A Double-blind Study to Assess the Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Participants Who Are Assessed to be at Imminent Risk for Suicide

Sponsor

Janssen Research & Development, LLC (Industry)

Overall Status

Completed

CT.gov ID

NCT02133001

Collaborator

(none)

Enrollment

Locations

Arms

20.3

Actual Duration (Months)

4.9

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of intranasal esketamine 84 milligram (mg) compared with intranasal placebo along with standard care treatment, in reducing the symptoms of major depressive disorder (MDD) (an affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities, the mood disturbance is prominent and relatively persistent), including the risk for suicide as assessed by the Investigator, in participants who will be assessed to be at imminent risk for suicide.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Esketamine Drug: Placebo	Phase 2

Detailed Description

This is a randomized (study medication assigned to participants by chance), double-blind (neither physician nor participant knows assigned study treatment), placebo-controlled (participants are randomly assigned to a test treatment or to an identical-appearing treatment that does not contain the test drug), and multicenter (when more than one hospital or medical school team works on a medical research study), study of esketamine in participants with major depressive disorder (MDD) in participants who will be assessed to be at imminent risk for suicide, as measured by the change from Baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) total score at 4 hours postdose on Day 1. The duration of study will be approximately 81 days per participant. The study consists of 3 parts: Screening (that is, with in 1 day before study commences on Day 1) and double-blind Treatment (from Day 1-25) and Follow-up (from Day 26 up to Day 81). All the eligible participants will be provided standard care treatment and will be randomly assigned to either esketmaine or placebo treatment. Esketamine/placebo will be administered by intranasal route (delivery of medications through the nasal mucosa) two times per week for 4 weeks. Efficacy of the participants will be primarily evaluated through MADRS. Participants' safety will be monitored throughout the study.

Study Design

Study Type:

Interventional

Actual Enrollment :

68 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Double-blind, Randomized, Placebo Controlled Study to Evaluate the Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Subjects Who Are Assessed to be at Imminent Risk for Suicide

Actual Study Start Date :

May 23, 2014

Actual Primary Completion Date :

Feb 1, 2016

Actual Study Completion Date :

Feb 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Esketamine Esketamine hydrochloride solution (containing 14 milligram (mg) of esketamine base per 100 microliter [mcl] of intranasal spray) will be administered by intranasal route using nasal spray pump as two times a week, for 4 weeks. Dose may be reduced to 56 mg per day based on Investigator's discretion.	Drug: Esketamine Esketamine 84 mg will be self-administered by participants as intranasal spray as two times a week, for 4 weeks (that is, Day 1,4,8,11,15,18,22,25). Dose may be reduced to 56 mg per day based on Investigator's discretion. Other Names: Esketamine hydrochloride
Placebo Comparator: Placebo Matching Placebo solution will be administered by intranasal route using nasal spray pump as two times a week, for 4 weeks.	Drug: Placebo Matching placebo will be self-administered by participants as intranasal spray as two times a week, for 4 weeks (that is, Day 1,4,8,11,15,18,22,25).

Arm

Intervention/Treatment

Experimental: Esketamine

Esketamine hydrochloride solution (containing 14 milligram (mg) of esketamine base per 100 microliter [mcl] of intranasal spray) will be administered by intranasal route using nasal spray pump as two times a week, for 4 weeks. Dose may be reduced to 56 mg per day based on Investigator's discretion.

Drug: Esketamine

Esketamine 84 mg will be self-administered by participants as intranasal spray as two times a week, for 4 weeks (that is, Day 1,4,8,11,15,18,22,25). Dose may be reduced to 56 mg per day based on Investigator's discretion.

Other Names:

Esketamine hydrochloride

Placebo Comparator: Placebo

Matching Placebo solution will be administered by intranasal route using nasal spray pump as two times a week, for 4 weeks.

Drug: Placebo

Matching placebo will be self-administered by participants as intranasal spray as two times a week, for 4 weeks (that is, Day 1,4,8,11,15,18,22,25).

Outcome Measures

Primary Outcome Measures

Change From Baseline to Day 1: 4-Hour Post-dose in Montgomery Asberg Depression Rating Scale (MADRS) Total Score (Double-blind Phase) [Baseline (Day 1-Predose) to Day 1: 4-hours post-dose]
The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition. The last observation carried forward (LOCF) approach was used for missing visit data in the ITT LOCF efficacy analyses.

Secondary Outcome Measures

Percentage of Participants With Sustained Response Based on MADRS Total Score (Double-blind Phase) [Day 1 to Day 25]
Sustained response is defined as a reduction from baseline in MADRS total score of greater than or equal to 50 percent, with onset on Day 1 that is maintained through the end of the double-blind phase (Day 25). The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses.
Change From Baseline to Day 2 in MADRS Total Score (Double-blind Phase) [Baseline (Day 1-predose) to Day 2]
The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses.
Change From Baseline to Double-blind Phase-End Point (Day 25) in MADRS Total Score (Double-blind Phase) [Baseline (Day 1-predose) to Double-blind Phase-End Point (Day 25)]
The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses. The last post baseline observation was carried forward as the "End Point" for the double-blind phase.
Percentage of Participants With Response Based on MADRS Total Score During the Double-Blind Phase [Day 1 (4 hours postdose), Day 2 (double blind phase), Double blind phase -Endpoint (Day 25)]
Percentage of participants with response (greater than or equal to (>=) 50% improvement from baseline in MADRS total score) during the double- blind phase was assessed. The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition.
Percentage of Participants With Response Based on MADRS Total Score at Follow up Phase Endpoint [Follow up phase-endpoint (Day 81)]
Percentage of participants with response (greater than or equal to (>=) 50% improvement from baseline in MADRS total score) during the follow up was assessed. The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition.
Change From Baseline to Day 1: 4-hours Post-dose in Suicide Ideation and Behavior Assessment Tool (SIBAT)-Clinical Global Judgment of Suicide Risk (CGJ-SR) Module 8 Score (Double-blind Phase) [Baseline (Day 1-predose) to Day 1: 4-hours Postdose]
SIBAT CGJ-SR: Module 8 operates numerous clinical global impression (CGI) severity scales used in other psychiatric studies. Changes in CGJ-SR designed to categorize clinically meaningful changes in clinician rated suicide risk from 'not at all suicidal' to 'participant is at imminent risk of suicide and immediate need for strong intervention (hospitalization with 24 hour 1:1 observation).' Patient scores for clinician-rated suicide risk: 0 (not suicidal); 1(occasional suicidal ideas, no intervention required);2(some clear suicidal ideas present),3(suicidal risk requires scheduled outpatient follow-up,no immediate intervention),4(suicidal risk requires immediate intervention, no hospitalization). 5( suicidal risk requires immediate hospitalization, no suicide precautions),6 (suicide risk requires hospitalization with suicide precautions). LOCF approach used for missing visit data in ITT LOCF efficacy analyses.
Change From Baseline to Day 2 in Suicide Ideation and Behavior Assessment Tool (SIBAT)-Clinical Global Judgment of Suicide Risk (SIBAT CGJ-SR) Module 8 Score (Double-blind Phase) [Baseline (Day 1-predose) to Day 2]
SIBAT CGJ-SR: Module 8 operates like numerous other CGI severity scales used in other psychiatric studies. Changes in CGJ-SR designed to categorize clinically meaningful changes in clinician rated suicide risk from 'not at all suicidal' to 'participant is at imminent risk of suicide and immediate need for strong intervention (hospitalization with 24 hour 1:1 observation).' Patient scores for clinician-rated suicide risk: 0 (not suicidal); 1(occasional suicidal ideas, no intervention required);2(some clear suicidal ideas present),3(suicidal risk requires scheduled outpatient follow-up,no immediate intervention),4(suicidal risk requires immediate intervention, no hospitalization). 5( suicidal risk requires immediate hospitalization, no suicide precautions),6 (suicide risk requires hospitalization with suicide precautions). LOCF approach used for missing visit data in ITT LOCF efficacy analyses.
Change From Baseline to Double-blind Phase-Endpoint (Day 25) Suicide Ideation and Behavior Assessment Tool (SIBAT)-Clinical Global Judgment of Suicide Risk (SIBAT CGJ-SR) Module 8 (Double-blind Phase) [Baseline (Day 1-predose) to Double-blind Phase-Endpoint (Day 25)]
SIBAT CGJ-SR: Module 8 operates like numerous other CGI severity scales used in other psychiatric studies. Changes in CGJ-SR designed to categorize clinically meaningful changes in clinician rated suicide risk from 'not at all suicidal' to 'participant is at imminent risk of suicide and immediate need for strong intervention (hospitalization with 24 hour 1:1 observation).' Patient scores for clinician-rated suicide risk: 0 (not suicidal); 1(occasional suicidal ideas, no intervention required);2(some clear suicidal ideas present),3(suicidal risk requires scheduled outpatient follow-up,no immediate intervention),4(suicidal risk requires immediate intervention, no hospitalization). 5( suicidal risk requires immediate hospitalization, no suicide precautions),6 (suicide risk requires hospitalization with suicide precautions). LOCF approach used for missing visit data in ITT LOCF efficacy analyses. Last post baseline observation was carried forward as "End Point" for the double-blind phase.
Change From Baseline to Follow-up Phase-Endpoint (Day 81) in Suicide Ideation and Behavior Assessment Tool (SIBAT)-Clinical Global Judgment of Suicide Risk Score (Follow-up Phase) [Baseline (Day 1-predose) to Follow-up Phase-Endpoint (Day 81)]
SIBAT CGJ-SR: Module 8 operates like numerous other CGI severity scales used in other psychiatric studies. Changes in CGJ-SR designed to categorize clinically meaningful changes in clinician rated suicide risk from 'not at all suicidal' to 'participant is at imminent risk of suicide and immediate need for strong intervention (hospitalization with 24 hour 1:1 observation).' Patient scores for clinician-rated suicide risk: 0 (not suicidal); 1(occasional suicidal ideas, no intervention required);2(some clear suicidal ideas present),3(suicidal risk requires scheduled outpatient follow-up,no immediate intervention),4(suicidal risk requires immediate intervention, no hospitalization). 5( suicidal risk requires immediate hospitalization, no suicide precautions),6 (suicide risk requires hospitalization with suicide precautions). LOCF approach used for missing visit data in ITT LOCF efficacy analyses. Last post baseline observation was carried forward as "End Point" for follow up phase.
Change From Baseline to Day 1: 4- Hours Postdose in SIBAT-Patient-Reported Global Assessment of Suicide Risk (Module 6) Score (Double-blind Phase) [Baseline (Day 1-predose) to Day 1: 4-hours postdose]
SIBAT was specifically developed to measure rapid change in suicidality, based on concerns that existing scales such as Beck Scale for Suicidal Ideation (BSS) are not designed to discriminate differences associated with rapid change. Patient-rated section includes following modules: Module 1 (M-1)(demographic information,suicide history), M-2(current suicidal thinking),M-3 (protective factors), M-4 (suicide behavior),M-5(suicide risk),M-6(suicide-implicit association test).Patient-reported global assessment of suicide risk summarizes patient's judgment of suicide risk (Module 6). Scores: 0(None), 1(Very weak), 2(Weak), 3(Moderately weak), 4(Mild), 5(Moderate), 6 (Moderately strong), 7(Strong), 8(Extremely strong), 9(Extremely strong,constant). Negative change in score indicates improvement. LOCF approach used for missing visit data in the ITT LOCF efficacy analyses.
Change From Baseline to Day 2 in Suicide Ideation and Behavior Assessment Tool Patient-Reported Global Assessment of Suicide Risk (Module 6) Score (Double-blind Phase) [Baseline (Day 1-predose) to Day 2]
SIBAT was specifically developed to measure rapid change in suicidality, based on concerns that existing scales such as BSS are not designed to discriminate differences associated with rapid change. Patient-rated section includes following modules: Module 1 (M-1)(demographic information,suicide history), M-2(current suicidal thinking),M-3 (protective factors), M-4 (suicide behavior),M-5(suicide risk),M-6(suicide-implicit association test).Patient-reported global assessment of suicide risk summarizes patient's judgment of suicide risk (Module 6). Scores: 0(None), 1(Very weak), 2(Weak), 3(Moderately weak), 4(Mild), 5(Moderate), 6 (Moderately strong), 7(Strong), 8(Extremely strong), 9(Extremely strong,constant). Negative change in score indicates improvement. LOCF approach used for missing visit data in the ITT LOCF efficacy analyses.
Change From Baseline to Double Blind Phase-Endpoint (Day 25) in Suicide Ideation and Behavior Assessment Tool Patient-Reported Global Assessment of Suicide Risk (Module 6) Score (Double-blind Phase) [Baseline (Day 1-predose) to Double-blind Phase-Endpoint (Day 25)]
SIBAT was specifically developed to measure rapid change in suicidality, based on concerns that existing scales such as BSS are not designed to discriminate differences associated with rapid change. Patient-rated section includes following modules: Module 1 (M-1)(demographic information,suicide history), M-2(current suicidal thinking),M-3 (protective factors), M-4 (suicide behavior),M-5(suicide risk),M-6(suicide-implicit association test).Patient-reported global assessment of suicide risk summarizes patient's judgment of suicide risk (Module 6). Scores: 0(None), 1(Very weak), 2(Weak), 3(Moderately weak), 4(Mild), 5(Moderate), 6 (Moderately strong), 7(Strong), 8(Extremely strong), 9(Extremely strong,constant). Negative change in score indicates improvement. LOCF approach used for missing visit data in the ITT LOCF efficacy analyses. Last post baseline observation was carried forward as "End Point" for double-blind phase.
Change From Baseline to Follow-up Phase-Endpoint (Day 81) in Suicide Ideation and Behavior Assessment Tool Patient-Reported Global Assessment of Suicide Risk (Module 6) Score (Follow-up Phase) [Baseline (Day 1-predose) to Follow-up Phase Endpoint (Day 81)]
SIBAT was specifically developed to measure rapid change in suicidality, based on concerns that existing scales such as BSS are not designed to discriminate differences associated with rapid change. Patient-rated section includes following modules: Module 1 (M-1)(demographic information,suicide history), M-2(current suicidal thinking),M-3 (protective factors), M-4 (suicide behavior),M-5(suicide risk),M-6(suicide-implicit association test).Patient-reported global assessment of suicide risk summarizes patient's judgment of suicide risk (Module 6). Scores: 0(None), 1(Very weak), 2(Weak), 3(Moderately weak), 4(Mild), 5(Moderate), 6 (Moderately strong), 7(Strong), 8(Extremely strong), 9(Extremely strong,constant). Negative change in score indicates improvement. LOCF approach used for missing visit data in ITT LOCF efficacy analyses, last post baseline observation was carried forward as the "End Point" follow up phase.
Change From Baseline to Day 1: 4-Hours Postdose in Beck Scale for Suicidal Ideation (BSS) Total Score (Double-blind Phase) [Baseline (Day 1-predose) to Day 1: 4-hours postdose]
BSS is 21-item self-reported instrument to detect and measure severity of suicidal ideation. BSS measures broad spectrum of attitudes and behaviors associated with risk of suicide. Items in scale assess respondent's suicidal plans, deterrents to suicide, level of openness to revealing suicidal thoughts. First 19 items of scale measure gradations of severity of suicidal wishes,attitude, plans.Statements reflect increasing gradations of this severity,are scored from 0 to 2. Final two items ask about number of suicide attempts, seriousness of intention to die associated with last attempt,they are not used in calculating BSS total score. Total BSS score represents severity of suicide ideation, calculated by summing ratings of first 19 items;total score ranges from 0 to 38, with higher score representing greater suicide ideation. LOCF approach used for missing visit data in ITT LOCF efficacy analyses.
Change From Baseline to Day 2 in Beck Scale for Suicidal Ideation (BSS) Total Score (Double-blind Phase) [Baseline (Day 1-predose) to Day 2]
BSS is 21-item self-reported instrument to detect and measure severity of suicidal ideation. BSS measures broad spectrum of attitudes and behaviors associated with risk of suicide. Items in scale assess respondent's suicidal plans, deterrents to suicide,level of openness to revealing suicidal thoughts. First 19 items of scale measure gradations of severity of suicidal wishes, attitude, plans.Statements reflect increasing gradations of this severity,are scored from 0 to 2. Final two items ask about number of suicide attempts, seriousness of intention to die associated with last attempt,they are not used in calculating BSS total score. Total BSS score represents severity of suicide ideation, calculated by summing ratings of first 19 items;total score ranges from 0 to 38, with higher score representing greater suicide ideation. LOCF approach used for missing visit data in ITT LOCF efficacy analyses.
Change From Baseline to Double-blind Phase-Endpoint (Day 25) in Beck Scale for Suicidal Ideation Total Score (Double-blind Phase) [Baseline (Day 1-predose) to Double-blind Phase-endpoint (Day 25)]
BSS is 21-item self-reported instrument to detect and measure severity of suicidal ideation.BSS measures broad spectrum of attitudes and behaviors associated with risk of suicide. Items in scale assess respondent's suicidal plans, deterrents to suicide, level of openness to revealing suicidal thoughts. First 19 items of scale measure gradations of severity of suicidal wishes, attitude, plans.Statements reflect increasing gradations of this severity,are scored from 0 to 2. Final two items ask about number of suicide attempts, seriousness of intention to die associated with last attempt,they are not used in calculating BSS total score. Total BSS score represents severity of suicide ideation, calculated by summing ratings of first 19 items;total score ranges from 0 to 38, with higher score representing greater suicide ideation. LOCF approach used for missing visit data in ITT LOCF efficacy analyses. Last post baseline observation was carried forward as "End Point" for double-blind phase.
Change From Baseline to Follow-up Phase-Endpoint (Day 81) in Beck Scale for Suicidal Ideation Total Score (Follow-up Phase) [Baseline (Day 1-predose) to Follow-up Phase-Endpoint (Day 81)]
BSS is 21-item self-reported instrument to detect and measure severity of suicidal ideation. BSS measures broad spectrum of attitudes and behaviors associated with risk of suicide. Items in scale assess respondent's suicidal plans, deterrents to suicide, level of openness to revealing suicidal thoughts. First 19 items of scale measure gradations of severity of suicidal wishes, attitude, plans.Statements reflect increasing gradations of this severity,are scored from 0 to 2. Final two items ask about number of suicide attempts, seriousness of intention to die associated with last attempt,they are not used in calculating BSS total score. Total BSS score represents severity of suicide ideation, calculated by summing ratings of first 19 items;total score ranges from 0 to 38, with higher score representing greater suicide ideation. LOCF approach used for missing visit data in ITT LOCF efficacy analyses, last post baseline observation was carried forward as the "End Point" follow up phase.
Change From Baseline to Day 1: 4-Hours Postdose in Beck Hopelessness Scale (BHS) Total Score (Double-blind Phase) [Baseline (Day 1-predose) to Day 1: 4-hours Postdose]
BHS is paper-based self-reported measure to assess one's level of negative expectations or pessimism regarding future. Consists of 20 true-false items that examine the respondent's attitude over past week by either endorsing a pessimistic statement or denying an optimistic statement; 9 are keyed false and 11 are keyed true. Items fall within 3 domains: feelings about future; loss of motivation; future expectations. each response is assigned a score of 0 or 1. Total BHS score is sum of item responses, with range from 0 to 20, with a higher score representing higher level of hopelessness. Total scores that range from 0 to 3 are (normal range), scores 4 to 8 (mild hopelessness, scores 9 to 14 (moderate hopelessness), scores <14 (severe hopelessness). Negative change in score indicates improvement. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses.
Change From Baseline to Double-blind Phase-Endpoint (Day 25) in Beck Hopelessness Scale Total Score (Double-blind Phase) [Baseline (Day 1-predose) to Double-blind Phase-Endpoint (Day 25)]
BHS is paper-based self-reported measure to assess one's level of negative expectations or pessimism regarding future. Consists of 20 true-false items that examine the respondent's attitude over past week by either endorsing a pessimistic statement or denying an optimistic statement; 9 are keyed false and 11 are keyed true. Items fall within 3 domains: feelings about future; loss of motivation; future expectations. each response is assigned a score of 0 or 1. Total BHS score is sum of item responses, with range from 0 to 20, with a higher score representing higher level of hopelessness. Total scores that range from 0 to 3 are (normal range), scores 4 to 8 (mild hopelessness, scores 9 to 14 (moderate hopelessness), scores <14 (severe hopelessness). Negative change in score indicates improvement. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses. The last post baseline observation was carried forward as the "End Point" for the double-blind phase.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 64 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participants must meet Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) diagnostic criteria for major depressive disorder
Participants must have current suicidal ideation with intent
In the Investigator's opinion, participant must be in need of acute psychiatric hospitalization due to imminent risk of suicide
Participant has a Montgomery Asberg Depression Rating Scale (MADRS) total score of greater than or equal to (>=) 22 predose on Day 1
As part of standard of care treatment, participant agrees to be hospitalized voluntarily for a recommended period of 5 days after randomization (that is, through Day 5), and take prescribed non-investigational antidepressant therapy(ies) for at least the duration of the double-blind treatment phase (Day 25)

Exclusion Criteria:

Participant has a current clinical diagnosis of bipolar or related disorders, intellectual disability, or cluster b personality disorder (example, borderline personality disorder, antisocial personality disorder, histrionic personality disorder, and narcissistic personality disorder)
Participant meets DSM-IV criteria for borderline personality disorder, based on clinical interview
Participant has a current or prior diagnosis of a psychotic disorder, major depressive disorder (MDD) with psychosis, or obsessive compulsive disorder
Participant with a history or current signs and symptoms of liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, or metabolic disturbances
Participant has uncontrolled hypertension (systolic blood pressure greater than [>] 160 millimeter of mercury [mmHg] or diastolic blood pressure > 90 mmHg) despite diet, exercise or a stable dose of an allowed anti-hypertensive treatment at Screening; or any past history of hypertensive crisis

Contacts and Locations

Locations

	City	State	Country
1	Birmingham	Alabama	United States
2	San Diego	California	United States
3	Hartford	Connecticut	United States
4	New Haven	Connecticut	United States
5	Atlanta	Georgia	United States
6	Iowa City	Iowa	United States
7	Baltimore	Maryland	United States
8	Towson	Maryland	United States
9	Ann Arbor	Michigan	United States
10	Rochester	Minnesota	United States
11	Cincinnati	Ohio	United States
12	Philadelphia	Pennsylvania	United States
13	Pittsburgh	Pennsylvania	United States
14	Houston	Texas	United States

Sponsors and Collaborators

Janssen Research & Development, LLC

Investigators

Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

A Double-blind Study to Assess the Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Participants Who are Assessed to be at Imminent Risk for Suicide

Publications

None provided.

Responsible Party:

Janssen Research & Development, LLC

ClinicalTrials.gov Identifier:

NCT02133001

Other Study ID Numbers:

CR103162
ESKETINSUI2001

First Posted:

May 7, 2014

Last Update Posted:

May 14, 2020

Last Verified:

May 1, 2020

Studies a U.S. FDA-regulated Drug Product:

Yes

Keywords provided by Janssen Research & Development, LLC

Major Depressive Disorder

Esketamine

Intranasal esketamine

Placebo

Additional relevant MeSH terms:

Disease

Depressive Disorder

Depression

Depressive Disorder, Major

Suicide

Suicidal Ideation

Esketamine

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Period Title: Double Blind (Day 1-25)
STARTED	32	36
Safety	31	35
COMPLETED	22	27
NOT COMPLETED	10	9
Period Title: Double Blind (Day 1-25)
STARTED	22	27
COMPLETED	20	24
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Placebo	Esketamine 84 mg	Total
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.	Total of all reporting groups
Overall Participants	31	35	66
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36 (12.82)	35.7 (13.4)	35.8 (13.03)
Sex: Female, Male (Count of Participants)
Female	21 67.7%	22 62.9%	43 65.2%
Male	10 32.3%	13 37.1%	23 34.8%
Region of Enrollment (Count of Participants)
United States	31 100%	35 100%	66 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Day 1: 4-Hour Post-dose in Montgomery Asberg Depression Rating Scale (MADRS) Total Score (Double-blind Phase)
Description	The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition. The last observation carried forward (LOCF) approach was used for missing visit data in the ITT LOCF efficacy analyses.
Time Frame	Baseline (Day 1-Predose) to Day 1: 4-hours post-dose

Outcome Measure Data

Analysis Population Description
Intent-To-Treat Analysis (ITT) analysis set defined as all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	35
Mean (Standard Deviation) [Units on a scale]	-9.1 (8.38)	-13.4 (9.03)

2. Secondary Outcome

Title	Percentage of Participants With Sustained Response Based on MADRS Total Score (Double-blind Phase)
Description	Sustained response is defined as a reduction from baseline in MADRS total score of greater than or equal to 50 percent, with onset on Day 1 that is maintained through the end of the double-blind phase (Day 25). The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses.
Time Frame	Day 1 to Day 25

Outcome Measure Data

Analysis Population Description
ITT analysis set defined as all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	35
Number [Percentage of participants]	6.7 21.6%	11.8 33.7%

3. Secondary Outcome

Title	Change From Baseline to Day 2 in MADRS Total Score (Double-blind Phase)
Description	The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses.
Time Frame	Baseline (Day 1-predose) to Day 2

Outcome Measure Data

Analysis Population Description
Intent-To-Treat Analysis (ITT) analysis set defined as all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	35
Mean (Standard Deviation) [Units on a scale]	-12.8 (9.77)	-19.3 (12.02)

4. Secondary Outcome

Title	Change From Baseline to Double-blind Phase-End Point (Day 25) in MADRS Total Score (Double-blind Phase)
Description	The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses. The last post baseline observation was carried forward as the "End Point" for the double-blind phase.
Time Frame	Baseline (Day 1-predose) to Double-blind Phase-End Point (Day 25)

Outcome Measure Data

Analysis Population Description
Intent-To-Treat Analysis (ITT) analysis set defined as all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	35
Mean (Standard Deviation) [units on a scale]	-23.0 (10.83)	-26.4 (14.52)

5. Secondary Outcome

Title	Percentage of Participants With Response Based on MADRS Total Score During the Double-Blind Phase
Description	Percentage of participants with response (greater than or equal to (>=) 50% improvement from baseline in MADRS total score) during the double- blind phase was assessed. The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition.
Time Frame	Day 1 (4 hours postdose), Day 2 (double blind phase), Double blind phase -Endpoint (Day 25)

Outcome Measure Data

Analysis Population Description
ITT analysis set defined as all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4-hour post dose evaluation for the MADRS total score.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	35
Day 1 (4 hours postdose)	12.9 41.6%	25.7 73.4%
Day 2 (double blind phase)	29.0 93.5%	54.3 155.1%
Double blind phase -Endpoint (Day 25)	54.8 176.8%	74.3 212.3%

6. Secondary Outcome

Title	Percentage of Participants With Response Based on MADRS Total Score at Follow up Phase Endpoint
Description	Percentage of participants with response (greater than or equal to (>=) 50% improvement from baseline in MADRS total score) during the follow up was assessed. The MADRS consists of 10 items that cover all of the core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item as well as the total score, a higher score represents a more severe condition.
Time Frame	Follow up phase-endpoint (Day 81)

Outcome Measure Data

Analysis Population Description
The ITT (Follow Up phase) analysis set was defined as all participants who had at least one measurement of MADRS total score during the follow up phase.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	22	27
Number [Percentage of participants]	63.6 205.2%	66.7 190.6%

7. Secondary Outcome

Title	Change From Baseline to Day 1: 4-hours Post-dose in Suicide Ideation and Behavior Assessment Tool (SIBAT)-Clinical Global Judgment of Suicide Risk (CGJ-SR) Module 8 Score (Double-blind Phase)
Description	SIBAT CGJ-SR: Module 8 operates numerous clinical global impression (CGI) severity scales used in other psychiatric studies. Changes in CGJ-SR designed to categorize clinically meaningful changes in clinician rated suicide risk from 'not at all suicidal' to 'participant is at imminent risk of suicide and immediate need for strong intervention (hospitalization with 24 hour 1:1 observation).' Patient scores for clinician-rated suicide risk: 0 (not suicidal); 1(occasional suicidal ideas, no intervention required);2(some clear suicidal ideas present),3(suicidal risk requires scheduled outpatient follow-up,no immediate intervention),4(suicidal risk requires immediate intervention, no hospitalization). 5( suicidal risk requires immediate hospitalization, no suicide precautions),6 (suicide risk requires hospitalization with suicide precautions). LOCF approach used for missing visit data in ITT LOCF efficacy analyses.
Time Frame	Baseline (Day 1-predose) to Day 1: 4-hours Postdose

Outcome Measure Data

Analysis Population Description
ITT analysis set: all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score. Here N (overall number of participants analyzed)signifies number of participants who were evaluable for this endpoint.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	33
Median (Full Range) [Units on a scale]	0	0

8. Secondary Outcome

Title	Change From Baseline to Day 2 in Suicide Ideation and Behavior Assessment Tool (SIBAT)-Clinical Global Judgment of Suicide Risk (SIBAT CGJ-SR) Module 8 Score (Double-blind Phase)
Description	SIBAT CGJ-SR: Module 8 operates like numerous other CGI severity scales used in other psychiatric studies. Changes in CGJ-SR designed to categorize clinically meaningful changes in clinician rated suicide risk from 'not at all suicidal' to 'participant is at imminent risk of suicide and immediate need for strong intervention (hospitalization with 24 hour 1:1 observation).' Patient scores for clinician-rated suicide risk: 0 (not suicidal); 1(occasional suicidal ideas, no intervention required);2(some clear suicidal ideas present),3(suicidal risk requires scheduled outpatient follow-up,no immediate intervention),4(suicidal risk requires immediate intervention, no hospitalization). 5( suicidal risk requires immediate hospitalization, no suicide precautions),6 (suicide risk requires hospitalization with suicide precautions). LOCF approach used for missing visit data in ITT LOCF efficacy analyses.
Time Frame	Baseline (Day 1-predose) to Day 2

Outcome Measure Data

Analysis Population Description
ITT analysis set: all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	35
Median (Full Range) [Units on a scale]	0	-1.0

9. Secondary Outcome

Title	Change From Baseline to Double-blind Phase-Endpoint (Day 25) Suicide Ideation and Behavior Assessment Tool (SIBAT)-Clinical Global Judgment of Suicide Risk (SIBAT CGJ-SR) Module 8 (Double-blind Phase)
Description	SIBAT CGJ-SR: Module 8 operates like numerous other CGI severity scales used in other psychiatric studies. Changes in CGJ-SR designed to categorize clinically meaningful changes in clinician rated suicide risk from 'not at all suicidal' to 'participant is at imminent risk of suicide and immediate need for strong intervention (hospitalization with 24 hour 1:1 observation).' Patient scores for clinician-rated suicide risk: 0 (not suicidal); 1(occasional suicidal ideas, no intervention required);2(some clear suicidal ideas present),3(suicidal risk requires scheduled outpatient follow-up,no immediate intervention),4(suicidal risk requires immediate intervention, no hospitalization). 5( suicidal risk requires immediate hospitalization, no suicide precautions),6 (suicide risk requires hospitalization with suicide precautions). LOCF approach used for missing visit data in ITT LOCF efficacy analyses. Last post baseline observation was carried forward as "End Point" for the double-blind phase.
Time Frame	Baseline (Day 1-predose) to Double-blind Phase-Endpoint (Day 25)

Outcome Measure Data

Analysis Population Description
Intent-To-Treat Analysis (ITT) analysis set defined as all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	35
Median (Full Range) [Units on a scale]	-5.0	-5.0

10. Secondary Outcome

Title	Change From Baseline to Follow-up Phase-Endpoint (Day 81) in Suicide Ideation and Behavior Assessment Tool (SIBAT)-Clinical Global Judgment of Suicide Risk Score (Follow-up Phase)
Description	SIBAT CGJ-SR: Module 8 operates like numerous other CGI severity scales used in other psychiatric studies. Changes in CGJ-SR designed to categorize clinically meaningful changes in clinician rated suicide risk from 'not at all suicidal' to 'participant is at imminent risk of suicide and immediate need for strong intervention (hospitalization with 24 hour 1:1 observation).' Patient scores for clinician-rated suicide risk: 0 (not suicidal); 1(occasional suicidal ideas, no intervention required);2(some clear suicidal ideas present),3(suicidal risk requires scheduled outpatient follow-up,no immediate intervention),4(suicidal risk requires immediate intervention, no hospitalization). 5( suicidal risk requires immediate hospitalization, no suicide precautions),6 (suicide risk requires hospitalization with suicide precautions). LOCF approach used for missing visit data in ITT LOCF efficacy analyses. Last post baseline observation was carried forward as "End Point" for follow up phase.
Time Frame	Baseline (Day 1-predose) to Follow-up Phase-Endpoint (Day 81)

Outcome Measure Data

Analysis Population Description
The ITT (Follow Up phase) analysis set was defined as all participants who had at least one measurement of MADRS total score during the follow up phase.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	22	27
Median (Full Range) [Units on a scale]	-5.0	-5.0

11. Secondary Outcome

Title	Change From Baseline to Day 1: 4- Hours Postdose in SIBAT-Patient-Reported Global Assessment of Suicide Risk (Module 6) Score (Double-blind Phase)
Description	SIBAT was specifically developed to measure rapid change in suicidality, based on concerns that existing scales such as Beck Scale for Suicidal Ideation (BSS) are not designed to discriminate differences associated with rapid change. Patient-rated section includes following modules: Module 1 (M-1)(demographic information,suicide history), M-2(current suicidal thinking),M-3 (protective factors), M-4 (suicide behavior),M-5(suicide risk),M-6(suicide-implicit association test).Patient-reported global assessment of suicide risk summarizes patient's judgment of suicide risk (Module 6). Scores: 0(None), 1(Very weak), 2(Weak), 3(Moderately weak), 4(Mild), 5(Moderate), 6 (Moderately strong), 7(Strong), 8(Extremely strong), 9(Extremely strong,constant). Negative change in score indicates improvement. LOCF approach used for missing visit data in the ITT LOCF efficacy analyses.
Time Frame	Baseline (Day 1-predose) to Day 1: 4-hours postdose

Outcome Measure Data

Analysis Population Description
Intent-To-Treat Analysis (ITT) analysis set defined as all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	35
Median (Full Range) [Units on scale]	-1.0	-1.0

12. Secondary Outcome

Title	Change From Baseline to Day 2 in Suicide Ideation and Behavior Assessment Tool Patient-Reported Global Assessment of Suicide Risk (Module 6) Score (Double-blind Phase)
Description	SIBAT was specifically developed to measure rapid change in suicidality, based on concerns that existing scales such as BSS are not designed to discriminate differences associated with rapid change. Patient-rated section includes following modules: Module 1 (M-1)(demographic information,suicide history), M-2(current suicidal thinking),M-3 (protective factors), M-4 (suicide behavior),M-5(suicide risk),M-6(suicide-implicit association test).Patient-reported global assessment of suicide risk summarizes patient's judgment of suicide risk (Module 6). Scores: 0(None), 1(Very weak), 2(Weak), 3(Moderately weak), 4(Mild), 5(Moderate), 6 (Moderately strong), 7(Strong), 8(Extremely strong), 9(Extremely strong,constant). Negative change in score indicates improvement. LOCF approach used for missing visit data in the ITT LOCF efficacy analyses.
Time Frame	Baseline (Day 1-predose) to Day 2

Outcome Measure Data

Analysis Population Description
Intent-To-Treat Analysis (ITT) analysis set defined as all randomized participants who received at least 1 dose of study medication during the double-blind phase and have both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	35
Median (Full Range) [Units on a scale]	-1.5	-2

13. Secondary Outcome

Title	Change From Baseline to Double Blind Phase-Endpoint (Day 25) in Suicide Ideation and Behavior Assessment Tool Patient-Reported Global Assessment of Suicide Risk (Module 6) Score (Double-blind Phase)
Description	SIBAT was specifically developed to measure rapid change in suicidality, based on concerns that existing scales such as BSS are not designed to discriminate differences associated with rapid change. Patient-rated section includes following modules: Module 1 (M-1)(demographic information,suicide history), M-2(current suicidal thinking),M-3 (protective factors), M-4 (suicide behavior),M-5(suicide risk),M-6(suicide-implicit association test).Patient-reported global assessment of suicide risk summarizes patient's judgment of suicide risk (Module 6). Scores: 0(None), 1(Very weak), 2(Weak), 3(Moderately weak), 4(Mild), 5(Moderate), 6 (Moderately strong), 7(Strong), 8(Extremely strong), 9(Extremely strong,constant). Negative change in score indicates improvement. LOCF approach used for missing visit data in the ITT LOCF efficacy analyses. Last post baseline observation was carried forward as "End Point" for double-blind phase.
Time Frame	Baseline (Day 1-predose) to Double-blind Phase-Endpoint (Day 25)

Outcome Measure Data

Analysis Population Description
Intent-To-Treat Analysis (ITT) analysis set defined as all randomized participants who received at least 1 dose of study medication during the double-blind phase and had both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	35
Mean (Full Range) [Units on a scale]	-3.0	-4.0

14. Secondary Outcome

Title	Change From Baseline to Follow-up Phase-Endpoint (Day 81) in Suicide Ideation and Behavior Assessment Tool Patient-Reported Global Assessment of Suicide Risk (Module 6) Score (Follow-up Phase)
Description	SIBAT was specifically developed to measure rapid change in suicidality, based on concerns that existing scales such as BSS are not designed to discriminate differences associated with rapid change. Patient-rated section includes following modules: Module 1 (M-1)(demographic information,suicide history), M-2(current suicidal thinking),M-3 (protective factors), M-4 (suicide behavior),M-5(suicide risk),M-6(suicide-implicit association test).Patient-reported global assessment of suicide risk summarizes patient's judgment of suicide risk (Module 6). Scores: 0(None), 1(Very weak), 2(Weak), 3(Moderately weak), 4(Mild), 5(Moderate), 6 (Moderately strong), 7(Strong), 8(Extremely strong), 9(Extremely strong,constant). Negative change in score indicates improvement. LOCF approach used for missing visit data in ITT LOCF efficacy analyses, last post baseline observation was carried forward as the "End Point" follow up phase.
Time Frame	Baseline (Day 1-predose) to Follow-up Phase Endpoint (Day 81)

Outcome Measure Data

Analysis Population Description
The ITT (Follow Up phase) analysis set was defined as all participants who had at least one measurement of MADRS total score during the follow up phase.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	22	27
Median (Full Range) [Units on a scale]	-4.0	-3.0

15. Secondary Outcome

Title	Change From Baseline to Day 1: 4-Hours Postdose in Beck Scale for Suicidal Ideation (BSS) Total Score (Double-blind Phase)
Description	BSS is 21-item self-reported instrument to detect and measure severity of suicidal ideation. BSS measures broad spectrum of attitudes and behaviors associated with risk of suicide. Items in scale assess respondent's suicidal plans, deterrents to suicide, level of openness to revealing suicidal thoughts. First 19 items of scale measure gradations of severity of suicidal wishes,attitude, plans.Statements reflect increasing gradations of this severity,are scored from 0 to 2. Final two items ask about number of suicide attempts, seriousness of intention to die associated with last attempt,they are not used in calculating BSS total score. Total BSS score represents severity of suicide ideation, calculated by summing ratings of first 19 items;total score ranges from 0 to 38, with higher score representing greater suicide ideation. LOCF approach used for missing visit data in ITT LOCF efficacy analyses.
Time Frame	Baseline (Day 1-predose) to Day 1: 4-hours postdose

Outcome Measure Data

Analysis Population Description
ITT analysis set: all randomized participants who received at least 1 dose of study medication during the double-blind phase and have both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score. Here 'N' signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	34
Mean (Standard Deviation) [Units on a scale]	-8.3 (7.12)	-10.2 (9.74)

16. Secondary Outcome

Title	Change From Baseline to Day 2 in Beck Scale for Suicidal Ideation (BSS) Total Score (Double-blind Phase)
Description	BSS is 21-item self-reported instrument to detect and measure severity of suicidal ideation. BSS measures broad spectrum of attitudes and behaviors associated with risk of suicide. Items in scale assess respondent's suicidal plans, deterrents to suicide,level of openness to revealing suicidal thoughts. First 19 items of scale measure gradations of severity of suicidal wishes, attitude, plans.Statements reflect increasing gradations of this severity,are scored from 0 to 2. Final two items ask about number of suicide attempts, seriousness of intention to die associated with last attempt,they are not used in calculating BSS total score. Total BSS score represents severity of suicide ideation, calculated by summing ratings of first 19 items;total score ranges from 0 to 38, with higher score representing greater suicide ideation. LOCF approach used for missing visit data in ITT LOCF efficacy analyses.
Time Frame	Baseline (Day 1-predose) to Day 2

Outcome Measure Data

Analysis Population Description
ITT analysis set: all randomized participants who received at least 1 dose of study medication during the double-blind phase and have both the baseline and the Day 1, 4-hour post dose evaluation for the MADRS total score. Here 'N' signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	34
Mean (Standard Deviation) [Units on a scale]	-10.7 (7.73)	-12.9 (9.63)

17. Secondary Outcome

Title	Change From Baseline to Double-blind Phase-Endpoint (Day 25) in Beck Scale for Suicidal Ideation Total Score (Double-blind Phase)
Description	BSS is 21-item self-reported instrument to detect and measure severity of suicidal ideation.BSS measures broad spectrum of attitudes and behaviors associated with risk of suicide. Items in scale assess respondent's suicidal plans, deterrents to suicide, level of openness to revealing suicidal thoughts. First 19 items of scale measure gradations of severity of suicidal wishes, attitude, plans.Statements reflect increasing gradations of this severity,are scored from 0 to 2. Final two items ask about number of suicide attempts, seriousness of intention to die associated with last attempt,they are not used in calculating BSS total score. Total BSS score represents severity of suicide ideation, calculated by summing ratings of first 19 items;total score ranges from 0 to 38, with higher score representing greater suicide ideation. LOCF approach used for missing visit data in ITT LOCF efficacy analyses. Last post baseline observation was carried forward as "End Point" for double-blind phase.
Time Frame	Baseline (Day 1-predose) to Double-blind Phase-endpoint (Day 25)

Outcome Measure Data

Analysis Population Description
ITT analysis set: all randomized participants who received at least 1 dose of study medication during the double-blind phase and have both the baseline and the Day 1, 4-hour post dose evaluation for the MADRS total score. Here 'N' signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	31	34
Mean (Standard Deviation) [Units on a scale]	-16.0 (10.54)	-19.3 (9.61)

18. Secondary Outcome

Title	Change From Baseline to Follow-up Phase-Endpoint (Day 81) in Beck Scale for Suicidal Ideation Total Score (Follow-up Phase)
Description	BSS is 21-item self-reported instrument to detect and measure severity of suicidal ideation. BSS measures broad spectrum of attitudes and behaviors associated with risk of suicide. Items in scale assess respondent's suicidal plans, deterrents to suicide, level of openness to revealing suicidal thoughts. First 19 items of scale measure gradations of severity of suicidal wishes, attitude, plans.Statements reflect increasing gradations of this severity,are scored from 0 to 2. Final two items ask about number of suicide attempts, seriousness of intention to die associated with last attempt,they are not used in calculating BSS total score. Total BSS score represents severity of suicide ideation, calculated by summing ratings of first 19 items;total score ranges from 0 to 38, with higher score representing greater suicide ideation. LOCF approach used for missing visit data in ITT LOCF efficacy analyses, last post baseline observation was carried forward as the "End Point" follow up phase.
Time Frame	Baseline (Day 1-predose) to Follow-up Phase-Endpoint (Day 81)

Outcome Measure Data

Analysis Population Description
The ITT (Follow Up phase) analysis set was defined as all participants who had at least one measurement of MADRS total score during the follow up phase. Here 'N' signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	22	26
Mean (Standard Deviation) [Units on a scale]	-18.0 (9.92)	-20.3 (8.02)

19. Secondary Outcome

Title	Change From Baseline to Day 1: 4-Hours Postdose in Beck Hopelessness Scale (BHS) Total Score (Double-blind Phase)
Description	BHS is paper-based self-reported measure to assess one's level of negative expectations or pessimism regarding future. Consists of 20 true-false items that examine the respondent's attitude over past week by either endorsing a pessimistic statement or denying an optimistic statement; 9 are keyed false and 11 are keyed true. Items fall within 3 domains: feelings about future; loss of motivation; future expectations. each response is assigned a score of 0 or 1. Total BHS score is sum of item responses, with range from 0 to 20, with a higher score representing higher level of hopelessness. Total scores that range from 0 to 3 are (normal range), scores 4 to 8 (mild hopelessness, scores 9 to 14 (moderate hopelessness), scores <14 (severe hopelessness). Negative change in score indicates improvement. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses.
Time Frame	Baseline (Day 1-predose) to Day 1: 4-hours Postdose

Outcome Measure Data

Analysis Population Description
ITT analysis set: all randomized participants who received at least 1 dose of study medication during the double-blind phase and have both the baseline and the Day 1, 4-hour post dose evaluation for the MADRS total score. Here 'N' signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	30	35
Mean (Standard Deviation) [Units on a scale]	-3.1 (5.71)	-4.1 (5.63)

20. Secondary Outcome

Title	Change From Baseline to Double-blind Phase-Endpoint (Day 25) in Beck Hopelessness Scale Total Score (Double-blind Phase)
Description	BHS is paper-based self-reported measure to assess one's level of negative expectations or pessimism regarding future. Consists of 20 true-false items that examine the respondent's attitude over past week by either endorsing a pessimistic statement or denying an optimistic statement; 9 are keyed false and 11 are keyed true. Items fall within 3 domains: feelings about future; loss of motivation; future expectations. each response is assigned a score of 0 or 1. Total BHS score is sum of item responses, with range from 0 to 20, with a higher score representing higher level of hopelessness. Total scores that range from 0 to 3 are (normal range), scores 4 to 8 (mild hopelessness, scores 9 to 14 (moderate hopelessness), scores <14 (severe hopelessness). Negative change in score indicates improvement. The LOCF approach was used for missing visit data in the ITT LOCF efficacy analyses. The last post baseline observation was carried forward as the "End Point" for the double-blind phase.
Time Frame	Baseline (Day 1-predose) to Double-blind Phase-Endpoint (Day 25)

Outcome Measure Data

Analysis Population Description
ITT analysis set: all randomized participants who received at least 1 dose of study medication during the double-blind phase and have both the baseline and the Day 1-4 hour post dose evaluation for the MADRS total score. Here 'N' signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 weeks on days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase.	Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment (determined by the treating physician based on clinical judgment) on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.
Measure Participants	30	35
Mean (Standard Deviation) [Units on a scale]	-7.7 (7.81)	-10.3 (5.51)

Adverse Events

	Double Blind (Day 1-25): Placebo		Double Blind (Day 1-25): Esketamine 84 mg		Follow Up Phase (Day 26-81): Placebo		Follow Up Phase (Day 26-81): Esketamine 84 mg
Time Frame	Up to Day 81
Adverse Event Reporting Description	Safety analysis set included all randomized participants who receive at least 1 dose of study drug in the double-blind phase. Safety (FU) analysis set included all participants who had at least 1 visit during the follow-up phase.

Arm/Group Title	Double Blind (Day 1-25): Placebo		Double Blind (Day 1-25): Esketamine 84 mg		Follow Up Phase (Day 26-81): Placebo		Follow Up Phase (Day 26-81): Esketamine 84 mg
Arm/Group Description	Participants received intranasal placebo (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) administered twice weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment determined by the treating physician based on clinical judgment on Day 1 and continued for the duration of the double-blind treatment phase.		Participants self-administered 1 spray into each nostril (1 spray in each nostril at 0, 5 and 10 minutes using 3 devices on a single day) of Esketamine 84 milligram (mg) twice Weekly for 4 Weeks on Days 1, 4, 8, 11, 15, 18, 22, and Day 25 along with standard of care antidepressant treatment determined by the treating physician based on clinical judgment on Day 1 and continued for the duration of the double-blind treatment phase. After Day 1, a single dose reduction from esketamine 84 mg to esketamine 56 mg was permitted if a participant was unable to tolerate the intranasal esketamine 84 mg. Participants continued to receive the reduced dose for the duration of the double-blind treatment phase.		Participants who completed the double blind treatment phase were continued to follow-up phase for 81 days.		Participants who completed the double blind treatment phase were continued to follow-up phase for 81 days.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Double Blind (Day 1-25): Placebo		Double Blind (Day 1-25): Esketamine 84 mg		Follow Up Phase (Day 26-81): Placebo		Follow Up Phase (Day 26-81): Esketamine 84 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		4/35 (11.4%)		5/22 (22.7%)		1/27 (3.7%)
Infections and infestations
Cellulitis	0/31 (0%)		0/35 (0%)		1/22 (4.5%)		0/27 (0%)
Psychiatric disorders
Agitation	0/31 (0%)		1/35 (2.9%)		0/22 (0%)		0/27 (0%)
Depressive Symptom	0/31 (0%)		1/35 (2.9%)		0/22 (0%)		0/27 (0%)
Suicidal Ideation	0/31 (0%)		2/35 (5.7%)		1/22 (4.5%)		1/27 (3.7%)
Suicide Attempt	0/31 (0%)		0/35 (0%)		3/22 (13.6%)		0/27 (0%)
Other (Not Including Serious) Adverse Events
	Double Blind (Day 1-25): Placebo		Double Blind (Day 1-25): Esketamine 84 mg		Follow Up Phase (Day 26-81): Placebo		Follow Up Phase (Day 26-81): Esketamine 84 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/31 (80.6%)		30/35 (85.7%)		6/22 (27.3%)		11/27 (40.7%)
Ear and labyrinth disorders
Hyperacusis	0/31 (0%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Tinnitus	0/31 (0%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Vertigo	0/31 (0%)		4/35 (11.4%)		0/22 (0%)		0/27 (0%)
Eye disorders
Blepharospasm	2/31 (6.5%)		0/35 (0%)		0/22 (0%)		0/27 (0%)
Diplopia	0/31 (0%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Vision Blurred	0/31 (0%)		3/35 (8.6%)		0/22 (0%)		0/27 (0%)
Gastrointestinal disorders
Abdominal Pain	2/31 (6.5%)		0/35 (0%)		0/22 (0%)		1/27 (3.7%)
Constipation	3/31 (9.7%)		0/35 (0%)		0/22 (0%)		0/27 (0%)
Diarrhoea	0/31 (0%)		3/35 (8.6%)		0/22 (0%)		1/27 (3.7%)
Dry Mouth	0/31 (0%)		3/35 (8.6%)		0/22 (0%)		2/27 (7.4%)
Flatulence	2/31 (6.5%)		1/35 (2.9%)		0/22 (0%)		0/27 (0%)
Hypoaesthesia Oral	0/31 (0%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Nausea	1/31 (3.2%)		13/35 (37.1%)		1/22 (4.5%)		0/27 (0%)
Paraesthesia Oral	0/31 (0%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Toothache	2/31 (6.5%)		0/35 (0%)		1/22 (4.5%)		0/27 (0%)
Vomiting	0/31 (0%)		7/35 (20%)		0/22 (0%)		1/27 (3.7%)
General disorders
Fatigue	1/31 (3.2%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Feeling Abnormal	0/31 (0%)		3/35 (8.6%)		0/22 (0%)		0/27 (0%)
Feeling Cold	0/31 (0%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Infections and infestations
Cellulitis	0/31 (0%)		0/35 (0%)		2/22 (9.1%)		0/27 (0%)
Pharyngitis	0/31 (0%)		0/35 (0%)		0/22 (0%)		2/27 (7.4%)
Upper Respiratory Tract Infection	2/31 (6.5%)		0/35 (0%)		1/22 (4.5%)		1/27 (3.7%)
Investigations
Blood Pressure Increased	0/31 (0%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Weight Increased	0/31 (0%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Nervous system disorders
Dizziness	4/31 (12.9%)		12/35 (34.3%)		0/22 (0%)		1/27 (3.7%)
Dizziness Postural	0/31 (0%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Dysgeusia	5/31 (16.1%)		11/35 (31.4%)		0/22 (0%)		1/27 (3.7%)
Headache	8/31 (25.8%)		11/35 (31.4%)		2/22 (9.1%)		2/27 (7.4%)
Hypoaesthesia	0/31 (0%)		3/35 (8.6%)		0/22 (0%)		0/27 (0%)
Paraesthesia	1/31 (3.2%)		6/35 (17.1%)		0/22 (0%)		0/27 (0%)
Sedation	2/31 (6.5%)		6/35 (17.1%)		0/22 (0%)		1/27 (3.7%)
Somnolence	2/31 (6.5%)		4/35 (11.4%)		1/22 (4.5%)		0/27 (0%)
Tremor	1/31 (3.2%)		1/35 (2.9%)		0/22 (0%)		2/27 (7.4%)
Psychiatric disorders
Agitation	0/31 (0%)		3/35 (8.6%)		0/22 (0%)		0/27 (0%)
Anxiety	1/31 (3.2%)		6/35 (17.1%)		0/22 (0%)		0/27 (0%)
Dissociation	4/31 (12.9%)		11/35 (31.4%)		0/22 (0%)		0/27 (0%)
Euphoric Mood	2/31 (6.5%)		4/35 (11.4%)		0/22 (0%)		0/27 (0%)
Insomnia	2/31 (6.5%)		3/35 (8.6%)		0/22 (0%)		3/27 (11.1%)
Panic Attack	2/31 (6.5%)		0/35 (0%)		0/22 (0%)		0/27 (0%)
Renal and urinary disorders
Pollakiuria	2/31 (6.5%)		0/35 (0%)		0/22 (0%)		0/27 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	2/31 (6.5%)		0/35 (0%)		0/22 (0%)		1/27 (3.7%)
Intranasal Paraesthesia	2/31 (6.5%)		0/35 (0%)		0/22 (0%)		0/27 (0%)
Nasal Congestion	2/31 (6.5%)		1/35 (2.9%)		0/22 (0%)		1/27 (3.7%)
Nasal Discomfort	1/31 (3.2%)		3/35 (8.6%)		0/22 (0%)		0/27 (0%)
Oropharyngeal Pain	1/31 (3.2%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Pharyngeal Hypoaesthesia	0/31 (0%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Rhinalgia	2/31 (6.5%)		0/35 (0%)		0/22 (0%)		0/27 (0%)
Rhinorrhoea	2/31 (6.5%)		0/35 (0%)		0/22 (0%)		0/27 (0%)
Throat Irritation	0/31 (0%)		3/35 (8.6%)		0/22 (0%)		0/27 (0%)
Skin and subcutaneous tissue disorders
Acne	0/31 (0%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Hyperhidrosis	0/31 (0%)		2/35 (5.7%)		0/22 (0%)		0/27 (0%)
Rash	3/31 (9.7%)		1/35 (2.9%)		1/22 (4.5%)		0/27 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.

Results Point of Contact

Name/Title	Senior Medical Director
Organization	Janssen Research & Development, LLC
Phone	844-434-4210
Email	ClinicalTrialDisclosure@its.jnj.com

Responsible Party:

Janssen Research & Development, LLC

ClinicalTrials.gov Identifier:

NCT02133001

Other Study ID Numbers:

CR103162
ESKETINSUI2001

First Posted:

May 7, 2014

Last Update Posted:

May 14, 2020

Last Verified:

May 1, 2020

A Double-blind Study to Assess the Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Participants Who Are Assessed to be at Imminent Risk for Suicide

Study Details

Study Description

Brief Summary

Detailed Description

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

More Information

Additional Information:

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

More Information

Certain Agreements

Results Point of Contact