on a scale | Standard Deviation 14.24 |
p-value: =0.03495% CI: [-6.67, -0.26]ANCOVA
Secondary
Change From Baseline in Clinical Global Impression-Severity (CGI-S) Total 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. CGI-S permits global evaluation of participant's condition at given time. The last post baseline observation during the phase was carried forward as End Point for that phase.
Time frame: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])
Population: FAS defined as 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' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Total Score up to Endpoint (Double-blind Induction Phase [Day 28]) | -2.0 Units on a scale |
| Intranasal Placebo Plus Oral AD | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Total Score up to Endpoint (Double-blind Induction Phase [Day 28]) | -2.0 Units on a scale |
Secondary
Change From Baseline in EQ 5D-5L- European Quality of Life - Visual Analogue Scale (EQ-VAS) to End of Double-blind Induction Phase (Day 28)
EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. The EQ VAS self-rating records the respondent's own assessment of his or her overall health status at the time of completion, on a 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 is defined as 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' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Change From Baseline in EQ 5D-5L- European Quality of Life - Visual Analogue Scale (EQ-VAS) to End of Double-blind Induction Phase (Day 28) | 29.1 Units on a scale | Standard Deviation 26.32 |
| Intranasal Placebo Plus Oral AD | Change From Baseline in EQ 5D-5L- European Quality of Life - Visual Analogue Scale (EQ-VAS) to End of Double-blind Induction Phase (Day 28) | 20.9 Units on a scale | Standard Deviation 26.6 |
Secondary
Change From Baseline in EQ 5D-5L-Health Status Index to End of Double-blind Induction Phase (Day 28)
European Quality of Life Group-5 Dimension-5-Level (EQ-5D-5L) is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a Health Status Index (HSI). Health Status Index range is -0.148 - 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 is defined as 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' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Change From Baseline in EQ 5D-5L-Health Status Index to End of Double-blind Induction Phase (Day 28) | 0.288 Units on a Scale | Standard Deviation 0.2317 |
| Intranasal Placebo Plus Oral AD | Change From Baseline in EQ 5D-5L-Health Status Index to End of Double-blind Induction Phase (Day 28) | 0.231 Units on a Scale | Standard Deviation 0.2506 |
Secondary
Change From Baseline in EQ 5D-5L- Sum Score to End of Double-blind Induction Phase (Day 28)
EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ VAS). EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a Health Status Index (HSI). Health Status Index range is -0.148 - 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 a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Sum score ranges from 0 to 100 where, sum score = (sum of the scores from the 5 dimensions minus 5) \*5. Higher score indicates worst health state.
Time frame: Baseline up to End of Double-blind Induction Phase (Day 28)
Population: FAS is defined as 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' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Change From Baseline in EQ 5D-5L- Sum Score to End of Double-blind Induction Phase (Day 28) | -23.2 Units on a scale | Standard Deviation 16.64 |
| Intranasal Placebo Plus Oral AD | Change From Baseline in EQ 5D-5L- Sum Score to End of Double-blind Induction Phase (Day 28) | -17.1 Units on a scale | Standard Deviation 19.66 |
Secondary
Change From Baseline in Generalized Anxiety Disorder (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])
GAD-7 is 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). The last post baseline observation during the phase was carried forward as End Point for that phase.
Time frame: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])
Population: FAS is defined as 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' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Change From Baseline in Generalized Anxiety Disorder (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28]) | -7.9 Units on a scale | Standard Deviation 6.12 |
| Intranasal Placebo Plus Oral AD | Change From Baseline in Generalized Anxiety Disorder (GAD-7) Total Score up to Endpoint (Double-blind Induction Phase [Day 28]) | -6.8 Units on a scale | Standard Deviation 5.75 |
Secondary
Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis
PHQ-9 is 9-item, self-report scale assessing depressive symptoms. Each item is rated on 4-point scale (0=Not at all, 1=Several Days, 2=More than half days, 3=Nearly every day. Scale scores each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria and it has been used both as screening tool and measure of response to treatment for depression. The participant's item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. Severity of PHQ-9 categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19), Severe (20-27).
Time frame: Baseline up to Day 28 of Double-blind Induction phase
Population: FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' signifies overall number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis | -13.0 Units on a scale | Standard Deviation 6.42 |
| Intranasal Placebo Plus Oral AD | Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis | -10.2 Units on a scale | Standard Deviation 7.8 |
Secondary
Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis
PHQ-9 is 9-item, self-report scale assessing depressive symptoms. Each item is rated on 4-point scale (0=Not at all, 1=Several Days, 2=More than half days, 3=Nearly every day). Scale scores each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders, Major Depressive Disorder criteria and it has been used both as screening tool and measure of response to treatment for depression. The participant's item responses are summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. 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 last post baseline observation during the phase was carried forward as End Point for that phase.
Time frame: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])
Population: FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' signifies overall number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | -12.2 Units on a scale | Standard Deviation 6.87 |
| Intranasal Placebo Plus Oral AD | Change From Baseline in Patient Health Questionnaire - 9-Item Depression Module (PHQ-9) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | -10.1 Units on a scale | Standard Deviation 7.87 |
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. 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 up to Day 28 of Double-blind Induction phase
Population: FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis | -13.6 Units on a scale | Standard Deviation 8.31 |
| Intranasal Placebo Plus Oral AD | Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Day 28 of Double-blind Induction Phase- MMRM Analysis | -9.4 Units on a scale | Standard Deviation 8.43 |
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. 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. The last post baseline observation during the phase was carried forward as End Point for that phase.
Time frame: Baseline up to Endpoint (Double-blind Induction Phase [Day 28])
Population: FAS is defined as all randomized participants who received at least 1 dose of intranasal study medication and 1 dose of oral AD medication during double-blind induction phase. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | -12.5 Units on a scale | Standard Deviation 8.85 |
| Intranasal Placebo Plus Oral AD | Change From Baseline in Sheehan Disability Scale (SDS) Total Score up to Endpoint (Double-blind Induction Phase [Day 28])- ANCOVA Analysis | -9.3 Units on a scale | Standard Deviation 8.39 |
Secondary
Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28])
Remission was defined as participants who had a MADRS total score of less than or equal to (=\<) 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. The last post baseline observation during the phase was carried forward as End Point for that phase.
Time frame: At Endpoint (Double-blind Induction Phase [Day 28])
Population: FAS is defined as 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' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28]) | 48.2 Percentage of participants |
| Intranasal Placebo Plus Oral AD | Percentage of Participants in Remission (MADRS<=12) at the Endpoint (Double-blind Induction Phase [Day 28]) | 30.3 Percentage of participants |
Secondary
Percentage of Participants in Remission (SDS Total Score <=6 and Individual Item Scores Each <=2) at the End of 4-Week Double-blind Induction Phase (Day 28)
Remission defined as SDS total score \<= 6 and individual item scores each \<= 2. 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 were 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.
Time frame: At Day 28 (End of Double-blind Induction Phase)
Population: FAS is defined as 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' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Percentage of Participants in Remission (SDS Total Score <=6 and Individual Item Scores Each <=2) at the End of 4-Week Double-blind Induction Phase (Day 28) | 39.5 Percentage of participants |
| Intranasal Placebo Plus Oral AD | Percentage of Participants in Remission (SDS Total Score <=6 and Individual Item Scores Each <=2) at the End of 4-Week Double-blind Induction Phase (Day 28) | 20.9 Percentage of participants |
Secondary
Percentage of Participants in Response (SDS Total Score <=12 and Individual Item Scores Each <=4) at the End of 4-Week Double-blind Induction Phase (Day 28)
Response defined as SDS total score \<= 12 and individual item scores each \<= 4. 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: At Day 28 [end of Double-blind Induction Phase]
Population: FAS is defined as 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' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Percentage of Participants in Response (SDS Total Score <=12 and Individual Item Scores Each <=4) at the End of 4-Week Double-blind Induction Phase (Day 28) | 57.0 Percentage of participants |
| Intranasal Placebo Plus Oral AD | Percentage of Participants in Response (SDS Total Score <=12 and Individual Item Scores Each <=4) at the End of 4-Week Double-blind Induction Phase (Day 28) | 39.5 Percentage of participants |
Secondary
Percentage of Participants Who Achieved >=50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [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. The percentage of participants with greater than or equal to (\>=) 50 % reduction from baseline in MADRS total score was reported. The last post baseline observation during the phase was carried forward as End Point for that phase.
Time frame: At Endpoint (Double-blind Induction Phase [Day 28])
Population: FAS is defined as 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' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Percentage of Participants Who Achieved >=50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28]) | 63.4 Percentage of participants |
| Intranasal Placebo Plus Oral AD | Percentage of Participants Who Achieved >=50% Reduction From Baseline in MADRS Total Score at the Endpoint (Double-blind Induction Phase [Day 28]) | 49.5 Percentage of participants |
Secondary
Percentage of Participants With Onset of Clinical Response on Day 2 and Day 8
A participant was defined as having a clinical response if there is at least 50 percent (%) improvement from baseline in the MADRS total score with onset by Day 2 and Day 8 that was maintained 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. Participants who did not meet such criterion or discontinue during the study before Day 28 for any reason were considered as non-responders.
Time frame: Day 2 up to Day 28 and Day 8 up to Day 28
Population: FAS is defined as 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 (Esk) Plus Oral Antidepressant (AD) | Percentage of Participants With Onset of Clinical Response on Day 2 and Day 8 | Onset of Clinical response on Day 2 | 7.9 Percentage of participants |
| Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | Percentage of Participants With Onset of Clinical Response on Day 2 and Day 8 | Onset of Clinical response on Day 8 | 10.5 Percentage of participants |
| Intranasal Placebo Plus Oral AD | Percentage of Participants With Onset of Clinical Response on Day 2 and Day 8 | Onset of Clinical response on Day 2 | 4.6 Percentage of participants |
| Intranasal Placebo Plus Oral AD | Percentage of Participants With Onset of Clinical Response on Day 2 and Day 8 | Onset of Clinical response on Day 8 | 6.4 Percentage of participants |