54135419SUI3001: A Study to Evaluate the Efficacy and Safety of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Adult Participants Assessed to be at Imminent Risk for Suicide

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to evaluate the efficacy of intranasal esketamine 84 milligram (mg) compared with intranasal placebo in addition to comprehensive standard of care in reducing the symptoms of Major Depressive Disorder (MDD), including suicidal ideation, in participants who are 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 24 hours post first dose.

Detailed Description
-----------------
This is a randomized (study medication assigned to participants by chance), double-blind (neither the researchers nor the participants know what treatment the participant is receiving), placebo-controlled (an inactive substance which contains no drug) that is compared in a clinical trial with a drug to test if the drug has a real effect), multicenter (when more than one hospital or study team work on a medical research study) study. Study will enroll participants with suicidal ideation who are assessed to be at imminent risk for suicide. The study will consist of a screening evaluation performed within 48 hours prior to the Day 1 intranasal dose immediately followed by a 25-day double-blind treatment phase (Day 1 to 25), and a 65 day follow-up phase (Day 26 to Day 90). The total study duration for each subject will be approximately 13 weeks. Participants' safety will be evaluated throughout the study. If you or a loved one are having thoughts of suicide, please seek immediate medical help. Go to the emergency room or call the National Suicide Prevention Lifeline at 1-800-273-8255.

Official Title
-----------------
A Double-blind, Randomized, Placebo-controlled Study to Evaluate the Efficacy and Safety of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Adult Subjects Assessed to be at Imminent Risk for Suicide

Conditions
-----------------
Depressive Disorder, Major

Intervention / Treatment
-----------------
* Drug: Esketamine
* Other: Placebo
* Other: Standard of Care


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant must meet Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5) diagnostic criteria for Major Depressive Disorder (MDD), without psychotic features, based upon clinical assessment and confirmed by the Mini International Psychiatric Interview (MINI) In the physician's opinion, acute psychiatric hospitalization is clinically warranted due to participant's imminent risk of suicide Participants must have current suicidal ideation with intent, confirmed by a Yes response to Question B3 [Think (even momentarily) about harming or of hurting or of injuring yourself: with at least some intent or awareness that you might die as a result; or think about suicide (ie, about killing yourself)?] and Question B10 [Intend to act on thoughts of killing yourself?] obtained from the MINI. Note: the response to B3 must refer to the present, whereas the response to B10 may reflect the past 24 hours. If the screening period is longer than 24 hours, assessment of B3 and B10 of MINI must be repeated prior to randomization to confirm eligibility Participant has a Montgomery Asberg Depression Rating Scale (MADRS) total score of greater than (>) 28 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 (may be shorter or longer if clinically warranted in the investigator's opinion) and take prescribed non-investigational antidepressant therapy(ies) for at least the duration of the double-blind treatment phase (Day 25) Participant is comfortable with self-administration of intranasal medication and able to follow instructions provided Exclusion Criteria: Participant has a current DSM-5 diagnosis of bipolar (or related disorders), antisocial personality disorder, or obsessive compulsive disorder Participant currently meets DSM-5 criteria for borderline personality disorder. Participant not meeting full DSM-5 criteria for borderline personality disorder but exhibiting recurrent suicidal gestures, threats, or self-mutilating behaviors should also be excluded Participant has a current clinical diagnosis of autism, dementia, or intellectual disability Participant has a current or prior DSM-5 diagnosis of a psychotic disorder, or MDD with psychotic features Participant meets the DSM-5 severity criteria for moderate or severe substance or alcohol use disorder, (except for nicotine or caffeine), within the 6 months before screening. A history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder is exclusionary

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Esketamine + Standard of care<br>Participants will receive intranasal esketamine 84 milligram (mg) two times per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) along with standard of care (SOC) antidepressant treatment. | Drug: Esketamine<br>* Intranasal esketamine solution 84 milligram (mg)<br>Other: Standard of Care<br>* The standard of care antidepressant treatment (antidepressant monotherapy or antidepressant plus augmentation therapy) will be determined by the treating physician(s) based on clinical judgement and practice guidelines prior to randomization, and the treatment will be initiated on Day 1.<br>|
| Placebo Comparator: Placebo + Standard of care<br>Participants will receive intranasal placebo two times per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25) along with standard of care antidepressant treatment. | Other: Placebo<br>* Intranasal Placebo solution<br>Other: Standard of Care<br>* The standard of care antidepressant treatment (antidepressant monotherapy or antidepressant plus augmentation therapy) will be determined by the treating physician(s) based on clinical judgement and practice guidelines prior to randomization, and the treatment will be initiated on Day 1.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at 24 Hours After the First Dose (Day 2) (Last Observation Carried Forward [LOCF] Data) During Double-blind Phase | MADRS is clinician-rated scale designed to be used in participants with Major Depressive Disorder (MDD) to measure depression severity and detect changes due to antidepressant treatment. It evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic and suicidal thoughts. Scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms), summed for total possible score of 0 to 60. Higher scores represent more severe condition. Negative change in score indicates improvement. | Baseline (Day 1, predose) and 24 hours first post dose (Day 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Clinical Global Impression of Severity of Suicidality- Revised (CGI-SS-R) Score at 24 Hours After the First Dose (Day 2) (LOCF Data) During Double-blind Phase | CGI-SS-R was derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a participants illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal participants). A higher score indicates a more severe condition and a reduction in score indicates improvement (that is, lower severity of suicidality). | Baseline (Day 1, predose) and 24 hours first post dose (Day 2) | 
| Number of Participants Who Achieved Remission (MADRS Total Score Less Than or Equal to [<=] 12) Through the Double-blind Phase | Participants who had a MADRS total score of <=12 were considered remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition and a negative change in score indicates improvement. | Days 1 (4 hours postdose), 2, 4, 8, 11, 15, 18, 22 and Day 25 (predose and 4 hours postdose) | 
| Change From Baseline in Montgomery Asberg Depression Rating Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase | MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition and a negative change in score indicates improvement. | Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 (predose and 4 hours postdose) | 
| Change From Baseline in Clinical Global Impression- Severity of Suicidality-Revised (CGI-SS-R) at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase | CGI-SS-R was derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a participants illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal participants). A higher score indicates a more severe condition. Negative change in score indicates improvement. | Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 | 
| Number of Participants Who Achieved Resolution of Suicidality (CGI-SS-R Score of 0 or 1) Through Double-blind Phase | CGI-SS-R was derived from the Clinical Global Impression Severity Scale (CGI-S), a global rating scale that gives an overall measure of the severity of a participants illness. The CGI-SS-R rating is scored on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal participants). A higher score indicates a more severe condition. Negative change in score indicates improvement. A participant was considered to achieve resolution of suicidality at a given time point if the CGI-SS-R score was 0 (normal, not at all suicidal) or 1 (questionably suicidal). | Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 | 
| Change From Baseline in Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I) Scale Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase | The CGI-SR-I is a scale summarizing the clinician's best assessment of the likelihood that the participant will attempt suicide in the next 7 days. The CGI-SR-I rating is scored on a 7-point scale: where' 0 (no imminent suicide risk); 1 (minimal imminent suicide risk), 2 (mild imminent suicide risk), 3 (moderate imminent suicide risk), 4 (marked imminent suicide risk), 5 (severely imminent suicide risk), 6 (extreme imminent suicide risk). Higher score indicates a more severe condition. Negative change in score indicates improvement. | Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 | 
| Change From Baseline in Beck Hopelessness Scale (BHS) Total Score at Days 8 and 25 During Double-blind Phase | BHS is a self-reported measure to assess one's level of negative expectations or pessimism regarding future. It consists of 20 true-false items that examine 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. For every statement, each response was assigned score of 0 or 1. Total BHS score is sum of item responses, ranged from 0-20, where higher score represented higher level of hopelessness. | Baseline, Days 8 and 25 | 
| Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) at Days 2, 11 and 25 During Double-blind Phase: Health Status Index | EQ-5D-5L measures health outcome. It consists of EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-VAS). EQ-5D-5L system comprises following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of 5 dimensions is divided into 5 levels of perceived problems (Level 1-no problem, Level 2-slight problems, Level 3-moderate problems, Level 4-severe problems, Level 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a health status index (HSI). Health Status Index ranges from 0.148 - 0.949, anchored at 0 (dead) and 1 (full health). Positive change in score indicates improvement. | Baseline and Days 2, 11 and 25 | 
| Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) at Days 2, 11 and 25 During Double-blind Phase: EQ-Visual Analogue Scale (EQ-VAS) | EQ-5D-5L measures health outcome. It consists of EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ-VAS). EQ-VAS score from 0 (worst health) to 100 (best health), positive change in score indicates improvement. | Baseline, Days 2, 11 and 25 | 
| Change From Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) at Days 2, 11 and 25 During Double-blind Phase: Sum Score | EQ-5D-5L measures health outcome. It consists of EQ-5D-5L system and EQ-VAS. EQ-5D-5L system comprises following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of 5 dimensions is divided into 5 levels of perceived problems (Level 1-no problem, Level 2-slight problems, Level 3-moderate problems, Level 4-severe problems, and Level 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health today. Responses were used to generate a health status index (HSI). Health Status Index ranges from 0.148 - 0.949, anchored at 0 (dead) and 1 (full health), a lower score indicates worse health. Sum score=(sum of the scores from the 5 dimensions minus 5)*5. Sum score ranges from 0-100. Higher score indicates a more severe problem. Negative change in score indicates improvement. | Baseline, Days 2, 11 and 25 | 
| Change From Baseline in Quality of Life in Depression Scale (QLDS) Total Score at Days 2, 11 and 25 During Double-blind Phase | The QLDS is a disease specific patient-reported outcome designed to assess health related quality of life in participants with major depressive disorder (MDD). The instrument has a recall period of at the moment, contains 34-items with true/not true response options and takes approximately 5-10 minutes to complete. The total score range is from 0 (good quality of life) to 34 (very poor quality of life). A higher score indicates a more severe condition. Negative change indicates improvement. | Baseline and Days 2, 11 and 25 | 
| Treatment Satisfaction Questionnaire for Medication (TSQM-9) Total Score at Days 15 and 25 During Double-blind Phase | The TSQM-9 is a 9-item generic patient-reported outcome instrument to assess participants' satisfaction with medication. It covers domains of effectiveness, convenience, and global satisfaction. The TSQM-9 domain scores were calculated as recommended by the instrument authors. (i) Effectiveness = [(item 1 + item 2 + item 3) - 3]/18*100, (ii) Convenience = [(item 4 + item 5 + item 6) - 3]/18*100 and (iii) Global satisfaction = [(item 7 + item 8 + item 9) - 3]/14*100. Each domain score can be calculated only if all the three items considered in the calculation of that score are not missing. The TSQM-9 domain score ranges from 0 to 100, with higher scores representing higher satisfaction. | Days 15 and 25 | 
| Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 5 (My Risk) Question 3 (Patient-reported FoST) Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase | SIBAT is an assessment tool that captures suicidal ideation, behavior, and risk. It permits assessment of change in suicidal ideation and behavior and documents clinician assessment of severity of suicidality and suicide risk. SIBAT is organized into 8 modules divided into 2 major divisions: patient-reported section (Modules 1-5) and clinician-rated section (Modules 6-8). Patient-reported section has modules of demographics and suicide history, risk/protective factors, suicidal thinking, suicide behavior, and suicide risk. Question 3 from Module 5 asks participants to describe their thinking about suicide right now from 5 response options ranging from 0 (I have no suicidal thoughts) to 4 (I have suicidal thoughts all of time). SIBAT Module 5 (My Risk) Question 3 (Patient-reported FoST) total score ranges from 0 to 4; a higher score indicates a more severe condition. Negative change in score indicates improvement. | Baseline, Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 | 
| Change From Baseline in Suicide Ideation and Behavior Assessment Tool (SIBAT) Module 7 - Clinician-rated FoST Total Score at Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 During Double-blind Phase | SIBAT is assessment tool that captures suicidal ideation, behavior, and risk. It permits assessment of change in suicidal ideation and behavior and documents clinician assessment of severity of suicidality and suicide risk. SIBAT has 8 modules divided into 2 major divisions: patient-reported section (Modules 1-5) and clinician-rated section (Modules 6-8). Clinician-rated section has modules for semi-structured interview, clinical global impressions of current severity of suicidality and imminent suicide risk, clinical global impression of long-term suicide risk, and clinical judgment of optimal suicide management. The score anchor point as in participant report frequency of suicidal thinking (FoST) that is, response options from never to all the time. Module 7-FoST score ranges from 0-5; higher score indicates more severe condition. Negative change in score indicates improvement. | Baseline and Days 1, 2, 4, 8, 11, 15, 18, 22 and 25 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs): DB Treatment Phase | An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non investigational) product, whether or not related to that medicinal (investigational or non-investigational) product. A TEAE is categorized as related if assessed by the investigator as possibly, probably, or very likely related to study agent. | Up to Day 25 | 
| Number of Participants With Treatment Emergent Abnormal Laboratory Values: DB Treatment Phase | Low/high abnormal values are: Alanine aminotransferase (ALT)-high=200 Units per liter(U/L); ALP-high=250U/L; aspartate aminotransferase(AST)-high=250U/L; gamma glutamyl transferase(GGT)=300U/L; Albumin(low=24g/L,high=60 g/L); Bicarbonate(low=15.1, high=34.9mmol/L); Bilirubin(high=51.3micromol/L); calcium(low=1.5,high=3mmol/L);Chloride(low=94,high=112mmol/L); CK(High=990U/L); Creatinine(High=265.2micromol/L); Eosinophils(High=10%); Erythrocytes(low=3.0*1012/L,high=6.4*1012/L); Glucose(low=2.2,high=16.7mmol/L); Hemoglobin(low=80g/L,high=190g/L);Hematocrit(low=0.28, high=0.55 fraction); LD(high=500U/L); Leukocytes(low=2.5*109/L,high=15.5*109/L); Lymphocytes(low=10%,high=60%); Monocytes(high=20%); Neutrophils(low=30%,high=90%); Phosphate(low=0.7 mmol/L,high=2.6mmol/L); Platelet count(low=100*109/L,high=600*109/L]; Potassium(low=3.0mmol/L,high=5.8 mmol/L]; Protein(low=50 g/L); Sodium(low=125 mmol/L,high=155 mmol/L); Urate(low=89.2 micromol/L,high=594.8micromol/L); Urine(high=8.0 pH). | Up to Day 25 | 
| Number of Participants With Abnormal Nasal Examinations at Day 25: DB Treatment Phase | Number of participants with abnormal nasal examination were reported. Nasal examination of visual inspection of the epistaxis, nasal crusts, nasal discharge, and nasal erythema was performed. | At Day 25 | 
| Number of Participants With Treatment Emergent Abnormal Electrocardiogram (ECG) Values at Any Time: DB Treatment Phase | Number of participants with treatment emergent abnormal ECG values for variables including heart rate (abnormally low refers to less than or equal to [<=] 50 beats per minute [bpm] , abnormally high refers greater than or equal to [>=] 100 bpm), pulse rate (PR) interval (abnormally high refers to >= 210 milliseconds [msec]), QRS interval (abnormally Low refers to <= 50, abnormally high refers to >= 120 msec) and QT interval (abnormally low refers to <= 200, abnormally high >= 500 msec) were reported. | Up to Day 25 | 
| Number of Participants With Abnormal Arterial Oxygen Saturation (SpO2) Levels (Less Than [<] 93%) as Assessed by Pulse Oximetry at Any Time: DB Treatment Phase | Pulse oximetry was used to measure arterial SpO2 levels. On each dosing day, the device was attached to the finger, toe, or ear, and SpO2 was monitored and documented. If oxygen saturation levels were less than (<) 93% at any time during the 1.5 hours postdose interval, pulse oximetry was recorded every 5 minutes until levels return to >= 93% or until the participant is referred for appropriate medical care, if clinically indicated. Participants with at least 2 consecutive postdose oxygen saturation below 93% during the DB treatment phase were reported. | Up to Day 25 | 
| Number of Participants With Treatment Emergent Vital Signs Abnormalities: DB Treatment Phase | Number of participants with treatment emergent vital signs abnormalities (pulse rate in bpm [abnormally low = a decrease from baseline of >= 15 to a value <= 50; abnormally high = an increase from baseline of >=15 to a value >=100] , systolic blood pressure [SBP] in mmHg [abnormally low = a decrease from baseline of >= 20 to a value <= 90; abnormally high = an increase from baseline of >= 20 to a value >= 180], and diastolic blood pressure [DBP] in mmHg [abnormally low= a decrease from baseline of >=15 to a value <= 50; abnormally high = an increase from baseline of >= 15 to a value >= 105) were reported. | Up to Day 25 | 
| Number of Sedated Participants as Assessed by Modified Observer's Assessment of Alertness/Sedation (MOAA/S) Score at Any Time: DB Treatment Phase | MOAA/S was used to measure treatment-emergent sedation with correlation to levels of sedation defined by the American society of anesthesiologists (ASA) continuum. The MOAA/S scores range from 0 to 5 where,0 = no response to painful stimulus; ASA continuum = general anesthesia, 1 = responds to trapezius squeeze; ASA continuum = deep sedation, 2 = purposeful response to mild prodding or mild shaking; ASA continuum = moderate sedation, 3 = responds after name called loudly or repeatedly; ASA continuum = moderate sedation, 4 = lethargic response to name spoken in normal tone; ASA continuum = moderate sedation and 5 = readily responds to name spoken in normal tone (awake); ASA continuum = minimal sedation. | Up to Day 25 | 
| Number of Participants With an Increase in Clinician-administered Dissociative States Scale (CADSS) Total Score Over Time: DB Treatment Phase | The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization (with score range from 0 to 28), derealization (with score range from 0 to 52), and amnesia (with score range from 0 to 8). Participants responses are coded on a 5-point scale (0 = Not at all, 1 = Mild, 2 = Moderate, 3 = 'Severe and 4 = Extreme). The total score is sum of the 23 items and range from 0 to 92, where 0 (best) and 92 (worst). A higher score indicates a more severe condition. Number of participants with an increase in CADSS total score (increase based on maximum CADSS total score change from predose of > 0) was reported. | Days 1, 4, 8, 11, 15, 18, 22 and 25 |