Conditions: Depressive Disorder, Major
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 230
Healthy volunteers: no

Brief summary:
The purpose of this 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:
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.

Arms:
arm 1: Participants will receive intranasal esketamine 84 milligram (mg) on Day 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment. arm 2: Participants will receive intranasal placebo on Day 1, 4, 8, 11, 15, 18, 22, and 25 along with standard of care antidepressant treatment.

Interventions: intervention 1: Esketamine intervention 2: Placebo intervention 3: Standard of Care
Intervention descriptions: intervention 1: 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). intervention 2: Participants will receive intranasal placebo two times per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25). intervention 3: 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.

Protocol document:
Prot_000.pdf: 
1
Status: Approved, Date: 31 January 2018
Janssen Research & Development *
Clinical Protocol
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
Protocol 54135419SUI3002; Phase 3
AMENDMENT 2
JNJ54135419 (esketamine)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Sciences Ireland UC; or Janssen 
Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent these 
various legal entities; the sponsor is identified on the Contact Information page that accompanies the 
protocol.
This compound is being investigated in Phase 3 clinical studies.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER:         2016-003992-23
Status:
Approved
Date:
31 January 2018
Prepared by:
Janssen Research & Development, LLC  
EDMS number:
EDMS-ERI-132549001, 3.0 
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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Status: Approved, Date: 31 January 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 16
TIME AND EVENTS SCHEDULE .............................................................................................................. 28
SIBAT TIME AND EVENTS SCHEDULE................................................................................................... 33
ABBREVIATIONS ...................................................................................................................................... 35
1.
INTRODUCTION................................................................................................................................ 37
1.1.
Background .................................................................................................................................... 37
1.1.1.
Nonclinical Studies ..................................................................................................................... 37
1.1.2.
Clinical Studies ........................................................................................................................... 38
1.1.2.1.
Completed and Ongoing Clinical Studies with Intranasal Esketamine.................................... 38
1.1.2.2.
Human Pharmacokinetics and Product Metabolism................................................................ 39
1.1.2.3.
Efficacy .................................................................................................................................... 40
1.1.2.4.
Safety and Tolerability............................................................................................................. 41
1.2.
Overall Rationale for the Study...................................................................................................... 43
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 44
2.1.
Objectives and Endpoints .............................................................................................................. 44
2.1.1.
Objectives ................................................................................................................................... 44
2.1.2.
Endpoints.................................................................................................................................... 46
2.2.
Hypothesis ..................................................................................................................................... 47
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 47
3.1.
Overview of Study Design.............................................................................................................. 47
3.2.
Study Design Rationale.................................................................................................................. 49
3.2.1.
Study Population......................................................................................................................... 49
3.2.2.
Treatment and Study Duration ................................................................................................... 50
3.2.3.
Control, Randomization and Blinding ......................................................................................... 51
3.2.4.
Dose............................................................................................................................................ 52
3.2.5.
Efficacy Measures ...................................................................................................................... 53
3.2.5.1.
Montgomery-Asberg Depression Rating Scale (MADRS)....................................................... 53
3.2.5.2.
Suicide Ideation and Behavior Assessment Tool (SIBAT)...................................................... 54
3.2.5.3.
Beck Hopelessness Scale (BHS) ............................................................................................ 56
3.2.5.4.
European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level (EQ-5D-5L) ...................... 56
3.2.5.5.
Quality of Life in Depression Scale (QLDS) ............................................................................ 56
3.2.5.6.
Treatment Satisfaction Questionnaire for Medication (TSQM-9) ............................................ 56
3.2.6.
Safety Evaluations...................................................................................................................... 56
3.2.7.
Pharmacokinetic Assessments................................................................................................... 57
3.2.8.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations .............................. 57
3.2.9.
Medical Resource Utilization ...................................................................................................... 58
4.
SUBJECT POPULATION.................................................................................................................. 58
4.1.
Inclusion Criteria ............................................................................................................................ 58
4.2.
Exclusion Criteria ........................................................................................................................... 61
4.3.
Prohibitions and Restrictions ......................................................................................................... 64
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5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 64
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 66
6.1.
Intranasal Study Drug .................................................................................................................... 66
6.1.1.
Guidance on Blood Pressure Monitoring on Intranasal Treatment Session Days ..................... 68
6.2.
Standard of Care Antidepressant Treatment ................................................................................. 69
7.
TREATMENT COMPLIANCE............................................................................................................ 69
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 69
9.
STUDY EVALUATIONS .................................................................................................................... 70
9.1.
Study Procedures........................................................................................................................... 70
9.1.1.
Overview..................................................................................................................................... 70
9.1.2.
Screening Phase ........................................................................................................................ 71
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 72
9.1.4.
Posttreatment Phase (Follow-Up) .............................................................................................. 74
9.2.
Efficacy Evaluations....................................................................................................................... 75
9.2.1.
Montgomery-Asberg Depression Rating Scale .......................................................................... 75
9.2.2.
Suicide Ideation and Behavior Assessment Tool....................................................................... 75
9.2.3.
Beck Hopelessness Scale .......................................................................................................... 76
9.2.4.
EuroQol 5-Dimension 5-Level .................................................................................................... 77
9.2.5.
Quality of Life in Depression Scale............................................................................................. 77
9.2.6.
Treatment Satisfaction Questionnaires for Medication............................................................... 77
9.3.
Pharmacokinetics........................................................................................................................... 77
9.3.1.
Evaluations ................................................................................................................................. 77
9.3.2.
Analytical Procedures................................................................................................................. 78
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 78
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 78
9.5.
Biomarker and Pharmacogenomic (DNA) Evaluations.................................................................. 78
9.6.
Medical Resource Utilization.......................................................................................................... 79
9.7.
Safety Evaluations ......................................................................................................................... 79
9.8.
Other Evaluations........................................................................................................................... 83
9.9.
Sample Collection and Handling.................................................................................................... 83
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 84
10.1.
Completion ..................................................................................................................................... 84
10.2.
Discontinuation of Study Treatment/Withdrawal From the Study .................................................. 84
10.3.
Withdrawal From the Use of Research Samples........................................................................... 86
11.
STATISTICAL METHODS................................................................................................................. 86
11.1.
Subject Information ........................................................................................................................ 86
11.2.
Sample Size Determination ........................................................................................................... 87
11.3.
Efficacy Analyses ........................................................................................................................... 87
11.4.
Pharmacokinetic Analyses............................................................................................................. 89
11.5.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 89
11.6.
Biomarker and Pharmacogenomic Analyses................................................................................. 89
11.7.
Medical Resource Utilization Analyses.......................................................................................... 90
11.8.
Safety Analyses ............................................................................................................................. 90
11.9.
Independent Data Monitoring Committee ...................................................................................... 91
12.
ADVERSE EVENT REPORTING ...................................................................................................... 91
12.1.
Definitions ...................................................................................................................................... 92
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 92
12.1.2.
Attribution Definitions.................................................................................................................. 93
12.1.3.
Severity Criteria .......................................................................................................................... 93
12.2.
Special Reporting Situations.......................................................................................................... 94
12.3.
Procedures..................................................................................................................................... 94
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12.3.1.
All Adverse Events...................................................................................................................... 94
12.3.2.
Serious Adverse Events ............................................................................................................. 95
12.3.3.
Pregnancy................................................................................................................................... 96
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 96
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 96
13.1.
Procedures..................................................................................................................................... 97
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 97
14.
STUDY DRUG INFORMATION......................................................................................................... 97
14.1.
Physical Description of Study Drug(s) ........................................................................................... 97
14.2.
Packaging ...................................................................................................................................... 98
14.3.
Labeling.......................................................................................................................................... 98
14.4.
Preparation, Handling, and Storage............................................................................................... 98
14.5.
Drug Accountability ........................................................................................................................ 98
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 99
16.
ETHICAL ASPECTS ......................................................................................................................... 99
16.1.
Study-Specific Design Considerations........................................................................................... 99
16.2.
Regulatory Ethics Compliance..................................................................................................... 101
16.2.1.
Investigator Responsibilities ..................................................................................................... 101
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 102
16.2.3.
Informed Consent ..................................................................................................................... 103
16.2.4.
Privacy of Personal Data .......................................................................................................... 104
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 105
16.2.6.
Country Selection ..................................................................................................................... 105
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 105
17.1.
Protocol Amendments.................................................................................................................. 105
17.2.
Regulatory Documentation .......................................................................................................... 106
17.2.1.
Regulatory Approval/Notification .............................................................................................. 106
17.2.2.
Required Prestudy Documentation........................................................................................... 106
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 107
17.4.
Source Documentation................................................................................................................. 107
17.5.
Case Report Form Completion .................................................................................................... 108
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 108
17.7.
Record Retention ......................................................................................................................... 109
17.8.
Monitoring .................................................................................................................................... 109
17.9.
Study Completion/Termination..................................................................................................... 110
17.9.1.
Study Completion/End of Study................................................................................................ 110
17.9.2.
Study Termination..................................................................................................................... 110
17.10.
On-Site Audits .............................................................................................................................. 110
17.11.
Use of Information and Publication.............................................................................................. 111
REFERENCES.......................................................................................................................................... 113
INVESTIGATOR AGREEMENT ............................................................................................................... 120
LIST OF ATTACHMENTS
Attachment 1:
Prohibited Therapies ................................................................................................ 117
Attachment 2:
Anticipated Events.................................................................................................... 119
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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Dose Administration of Esketamine 84 mg or Placebo ............................................................ 67
Table 2:
Dose Administration of Esketamine 56 mg or Placebo ............................................................ 67
Table 3:
Guidance for Blood Pressure Monitoring.................................................................................. 68
Table 4:
Approximate Volume of Blood to be Collected From Each Subject ......................................... 71
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 49
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Status: Approved, Date: 31 January 2018
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
8 December 2016
Amendment 1
20 April 2017
Amendment 2
31 January 2018
Amendments below are listed beginning with the most recent amendment.
Amendment 2 (31 January 2018)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: The overall reason for the amendment is to remove the interim analysis 
from the 54135419SUI3002 protocol; to clarify that Module 3 Suicide Ideation and Behavior Assessment Tool 
(SIBAT) is an exploratory objective; to modify the timing of screening procedures in Figure 1 to be consistent with 
the Time and Events Schedule; to clarify which potential subjects are not excluded from participation in the 
54135419SUI3002 study due to having a positive screening test for prescribed psychostimulants that are permitted 
during the study; and updated text regarding the presentation of nasal examination data.
Applicable Section(s)
Description of Change(s)
Rationale: The interim analysis was removed from the 54135419SUI3002 protocol to ensure that the study has 
sufficient numbers of subjects from key global regions/countries needed to support global health authority 
registration.
Synopsis Overview of 
Study Design;
3.1. Overview of Study 
Design; 11.2. Sample 
Size Determination; 
11.3. Efficacy 
Analyses
Deleted text stating that an interim analysis will be conducted when 60% of randomized 
subjects have completed Day 2 of the double-blind phase.
Synopsis Statistical 
Methods; 11.9. 
Independent Data 
Monitoring Committee
The following text was deleted from the Synopsis Statistical Analysis section (Interim 
Analysis subsection):
A 2-stage group-sequential design with 1 interim analysis will be implemented to allow 
for early stopping if there is significant evidence of efficacy or futility based on the 
interim analysis after 60% of the subjects have been randomized and have completed Day 
2 of the double-blind phase. If the study is not stopped based upon the interim analysis, it 
will be continued until the maximum sample size (224 subjects) has been reached. An 
external independent Data Monitoring Committee (IDMC) will provide recommendations 
about stopping or continuing the study based on the results of an interim efficacy and 
safety analysis.
Section 11.3, Interim Analysis was removed. As a result, the numbered headings 
following Section 11.3 were updated.
Cross-references to Section 11.3 Interim Analysis (in Sections 3.1 [Overview of Study 
Design], 11.2 [Sample Size Determination], 11.3 [Efficacy Analyses]) were also deleted.
The following text was modified in Section 11.9 Independent Data Monitoring Committee 
(strikeout text deleted):
An external Independent Data Monitoring Committee will be established to monitor data 
on an ongoing basis to ensure the continuing safety of the subjects enrolled in this study.
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Applicable Section(s)
Description of Change(s)
In addition, the committee will review 1 interim analysis for efficacy. The committee will 
meet every 6 months to review safety data and will meet once to review efficacy data after 
the interim analysis has been completed. After the reviews, the IDMC will make 
recommendations regarding the continuation of the study or, in the case of the interim 
analysis for efficacy, to either stop the study due to efficacy or futility. The details will be 
provided in a separate IDMC charter.
Synopsis Secondary 
Efficacy Endpoints; 
10.2 Discontinuation 
of Study 
Treatment/Withdrawal 
From the Study; 11.3. 
Efficacy Analysis
In the Synopsis (Secondary Efficacy Endpoints), deleted text stating that 1 interim 
analysis for efficacy and futility will be performed.
The following bullet point text was removed from Section 10.2 Discontinuation of Study 
Treatment/Withdrawal From the Study:
Study is terminated by the sponsor for futility
Section 11.4, Efficacy Analysis became Section 11.3 since the Interim Analysis section 
was deleted.
5. Treatment 
Allocation and 
Blinding
The following text was deleted in the Blinding subsection:
However, if an interim analysis is specified, the randomization codes and, if required, the 
translation of randomization codes into treatment and control groups will be disclosed to 
those authorized and only for those subjects included in the interim analysis.
Rationale: Module 3 SIBAT My Current Thinking assessment was changed from a secondary to an exploratory 
objective as Module 3 My Current Thinking was not designed as a stand-alone endpoint.
Synopsis, Objectives, 
Endpoints, Hypothesis, 
Exploratory 
Objectives, Endpoints; 
2.1.1. Objectives; 
2.1.2. Endpoints; 
3.2.5.2. Suicidal 
Ideation and Behavior 
Assessment Tool 
(SIBAT)
Text regarding Module 3 SIBAT Assessment was removed from the secondary objective 
and endpoint subsections and moved to the exploratory objective subsections of the 
54135419SUI3002 protocol.
Rationale: Modified Figure 1 to be consistent with the Time and Events Schedule timing of screening procedures 
prior to the first dose.
3.1. Overview of Study 
Design (Figure 1)
“24 hours” was replaced with “48 hours” in the Screening text box of Figure 1.
Footnote c text was modified as follows (bold text added; strikethrough text deleted):
Screening phase may be extended to up to 48 hours prior to Day 1 intranasal dose. If 
possible, screening should be performed within 24 hours prior the Day 1 intranasal 
dose.
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Status: Approved, Date: 31 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: Exclusion criterion #8 was modified to clarify which potential subjects are not excluded from 
participation in the study due to having a positive screening test for prescribed psychostimulants that are permitted 
during the study.
4.2. Exclusion Criteria
The following text was added to exclusion criterion #8:
8.2 Criterion modified per Amendment 2
- Subjects, who have a positive test result at screening due to prescribed psychostimulants 
(eg. amphetamine, methylphenidate, etc) that are permitted during the study in accordance 
with Attachment 1, are eligible for study participation.
Rationale: Updated text regarding presentation of nasal examination data.
Synopsis, Safety 
Analyses; 11.8. Safety 
Analyses
The following text was modified (bold text added; strikethrough text deleted):
Abnormalities observed during the targeted nasal examinations at screening and 
post-baseline will be summarized and listed by treatment group.Changes in findings 
from the baseline nasal examination (including the upper respiratory tract/throat) will be 
listed by treatment group. Examinations will provide ratings (absent, mild, moderate, or 
severe) that are based on a visual inspection of the nostrils, nasal mucosa, and throat for 
nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption and epistaxis. A shift 
table for changes from baseline in ratings for each examination will be presented by 
treatment group at each scheduled visit.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 1 (20 April 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: The overall reason for the amendment is to update and/or clarify protocol 
content based on feedback received during study initiation activities.
Applicable Section(s)
Description of Change(s)
Rationale: Exclusion criterion #5 was revised to clarify which potential subjects are excluded from participation in 
the study due to substance or alcohol use disorder. 
Synopsis, Subject
Population; 
4.2. Exclusion Criteria
Exclusion criterion #5 was revised as follows (bold text added; strikeout text deleted):
Subject has a history of meets the DSM-5 severity criteria for moderate or severe 
substance or alcohol use disorder, as defined by DSM-5 criteria, (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.
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Status: Approved, Date: 31 January 2018
Applicable Section(s)
Description of Change(s)
3.2.1. Study 
Population
Text in this section modified as follows (bold text added) for consistency with exclusion 
criterion #5:
Subjects with a recent history (< 6 months) of moderate or severe substance or alcohol 
use disorders will be excluded to ensure the subject’s depression is not attributed to 
substance or alcohol use (ie, substance-induced depressive disorder).
Rationale: The text was updated to amend the duration of hospitalization without the need for discussion with the 
Sponsor and to clarify that shorter or longer hospitalizations should follow local practice.
9.1.3. Double-blind 
Treatment Phase
Text was revised as follows (bold text added; strikeout text deleted):
Subjects will remain in the inpatient psychiatry unit for a recommended duration of 5 days, 
with shorter or longer hospitalizations permitted if clinically warranted per local standard 
of care. The discharge decision will be made based upon the investigator’s judgment that 
the subject is no longer imminently suicidal and meets standard discharge criteria per local 
practice. Discharge beforeafter less than 5 days must be discussed and approved by the 
sponsor’s medical monitor. The investigator must discuss in advance the need for 
continued hospitalization beyond 107 days and thereafter on a weekly basis with the 
sponsor’s medical monitor.
Synopsis, Overview 
of Study Design and 
Dosage and 
Administration; 
Time and Events 
Schedule; 
3.1. Overview of 
Study Design; 
6.1. Intranasal Study 
Drug;
The text in these sections and Figure 1 (Schematic Overview of the Study) were revised 
for consistency with the changes described above in Section 9.1.3.
12.3.2. Serious 
Adverse Events 
The following text was corrected for clarity and consistency with the above text in 
Section 9.1.3 (strikeout text deleted):

Inpatient hospitalizations that extend beyond the protocol-required recommended  
5 days (not due to adverse event, ie, clinical worsening)
Rationale: A remote contact was added at Day 35 with evaluations to be performed according to the revised Time 
and Events Schedule to ensure twice weekly monitoring for the first two weeks (Days 28, 32, 35, and 39) after study 
drug treatment.
Time and Events 
Schedule
-
A remote contact has been added at Day 35 (35 RC) for MADRS assessment (recall 
since last assessment) and adverse event collection.
-
MADRS assessments at Days 32 and 39 were changed to recall since last assessment 
from 7-day recall.
-
Visit numbers for Days 39, 46, 53, 67, and 90 were changed to Visits 14, 15, 16, 17, 
and 18, respectively.
-
The window for the Day 32 visit has been changed to ±1 day from ±3 days (ie, footnote 
for Visit 12 was changed to “b” from “a”).
-
Rows for “Prior and concomitant therapy” and “Adverse events” were modified to 
indicate when these data are reviewed during the follow-up phase.
SIBAT Time and 
Events Schedule
An additional column was added for the Day 35 remote contact and the visit numbers were 
revised for consistency with the main Time and Events Schedule.
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Applicable Section(s)
Description of Change(s)
Synopsis, Overview 
of Study Design; 
3.1. Overview of 
Study Design; 
3.2.2. Treatment and 
Study Duration;
9.1.4. Posttreatment 
Phase (Follow-up)
Text has been revised to include the Day 35 remote contact and mention the frequency of 
monitoring during the follow-up phase, ie, to mention that during the follow-up phase, 
subjects will be monitored twice weekly for the first two weeks (Days 28, 32, 35, and 39) 
after study drug treatment. Subjects will then be followed up weekly for the next two 
weeks (Days 46 and 53) and every two weeks for the rest of the follow-up period (Days 67 
and 90).
3.1. Overview of 
Study Design, 
Figure 1
Figure 1 has been revised to include remote contacts at Days 28 and 35 during the follow-
up phase.
Rationale: The text regarding discontinuation of study treatment was modified to add that if the legal status of a 
subject changes during the study and the subject’s participation can no longer be considered voluntary, then he/she 
will be discontinued from study treatment.
10.2. Discontinuation 
of Study 
Treatment/Withdrawal 
From the Study  
The following bullet point was added to the list of reasons for which a subject’s study 
treatment will be discontinued:

Change in the in-patient hospitalization status from voluntary to involuntary as a result 
of a judicial or other legal administrative order
Rationale: The text regarding discontinuation of study treatment was modified to include worsening of underlying 
condition as an example of a safety or tolerability reason which would result in discontinuation of study treatment.
10.2. Discontinuation 
of Study 
Treatment/Withdrawal 
From the Study  
Worsening of underlying condition was added as an example of a safety or tolerability 
reason which would result in discontinuation of study treatment. Bold text added as shown 
below: 

The investigator believes that for safety reasons or tolerability reasons (eg, adverse 
event or worsening of underlying condition)  it is in the best interest of the subject to 
discontinue study treatment
Rationale: Exclusion criteria were revised to explicitly specify a detailed list of important medical conditions which 
are exclusionary.
Synopsis, Subject 
Population; 
4.2. Exclusion Criteria
Exclusion criterion #6 was revised as follows (strikeout text deleted; bold text added):
Subject has any of the following conditions: 
-
a history or current signs and symptoms of liver or renal insufficiency or of
-
clinically significant cardiac (including unstable coronary artery disease and 
congestive heart failure, tachyarrhythmias and recent myocardial infarction), or
vascular, pulmonary, gastrointestinal, endocrine (including uncontrolled 
hyperthyroidism), neurologic (including current or past history of seizures except 
uncomplicated childhood febrile seizures with no sequelae), hematologic, 
rheumatologic, or metabolic (including severe dehydration/hypovolemia) disease.
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Applicable Section(s)
Description of Change(s)
Synopsis, Subject 
Population; 
4.2. Exclusion Criteria
Exclusion criterion #7 was revised as follows (bold text added):
Subject has uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic 
blood pressure >90 mmHg) despite diet, exercise or a stable dose of anti-hypertensive 
treatment for at least 2 weeks at screening; or any past history of hypertensive crisis. 
-
Subjects with conditions in which the elevation of blood pressure could be a 
serious risk (including unstable heart failure, severe cardiovascular disease, 
recent cerebral injury, increased intracranial pressure / intracranial mass lesion, 
intracranial bleeding or acute stroke, untreated glaucoma or perforating eye 
injury) are excluded.
-
An abnormal blood pressure value at screening can be repeated once after 5 minutes of 
relaxation for subject eligibility. On Day 1 of the double-blind phase prior to 
randomization, a supine or semi-supine systolic blood pressure >140 mmHg or 
diastolic blood pressure >90 mmHg is exclusionary.
Synopsis, Subject 
Population
Corrections were made to the text of exclusion criterion #7 shown in the synopsis to 
maintain consistency with the text of exclusion criterion #7 shown in Section 4.2.
Rationale: Exclusion criteria were revised to clarify which subjects are excluded due to a positive urine test result.
4.2. Exclusion Criteria
Exclusion criterion #8 was revised as follows (bold text added):
Subject has a positive urine test result(s) for phencyclidine (PCP), cocaine, or 
amphetamines (inclusive of amphetamine, methamphetamine [mAMP], and 3, 4-
methylenedioxy-methamphetamine [MDMA]) at screening. 
-
Subjects who have a positive test due to the appropriate use of prescribed opiates, 
benzodiazepines, or barbiturates may be eligible for study participation per clinician 
judgment. In addition, subjects who have a positive test for opiates, benzodiazepines, 
or barbiturates used without a prescription, may be considered eligible per clinician 
judgment and in consultation with the sponsor’s medical monitor. Subjects known to 
be using heroin should be excluded from the study.
-
Subjects who have a positive test due to opiates, benzodiazepines, or barbiturates taken 
in a suicide attempt (eg, overdose) may be eligible for study participation per clinician 
judgment and in consultation with the sponsor’s medical monitor.
Rationale: Exclusion criterion #13 was revised to clarify that subjects who were previously enrolled in this study or 
the Sponsor’s other studies in this population (54135419SUI3001 and ESKETINSUI2001) are excluded from 
participation in this study.
4.2. Exclusion Criteria
Exclusion criterion #13 was revised as follows (bold text added):
Subject has received an investigational drug (including esketamine, ketamine, or 
investigational vaccines) or used an invasive investigational medical device within 60 days 
before the planned first dose of study drug or is currently enrolled in an investigational 
study or was previously enrolled in this study or the Sponsor’s other studies in this 
population, 54135419SUI3001 and ESKETINSUI2001.
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
12
Status: Approved, Date: 31 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: Text was added to further describe how the effect size of 0.45 for MADRS total score (at 24 hours post
first dose) was computed in the sample size determination.
Synopsis, Sample Size 
Determination; 
11.2. Sample Size 
Determination
The following bold text was added:
The effect size used in this calculation was based on results of the ESKETINSUI2001 
study where the effect size for the change from baseline to Day 2 was 0.65 (mean 
difference between treatment groups of -7.2 and a pooled SD of 11.02) for MADRS 
total score. Given that the ESKETINSUI2001 study was a Phase 2 study carried out 
in only one country, the maximum sample size for this Phase 3 study was determined 
using a smaller effect size of 0.45 to allow for greater variability that can be expected 
for a study conducted globally.
Rationale: The statistical methods were revised to add that summary statistics by study center for the primary 
efficacy endpoint will be provided.
Synopsis, Primary 
Efficacy Endpoint; 
11.4. Efficacy 
Analyses, Primary 
Efficacy Endpoint
The following statement has been added:
In addition, descriptive statistics (N, mean, standard deviation, median, minimum and 
maximum) of the primary efficacy variable will be provided by study center.
Rationale: The statistical methods were revised to confirm that treatment differences will be estimated using the 
Hodges-Lehman estimate for the key secondary variable.
Synopsis, Secondary 
Efficacy Endpoints; 
11.4. Efficacy 
Analyses, Secondary 
Efficacy Endpoints
The following statement has been added:
The treatment difference will be estimated using the Hodges-Lehmann estimate, which is 
the median of all possible paired differences for the change from baseline for CGI-SS-R at 
24 hours.
Rationale: Text was added to state which summary (descriptive) statistics will be used for continuous variables and 
categorical variables.
Synopsis, Secondary 
Efficacy Endpoints; 
11.4. Efficacy 
Analyses, Secondary 
Efficacy Endpoints
The following statement has been added:
Descriptive statistics (N, mean, standard deviation, median, minimum and maximum) will 
be provided for continuous variables and frequency distributions will be provided for 
categorical variables.
Rationale: The statistical methods have been revised to add descriptions of confidence intervals for treatment 
differences based on analysis of covariance (ANCOVA) model, mixed model with repeated measures (MMRM), 
and nonlinear mixed-effects model analyses.
Synopsis, Primary 
Efficacy Endpoint; 
11.4. Efficacy 
Analyses, Primary 
Efficacy Endpoint
The following statement has been added:
A point estimate and 95% confidence interval for the treatment difference will be 
provided.
Synopsis, Secondary 
Efficacy Endpoints; 
11.4. Efficacy 
Analyses, Secondary 
Efficacy Endpoints
The following statement has been added:
Point estimates and 95% confidence intervals for the treatment differences will be 
provided.  
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
13
Status: Approved, Date: 31 January 2018
Applicable Section(s)
Description of Change(s)
Synopsis, 
Pharmacokinetic 
Analyses; 
11.5 Pharmacokinetic 
Analyses
The following statement has been added:
For the parameter estimates, the standard error and 95% confidence interval will be 
provided. This will be determined after the population pharmacokinetic modeling of the 
data is completed.
Rationale: Text was added to emphasize that subjects may participate in the study only if they have adequate 
capacity to give consent and after fully understanding the potential risks, benefits, and potential adverse events of 
the study.
16.1 Study-Specific 
Design Considerations
The following text has been added in the subsection “Selection of Subjects”:
Subjects may participate in the study only if they have adequate capacity to give consent 
and after fully understanding the potential risks, benefits, and potential adverse events of 
the study. Determination of a subject’s decisional capacity will be made by the study 
investigator.
Rationale: Time and Events Schedule was clarified to note that the Remote Contact on Day 90 is the same for 
subjects who discontinue during double-blind phase and those who discontinue during the follow-up phase.
Time and Events 
Schedule; SIBAT 
Time and Events 
Schedule
-
Footnote “d” in the Time and Events Schedule and footnote “f” in the SIBAT Time and 
Events Schedule were revised as follows (bold text added; strikeout text deleted):
For subjects who discontinue from double-blind treatment with reasons other than lost 
to follow up, death, or withdrawal of consent, Remote Contact (RC) will be 
implemented 3 days after the last dose of intranasal study medication (if the date of the 
DB ET visit is less than 3 days after the last dose of intranasal study medication), and 
on Day 25 and on Day 90 for MADRS assessment and adverse event collection. 
-
The following statement was added to footnote “dd” in the Time and Events Schedule 
and footnote “h” in the SIBAT Time and Events Schedule:
Subjects who discontinue during the double-blind treatment phase prior to Day 25 will 
also have a Remote Contact on Day 90 for MADRS assessment and adverse event 
collection.
Rationale: Text added to state that subjects should refrain from using alcohol within 24 hours before and after each 
intranasal treatment session. 
4.3. Restrictions and 
Prohibitions; 
6.1. Intranasal Study 
Drug
The following text was added:
Subjects should refrain from using alcohol within 24 hours before and after each intranasal 
treatment session. If a subject appears intoxicated, dosing should not occur (delayed per 
the permitted visit window; see the Time and Events Schedule).
Rationale: Text revised to clarify procedures regarding collection of the Healthcare Resource Use Questionnaire.
9.6. Medical Resource 
Utilization
Text was revised as follows (bold text added; strikeout text deleted):
Medical resource utilization data, associated with medical encounters, will be collected 
using the Healthcare Resource Use Questionnaire (HRUQ) on an ongoing basis 
whenever an encounter occurs, and will be reviewed as indicated in the Time and Events 
Schedule.
Time and Events 
Schedule
Text revised to indicate that medical resource utilization data is collected using the 
Healthcare Resource Use Questionnaire.
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
14
Status: Approved, Date: 31 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: The text describing evaluation of pulse oximetry and Modified Observer’s Assessment of 
Alertness/Sedation (MOAA/S) was corrected to accurately describe when these data are collected.
9.7. Safety 
Evaluations, Pulse 
Oximetry
The following text was revised (bold text added; strikeout text deleted): 
Pulse oximetry will be used to measure arterial oxygen saturation (SpO2). On each dosing 
day, the device will be attached to the finger, toe, or ear at approximately 15 minutes 
before the first nasal spray, and SpO2 will be monitored and documented every 15 minutes 
from predose to for approximately 1.5 hours postdose.after the first nasal spray is 
administered (ie, SpO2 will be measured at t = -15 minutes, 0 [after administration of the 
first intranasal device], 15 minutes, 30 minutes, etc.). 
9.7. Safety 
Evaluations, Modified 
Observer’s 
Assessment of 
Alertness and 
Sedation (MOAA/S)
The following text was revised (strikeout text deleted): 
On each intranasal dosing day, the MOAA/S will be performed every 15 minutes from t =  
15 minutes (predose) to 1.5 hours postdose (ie, at t= -15 minutes, 0 [after administration of 
the first intranasal device], 15 minutes, 30 minutes, etc.).
Time and Events 
Schedule
-
Collection of pulse oximetry and MOAA/S data on Day 1 revised to state “every 
15 min” instead of “-15 min to 1.5 hr”
-
Footnotes “r” and “t” revised for consistency with the revisions in Section 9.7 
(described above) regarding evaluation of pulse oximetry and MOAA/S.
Rationale: The restriction on drinking before administration of intranasal study medication was revised to clarify.
Synopsis, Dosage and 
Administration; 
4.3. Prohibitions and 
Restrictions; 
6.1. Intranasal Study 
Drug
Text has been revised as follows (bold text added; strikeout text deleted):
Drinking of water or any other permitted beveragefluids will be restricted at least 30 
minutes before the first nasal spray on each dosing day.
Rationale: Text was revised to indicate that biomarker evaluations are not considered optional in this study.
Synopsis, Biomarker 
and 
Pharmacogenomic
(DNA) Evaluations, 
and Overview of 
Study Design; 
3.1. Overview of 
Study Design; 
9.1.1. Overview, 
Table 4; 
9.5. Biomarker and 
Pharmacogenomic 
(DNA) Evaluations
Statements which indicated that site participation in biomarker evaluations is optional 
based on operational capabilities have been deleted.
Time and Events 
Schedule
-
The following text was deleted from footnote “y”:
Optional site participation based on operational capabilities; required for subjects at 
participating sites.
-
The following text was deleted from the subheading “Biomarkers” as indicated below 
(strikeout text deleted):
Biomarkers (optional site participation) y
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
15
Status: Approved, Date: 31 January 2018
Applicable Section(s)
Description of Change(s)
9.1.1. Overview, 
Table 4
-
Deleted row showing approximate total blood volume for double-blind treatment phase 
without biomarker and pharmacogenomic/epigenetic samples.
-
Text in footnote “c” was deleted and replaced with text in footnote “e”. Footnote “e” 
deleted.
Rationale: Procedure for collection of menstrual cycle information was revised to clarify.
Time and Events 
Schedule
-
The following text was added to footnote “y” (replacing deleted text described above):
Menstrual cycle information will be collected on these visits.
-
Footnote “y” was added at Day 1, Predose and Day 25 in the row for “Blood sample 
collection (serum and plasma biomarkers)”.
9.5. Biomarker and 
Pharmacogenomic 
(DNA) Evaluations
Text was modified as follows for consistency with revisions to the Time and Events 
Schedule (bold text added; strikeout text deleted):
Information on menstrual cycle (date of first day of last period, average length of cycle) 
will be recorded at each visit on Day 1 (predose) and Day 25 when blood samples for 
biomarker analysis are collected.
Rationale: Text was revised to clarify procedures for clinical laboratory assessments and electrocardiogram 
recording.
9.7. Safety 
Evaluations, Clinical 
Laboratory Tests
Text revised to indicate that the urine pregnancy test and urine drug screen will be 
performed on-site.
9.7. Safety 
Evaluations,
Electrocardiogram 
(ECG)
The following statement was deleted:
If blood sampling or vital sign measurement is scheduled for the same time point as ECG 
recording, the procedures should be performed in the following order: ECG(s), vital signs, 
blood draw.
Rationale: Minor errors were noted
Synopsis, Study 
Population
Lists of key inclusion and exclusion criteria revised to use bullets instead of numbers.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
16
Status: Approved, Date: 31 January 2018
SYNOPSIS
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
Major depressive disorder (MDD) is the most prevalent mental health condition and the psychiatric 
diagnosis most commonly associated with suicide. Epidemiology studies suggest that nearly 60% of those 
who die by suicide suffer from affective disorders, and at least one-half of people who complete suicide 
are depressed at the time of their deaths. Although MDD with imminent risk for suicide is a potentially 
lethal condition that requires immediate intervention, there is no approved treatment. The current standard 
of care is hospitalization and treatment with antidepressant medication. However, hospitalization is 
temporary and not completely effective, and the risk for suicide remains high in the weeks after discharge. 
As standard antidepressants may take up to 4-6 weeks to exert their full effect, there is a significant unmet 
therapeutic need for effective drugs with rapid onset of effect.
Ketamine and esketamine (the S-enantiomer of ketamine) are approved and widely used for the induction 
and maintenance of anesthesia via intramuscular (IM) or intravenous (IV) administration. The anesthetic 
effects of esketamine are attributed to the blockade of ionotropic N-methyl-D-aspartate (NMDA) 
glutamate receptors. Janssen Research & Development (JRD) is developing intranasal esketamine as an 
antidepressant therapy. The mechanism of action of esketamine is distinct from conventional 
monoaminergic antidepressant treatments, and esketamine profoundly affects fast excitatory glutamate 
transmission, increases brain-derived neurotrophic factor (BDNF) release, and stimulates synaptogenesis. 
In addition, a higher NMDA receptor binding affinity of esketamine compared to ketamine allows a lower 
volume of medication to be administered via the non-invasive and rapidly-absorbed intranasal route.
The current study is being conducted to evaluate the efficacy and safety of intranasal esketamine in 
addition to comprehensive standard of care in subjects with MDD who are at imminent risk for suicide as 
a pivotal Phase 3 study in support of regulatory agency requirements for registration of intranasal 
esketamine.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Primary Objective
The primary objective is to evaluate the efficacy of intranasal esketamine 84 mg compared with intranasal 
placebo in addition to comprehensive standard of care in reducing the symptoms of MDD, including 
suicidal ideation, in subjects 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.
Key Secondary Objective
The key secondary objective is to assess the efficacy of intranasal esketamine compared with intranasal 
placebo in reducing severity of suicidality as measured by the clinical global impression of severity of 
suicidality revised version (CGI-SS-R) at 24 hours post first dose.
Other Secondary Objectives
The other secondary objectives are:

To evaluate the efficacy of intranasal esketamine compared with intranasal placebo in remission of 
MDD (defined as MADRS total score ≤12) at 4 hours and 24 hours post first dose, and through the 
end of the double-blind treatment phase (Day 25).
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
17
Status: Approved, Date: 31 January 2018

To evaluate the efficacy of intranasal esketamine compared with intranasal placebo in reducing 
symptoms of MDD as assessed by the MADRS total score at 4 hours post first dose on Day 1, and 
through the end of the double-blind treatment phase (Day 25).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in reducing 
severity of suicidality as measured by the CGI-SS-R at 4 hours post first dose on Day 1, and through 
the end of the double-blind treatment phase (Day 25).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in achieving 
resolution of suicidality as measured by the score of 0 (normal, not at all suicidal) or 1 (questionably 
suicidal) of the CGI-SS-R at 4 hours and 24 hours post first dose, and through the end of the double-
blind treatment phase (Day 25).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in reducing 
imminent suicide risk as measured by the clinical global impression of imminent suicide risk 
(CGI-SR-I) at 4 hours and 24 hours post first dose, and through the end of the double-blind treatment 
phase (Day 25).

To assess the impact of intranasal esketamine compared with intranasal placebo on the following 
patient-relevant concepts through the end of the double-blind treatment phase (Day 25)

Hopelessness as measured by Beck Hopelessness Scale (BHS)

Health related quality of life and health status, using the European Quality of Life (EuroQol) 
Group, 5-Dimension, 5-Level (EQ-5D-5L)

Health related quality of life using the Quality of Life in Depression Scale (QLDS)

Treatment satisfaction using the Treatment Satisfaction Questionnaire for Medication (TSQM-9)

Patient-reported suicidality using the Suicidal Ideation and Behaviors Assessment Tool 
(SIBAT), including Module 5 My Risk, Question 3 (patient-reported frequency of suicidal 
thinking)

To assess the safety and tolerability of intranasal esketamine during the double-blind treatment phase 
and the follow-up phase, with special attention given to the following assessments:

Potential effects on suicidal ideation and behavior using the SIBAT

On dosing days:
o
Effect on heart rate, blood pressure, respiratory rate, and blood oxygen saturation 
o
Effect on alertness and sedation using the Modified Observer's Assessment of 
Alertness/Sedation (MOAA/S) scale
o
Treatment-emergent dissociative symptoms using the Clinician Administered Dissociative 
States Scale (CADSS)

To assess the pharmacokinetics of intranasal esketamine.
Exploratory Objectives
The exploratory objectives are:

To evaluate the efficacy of intranasal esketamine compared with intranasal placebo in reducing 
symptoms of MDD as assessed by the MADRS total score and remission rate through the end of the 
follow-up phase (Day 90).
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
18
Status: Approved, Date: 31 January 2018

To assess the efficacy of intranasal esketamine compared with intranasal placebo in reducing 
severity of suicidality as measured by the CGI-SS-R through the end of the follow-up phase 
(Day 90).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in reducing 
imminent suicide risk as measured by the CGI-SR-I through the end of the follow-up phase 
(Day 90).

To assess the impact of intranasal esketamine compared with intranasal placebo through the end of 
the follow-up phase (Day 90) on the following patient-relevant concepts:

Hopelessness (BHS)

Health related quality of life and health status (EQ-5D-5L)

Health related quality of life (QLDS)

Subject treatment satisfaction (TSQM-9)

To assess the effect of intranasal esketamine compared with intranasal placebo on the SIBAT 
Module 3 My Current Thinking through the double-blind treatment (Day 25) and follow-up (Day 90) 
phases.

To assess medical resource utilization as measured by the Healthcare Resource Use Questionnaire 
(HRUQ) of intranasal esketamine compared with intranasal placebo through the end of the follow-up 
phase (Day 90), including 30-day and 60-day readmission, and emergency room visits related to 
MDD and suicidality. 

To evaluate whether pretreatment concentrations or post-treatment change in MDD-related 
biomarkers (eg, hypothalamic-pituitary-adrenal [HPA] axis function, immune system activation, 
growth factors, metabolic markers) correlate with clinical response or non-response as measured by 
the MADRS, following intranasal administration of esketamine.
Endpoints
The primary efficacy endpoint will be the change from baseline (Day 1, predose) to 24 hours post first 
dose in depressive symptoms, as measured by the MADRS total score.
The key secondary efficacy endpoint will be the change from baseline (Day 1, predose) at 24 hours post 
first dose in severity of suicidality, as measured by the CGI-SS-R.
The other secondary endpoints are:

MADRS

Remission rate (MADRS ≤12) at 4 hours and 24 hours post first dose, and through the end of 
the double-blind treatment phase (Day 25)

Change from baseline of MADRS total score at 4 hours post first dose and through the end of 
the double-blind treatment phase (Day 25)

CGI-SS-R

Change from baseline at 4 hours post first dose and through the end of the double-blind 
treatment phase (Day 25).

Proportion of subjects achieving resolution of suicidality (CGI-SS-R score of 0 or 1) at 4 hours 
and 24 hours post first dose, and through the end of the double-blind treatment phase (Day 25)

CGI-SR-I: Change from baseline at 4 hours and 24 hours post first dose, and through the end of the 
double-blind treatment phase (Day 25)
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
19
Status: Approved, Date: 31 January 2018

BHS: Change from baseline through the end of the double-blind treatment phase (Day 25)

EQ-5D-5L: Change from baseline through the end of the double-blind treatment phase (Day 25)

QLDS: Change from baseline through the end of the double-blind treatment phase (Day 25)

TSQM-9: Scores through the end of the double-blind treatment phase (Day 25)

SIBAT: Change from baseline in Module 5 My Risk, Question 3 (patient-reported frequency of 
suicidal thinking), through the end of the double-blind treatment phase (Day 25)

Pharmacokinetics: Plasma esketamine and noresketamine concentrations will be summarized; 
plasma concentrations of esketamine (and noresketamine concentrations, if warranted) will be 
included in a population analysis

Safety endpoints will be evaluated throughout the study:

Monitoring of treatment emergent adverse events (TEAEs)

Clinical laboratory tests, physical examination, nasal examination, 12-lead electrocardiogram 
(ECG), and vital signs

SIBAT

On dosing days: MOAA/S, CADSS, and pulse oximetry
The exploratory endpoints include:

Change from baseline in MADRS, CGI-SS-R, CGI-SR-I, BHS, QLDS, and EQ-5D-5L through the 
end of the follow-up phase (Day 90)

TSQM-9 scores, medical resource utilization, and biomarkers through the end of the follow-up phase 
(Day 90)

SIBAT: Change from baseline in Module 3 My Current Thinking through the end of the double-
blind (Day 25) and follow-up (Day 90) phases
Hypothesis
The primary hypothesis is that, in addition to comprehensive standard of care, intranasal esketamine 
84 mg is superior to intranasal placebo in rapidly reducing the symptoms of MDD, including suicidal 
ideation, as assessed by the change from baseline in the MADRS total score at 24 hours post first dose in 
subjects who are assessed to be at imminent risk for suicide.
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, multicenter study. A target of 224 male and 
female subjects, 18 to 64 years of age, with MDD presenting to an emergency room (ER) or other 
permitted setting and assessed to be at imminent risk for suicide will be enrolled in this study. 
The study will consist of a screening evaluation performed within 48 hours prior to the Day 1 intranasal 
dose (if possible, screening should occur within 24 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. 
On Day 1 of the double-blind treatment phase, approximately 224 subjects will be randomized in a 1:1 
ratio to 1 of 2 treatments: intranasal esketamine 84 mg (n = 112) or intranasal placebo (n = 112), 
administered two times per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25). Randomization will 
be stratified by study center and by the physician’s assessment of the subject’s need of standard of care 
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
20
Status: Approved, Date: 31 January 2018
antidepressant treatment (ie, antidepressant monotherapy or an antidepressant plus augmentation therapy); 
the standard of care will be determined prior to randomization on Day 1. 
The first dose of study medication will be administered in the ER or other permitted setting, including the 
inpatient psychiatric unit. All subjects will be treated in the context of comprehensive standard clinical 
care, including hospitalization and the initiation or optimization of antidepressant treatment, which will be 
determined by the treating physician(s). The standard of care antidepressant treatment will be initiated or 
optimized for all subjects on Day 1. 
After the first dose (ie, starting with the Day 4 dose or later), a one-time dose reduction to intranasal 
esketamine 56 mg or intranasal placebo is allowed if a subject is unable to tolerate the intranasal 
esketamine 84 mg or placebo dose assigned at randomization. No further dose adjustment is allowed 
during the double-blind treatment phase.
Dose titration/adjustments of newly initiated or optimized standard of care antidepressant treatment 
should occur during the first 2 weeks of double-blind treatment (ie, by Day 15), with doses remaining 
stable thereafter through the end of the double-blind phase (Day 25). During the follow-up phase, the 
antidepressant treatment will be managed based on clinician’s judgment.
Subjects will remain in the inpatient psychiatry unit for a recommended duration of 5 days, with shorter 
or longer hospitalizations permitted if clinically warranted per local standard of care. Discharge before
5 days must be discussed and approved by the sponsor’s medical monitor. Following discharge from the 
inpatient psychiatric unit, subsequent visits for the double-blind treatment phase will be conducted twice-
weekly at an outpatient psychiatric facility through Day 25. During the follow-up phase, subjects will be 
monitored twice weekly for the first two weeks (Days 28, 32, 35, and 39) after study drug treatment. 
Subjects will then be followed up weekly for the next two weeks (Days 46 and 53) and every two weeks 
for the rest of the follow-up period (Days 67 and 90). 
Efficacy, safety, pharmacokinetic, biomarker, and pharmacogenomic evaluations will be performed as 
described in the Time and Events Schedule. 
The primary efficacy evaluation is the MADRS, the key secondary evaluation is CGI-SS-R, and other 
efficacy evaluations include the SIBAT, BHS, EQ-5D-5L, QLDS, and TSQM-9.
Safety evaluations include monitoring and collection of adverse events and concomitant therapies, 
physical examination, nasal examination, body weight, height, vital signs, 12-lead ECG, pulse oximetry, 
respiratory rate, clinical laboratory tests, SIBAT, MOAA/S, and CADSS. 
Blood samples will be collected for measurement of plasma concentrations of esketamine, noresketamine, 
and other metabolites if warranted.
Blood samples will be collected for biomarker evaluations.
Pharmacogenomic blood samples will be collected from subjects who consent separately to this 
component of the study (where local regulations permit). Subject participation in pharmacogenomic 
research is optional.
An Independent Data Monitoring Committee will be commissioned for this study.
SUBJECT POPULATION
The key inclusion and exclusion criteria for enrolling subjects in this study are described below.
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
21
Status: Approved, Date: 31 January 2018
Key Inclusion Criteria

Subject must be a man or woman, 18 to 64 years of age, inclusive.

Subject must meet Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5) 
diagnostic criteria for MDD, without psychotic features, based upon clinical assessment and 
confirmed by the Mini International Psychiatric Interview (MINI).

Subjects 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.

In the physician’s opinion, acute psychiatric hospitalization is clinically warranted due to subject’s 
imminent risk of suicide.

Subject has a MADRS total score of >28 predose on Day 1.

As part of standard of care treatment, subject 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).
Key Exclusion Criteria

Subject has a current DSM-5 diagnosis of bipolar (or related disorders), antisocial personality 
disorder, or obsessive compulsive disorder.

Subject currently meets DSM-5 criteria for borderline personality disorder. 

Subjects not meeting full DSM-5 criteria for borderline personality disorder but exhibiting 
recurrent suicidal gestures, threats, or self-mutilating behaviors should also be excluded.

Subject has a current clinical diagnosis of autism, dementia, or intellectual disability 

Subject has a current or prior DSM-5 diagnosis of a psychotic disorder, or MDD with psychotic 
features.

Subject 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.

Subject has any of the following conditions: 

a history or current signs and symptoms of liver or renal insufficiency 

clinically significant cardiac (including unstable coronary artery disease and congestive heart 
failure, tachyarrhythmias and recent myocardial infarction)
or
vascular, pulmonary, 
gastrointestinal, endocrine (including uncontrolled hyperthyroidism), neurologic (including 
current or past history of seizures except uncomplicated childhood febrile seizures with no 
sequelae), 
hematologic, 
rheumatologic, 
or 
metabolic 
(including 
severe 
dehydration/hypovolemia) disease.
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
22
Status: Approved, Date: 31 January 2018

Subject has uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic blood 
pressure >90 mmHg) despite diet, exercise or a stable dose of anti-hypertensive treatment for at least 
2 weeks at screening; or any past history of hypertensive crisis. 

Subjects with conditions in which the elevation of blood pressure could be a serious risk 
(including unstable heart failure, severe cardiovascular disease, recent cerebral injury, increased 
intracranial pressure / intracranial mass lesion, intracranial bleeding or acute stroke, untreated 
glaucoma or perforating eye injury) are excluded.

An abnormal blood pressure value at screening can be repeated once after 5 minutes of 
relaxation for subject eligibility. On Day 1 of the double-blind phase prior to randomization, a 
supine or semi-supine systolic blood pressure >140 mmHg or diastolic blood pressure
>90 mmHg is exclusionary.
DOSAGE AND ADMINISTRATION
Intranasal Study Medication
All intranasal doses of study medication will be self-administered under the direct supervision of the 
investigator or designee. On Day 1, subjects will be randomized to treatment with either intranasal 
esketamine 84 mg or intranasal placebo, administered two times per week for 4 weeks. Intranasal 
treatment sessions should not take place on consecutive days.
Food will be restricted for at least 2 hours before each administration of study medication. Drinking of 
any fluids will be restricted at least 30 minutes before the first nasal spray on each dosing day. If the 
subject has nasal congestion on the dosing day, an intranasal decongestant can be used to reduce 
congestion, or with the exception of the Day 1 dose, the dosing day may be delayed (per the permitted 
visit window; see the Time and Events Schedule). If an intranasal decongestant is used to reduce 
congestion, it cannot be used within 1 hour prior to intranasal study drug dosing.
The first dose of study medication will be administered in the ER or other permitted setting that has 
appropriate staffing to manage acutely suicidal subjects. If the first dose is administered in the ER, it is 
recommended that the subject not be transferred from the ER to the inpatient psychiatric unit after the 
postdose assessments (approximately 4 hours in length) are completed. Subjects who have been admitted 
directly into the inpatient psychiatric unit due to imminent risk for suicide or transferred from a medical 
unit (following medical stabilization for recent suicide attempt) will receive their first dose of study 
medication in the inpatient psychiatric unit. 
Subjects will remain in the inpatient psychiatry unit for a recommended duration of 5 days, with shorter 
or longer hospitalizations permitted if clinically warranted per local standard of care. Following discharge 
from the inpatient psychiatric unit, subsequent visits for the double-blind treatment phase will be 
conducted twice-weekly at an outpatient psychiatric facility through Day 25.
On all outpatient intranasal dosing days, all subjects must remain at the clinical site until study procedures 
have been completed and the subject is ready for discharge per clinician’s assessment. The minimum time 
required for postdose monitoring is 1.5 hours. Subjects should be accompanied when released from the 
clinical study site. Subjects must not drive a car or work with machines for 24 hours after study drug 
dosing.
On each dosing day: Subjects will self-administer 1 spray into each nostril (ie, a total of 2 sprays using 
1 intranasal device) at each of the following 3 time points: t = 0, 5 minutes and 10 minutes; time = 0 is 
defined as the time of the first 100-μL spray. Subjects will use a separate intranasal device at each of 
these 3 time points (ie, a total of 3 devices). Sprays to each nostril should be delivered in rapid succession 
at the scheduled time points.
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
23
Status: Approved, Date: 31 January 2018
After the first dose (ie, starting with the Day 4 dose or later), if required due to tolerability issues, a one-
time dose reduction to intranasal esketamine 56 mg or intranasal placebo is allowed for subsequent doses. 
No further dose adjustment is allowed during the double-blind treatment phase. The subject would receive 
the decreased dose at all remaining dosing days.
Standard of Care Antidepressant Treatment
All subjects will be treated in the context of comprehensive standard clinical care, including 
hospitalization and the initiation or optimization of antidepressant treatment, which will be determined by 
the treating physician(s) based on clinical judgment and practice guidelines. The standard of care 
antidepressant treatment (antidepressant monotherapy or antidepressant plus augmentation therapy) will 
be initiated or optimized for all subjects at the time of randomization on Day 1. Subjects who are on 
antidepressant monotherapy from Day 1 should remain on antidepressant monotherapy through the end of 
double-blind phase (Day 25) whereas subjects who are on antidepressant plus augmentation therapy from 
Day 1 will remain on antidepressants plus augmentation therapy through the end of double-blind phase 
(Day 25). Eligible subjects may or may not be receiving antidepressants at the time of study entry. Dose 
titration/adjustments of newly initiated or optimized standard of care antidepressant treatment should 
occur during the first 2 weeks of double-blind treatment (ie, by Day 15), with doses remaining stable 
thereafter through the end of the double-blind phase (Day 25). Subjects who are currently taking a 
recently initiated antidepressant treatment at screening (initiated <2 weeks prior) may continue taking the 
antidepressant at the current dose or at an optimized dose (dose adjustment is allowed during the first 
2 weeks of double-blind treatment) through the end of the double-blind phase (Day 25), if deemed 
clinically appropriate by the investigator. During the double-blind treatment phase, the investigator needs 
to consult with the sponsor’s medical monitor in advance if additional changes on antidepressant 
treatment are clinically indicated. During the follow-up phase, the antidepressant treatment will be 
managed based on the clinician’s judgment. 
EFFICACY EVALUATIONS
The primary efficacy evaluation will be the MADRS total score. The assessment will be performed using 
the Structured Interview Guide for the MADRS. 
The other secondary and exploratory efficacy evaluations include the SIBAT, BHS, QLDS, EQ-5D-5L, 
TSQM-9, and HRUQ.
PHARMACOKINETIC EVALUATIONS
Venous blood samples will be collected for measurement of plasma concentrations of esketamine, 
noresketamine, and other metabolites if warranted. Plasma collected for pharmacokinetic (PK) evaluation
may additionally be used to evaluate safety or efficacy aspects that address concerns arising during or 
after the study period.
BIOMARKER AND PHARMACOGENOMIC (DNA) EVALUATIONS
Blood samples will be collected for exploratory analysis of biomarkers (protein, metabolites, and RNA) 
related to immune system activity, HPA axis activation, neurotrophic and metabolic factors. Exploratory 
analyses may be performed for additional biomarkers as well. 
A pharmacogenomic blood sample will be collected to allow for pharmacogenomic research, as necessary 
(where local regulations permit). Subject participation in the pharmacogenomic research is optional.
MEDICAL RESOURCE UTILIZATION
Medical resource utilization data, associated with medical encounters, will be collected using the
Healthcare Resource Use Questionnaire (HRUQ). The HRUQ includes information regarding utilization 
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
24
Status: Approved, Date: 31 January 2018
of healthcare services (including the timing and type of serves), enabling changes in level and quantity of 
services to be considered as a variable in economic models.
SAFETY EVALUATIONS
Safety evaluations include monitoring and collection of adverse events and concomitant therapies, 
physical examination, body weight, height, vital signs, 12-lead ECG, pulse oximetry, clinical laboratory 
tests, and nasal examination. 
Although the SIBAT will be an efficacy evaluation, it will also inform the safety evaluation to detect 
potential effects on suicidal ideation and behavior throughout the study.
The CADSS will be administered to assess treatment-emergent dissociative symptoms, and the MOAA/S 
will be used to measure treatment-emergent sedation.
STATISTICAL METHODS
Subject Information
The primary efficacy and safety analysis sets are defined below.

Full analysis set: The full analysis set will include all randomized subjects who have received at least 
one dose of double-blind study medication and have both a baseline and a post dose evaluation for 
the MADRS total score.

Safety analysis set: The safety analysis set will include all randomized subjects who receive at least 
one dose of double-blind study medication.
Sample Size Determination
The maximum sample size for this study was calculated assuming an effect size of 0.45 for the MADRS 
total score at 24 hours post first dose (Day 2), a one-sided significance level of 0.025, and a drop-out rate 
at 24 hours of 5%. Approximately 112 subjects will need to be randomized to each treatment group to 
achieve 90% power. The effect size used in this calculation was based on results of the 
ESKETINSUI2001 study where the effect size for the change from baseline to Day 2 was 0.65 (mean 
difference between treatment groups of -7.2 and a pooled SD of 11.02) for MADRS total score. Given 
that the ESKETINSUI2001 study was a Phase 2 study carried out in only one country, the maximum 
sample size for this Phase 3 study was determined using a smaller effect size of 0.45 to allow for greater 
variability that can be expected for a study conducted globally.
Efficacy Analysis
Primary Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined by the 
following 3 components:
Population: subjects with MDD who are at imminent risk of suicide
Endpoint: change from baseline to 24 hours post first dose (Day 2) in the MADRS total score 
Measure of Intervention: the effect of the initially randomized treatment that would have been observed 
had all subjects remained on their treatment until Day 2 of the double-blind phase. 
The primary analysis will be based on the full analysis set and the MADRS total scores collected at 
Day 2.
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
25
Status: Approved, Date: 31 January 2018
Primary Efficacy Endpoint
The primary efficacy variable, change from baseline in MADRS total score at 24 hours post first dose 
(Day 2), will be analyzed using an analysis of covariance (ANCOVA) model. The model will include 
factors for treatment, center, standard of care antidepressant treatment (ie, antidepressant monotherapy or 
an antidepressant plus augmentation therapy), and baseline MADRS total score as a covariate. A point 
estimate and 95% confidence interval for the treatment difference will be provided. Since subjects are 
hospitalized at the time of the primary endpoint, it is anticipated that missing data will be infrequent. 
However, if a subject has a MADRS total score at a time earlier than 24 hours post first dose but does not 
have the 24 hour value, the earlier value will be used for the primary efficacy analysis. In addition, 
descriptive statistics (N, mean, standard deviation, median, minimum and maximum) of the primary 
efficacy variable will be provided by study center.
Secondary Efficacy Endpoints
The analysis of the key secondary efficacy endpoint, change from baseline for CGI-SS-R at 24 hours post 
first dose (Day 2), will be performed using an ANCOVA model on the ranks of change with factors for 
treatment, center, standard of care antidepressant treatment (ie, antidepressant monotherapy or an 
antidepressant plus augmentation therapy) and baseline CGI-SS-R (unranked) as a covariate. The 
treatment difference will be estimated using the Hodges-Lehmann estimate, which is the median of all 
possible paired differences for the change from baseline for CGI-SS-R at 24 hours.
The multiplicity with regard to testing multiple endpoints (the primary and the key secondary) will be 
controlled by a fixed sequence testing procedure, ie, the key secondary hypothesis will be tested only after 
the null hypothesis for the primary endpoint is rejected.
The secondary efficacy endpoints, proportion of subjects with remission (MADRS total score ≤12) and 
the proportion of subjects achieving resolution of suicidality (CGI-SS-R score of 0 or 1) at each visit 
during the double-blind phase will be analyzed using a Cochran-Mantel-Haenszel chi-square test 
adjusting for center and standard of care antidepressant treatment (ie, antidepressant monotherapy or 
antidepressant plus augmentation therapy). Subjects who discontinue treatment prior to the particular visit 
of the double-blind phase will not be considered to have remission or resolution of suicidality.
Changes from baseline over time in MADRS total score, BHS, and QLDS total scores will be analyzed 
based on last observation carried forward (LOCF) data using an ANCOVA model with treatment, center, 
and standard of care antidepressant treatment (ie, antidepressant monotherapy or an antidepressant plus 
augmentation therapy) as factors and baseline value as a covariate. Additionally, the change from baseline 
in MADRS total score at Day 25 will be analyzed using a mixed model for repeated measures (MMRM)
analysis with baseline MADRS total score as a covariate, and treatment, center, standard of care
antidepressant treatment (ie, antidepressant monotherapy or antidepressant plus augmentation therapy), 
day, and day-by-treatment interaction as fixed effects, and a random subject effect. Comparison of 
esketamine versus placebo will be performed using the appropriate contrast. Point estimates and 95% 
confidence intervals for the treatment differences will be provided. Missing data will be closely 
monitored and additional sensitivity analyses will be specified in the SAP, if necessary.
Ranks of changes from baseline over time for CGI-SS-R and CGI-SR-I will be analyzed based on LOCF 
data using an ANCOVA model with treatment, center, and standard of care antidepressant treatment (ie, 
antidepressant monotherapy or an antidepressant plus augmentation therapy) as factors and baseline value 
(unranked) as a covariate.
SIBAT Module 5 My Risk, Question 3 (patient reported frequency of suicidal thinking), TSQM-9, 
dimension scores of EQ-5D-5L data, and health status index will be summarized over time.
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
26
Status: Approved, Date: 31 January 2018
Additionally, scores of all efficacy endpoints will be summarized for all visits. Descriptive statistics (N, 
mean, standard deviation, median, minimum and maximum) will be provided for continuous variables 
and frequency distributions will be provided for categorical variables.
Pharmacokinetic Analyses
Plasma esketamine and noresketamine concentrations will be listed for all subjects. All concentrations 
below the lowest quantifiable concentration or missing data will be labeled as such in the concentration 
database. All subjects and samples excluded from the analysis will be clearly documented in the study 
report.
Population PK analysis of plasma concentration-time data of esketamine may be performed using 
nonlinear mixed-effects modeling. Data may be combined with those of other selected studies to support a 
relevant structural model. Available baseline subject characteristics (demographics, laboratory variables, 
genotypes, race, etc.) will be tested as potential covariates affecting PK parameters. For the parameter 
estimates, the standard error and 95% confidence interval will be provided. This will be determined after 
the population pharmacokinetic modeling of the data is completed. Details will be given in a population 
PK analysis plan and the results of the population PK analysis will be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
The relationship between MADRS total score (and possibly selected adverse events and additional 
pharmacodynamic parameters), and PK metrics of esketamine may be evaluated. The results of the 
pharmacokinetic/pharmacodynamic analyses may be reported separately.
Biomarker and Pharmacogenetic Analyses
Biomarkers will be tabulated by treatment and summary statistics will be calculated. Posttreatment 
changes in biomarkers over time will be summarized by treatment group. Associations between baseline 
levels and changes from baseline in selected biomarkers and clinical endpoints will be explored. 
Exploratory analyses may include comparison of biomarker measures between the treatment groups and 
correlation with baseline and change from baseline biomarker values in the efficacy and other measures. 
Exploratory analyses may be performed for additional biomarkers. In addition, all biomarker data 
obtained from this study may also be included in an ongoing cross-study analysis to investigate the 
relationship between depression severity, phenotypes, and biomarkers.
Pharmacogenomic analyses may include candidate gene analyses or genome-wide association analyses in 
relation to treatment response, non-response, and MDD. Expression analyses may include testing of 
known messenger RNA/microRNA (mRNA/miRNA) transcripts or transcriptome-wide analysis in 
relationship to antidepressant treatment response and MDD. Additional exploratory analyses may be 
performed.
Details of the analysis plan and summary of results from both biomarker and pharmacogenomic analyses 
will be reported separately.
Medical Resource Utilization Analysis
Medical resource utilization data will be descriptively summarized by treatment group.
Safety Analyses
Safety data will be analyzed for the double-blind phase using the safety analysis set. The safety data from 
the follow-up phase will be summarized separately.
The verbatim terms used in the electronic case report form (eCRF) by investigators to identify adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). All reported 
adverse events with onset during each phase will be included in the analysis. For each adverse event, the 
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
27
Status: Approved, Date: 31 January 2018
percentage of subjects who experience at least 1 occurrence of the given event will be summarized by 
treatment group. Subjects who die, who discontinue treatment due to an adverse event, or who experience 
a serious adverse event will be summarized separately.
The TEAEs of special interest will be examined separately grouped in the following categories: drug 
abuse, dependence and withdrawal (standardized MedDRA queries [SMQ]), transient dizziness/vertigo, 
impaired cognition, anxiety, cystitis, and suicidality. The adverse events of special interest will be further 
listed in the SAP.
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly abnormal 
results will be used in the summary of laboratory data. Descriptive statistics will be calculated for each 
laboratory analyte at baseline and for observed values and changes from baseline at each scheduled time 
point. Frequency tabulations of the abnormalities will be provided. A listing of subjects with any 
markedly abnormal laboratory results will also be provided.
The ECG data will be summarized by ECG parameter. Descriptive statistics will be calculated at baseline 
and for observed values and changes from baseline at each scheduled time point. Frequency tabulations of 
the abnormalities will be made. All clinically relevant abnormalities in ECG waveform that are changes 
from the baseline readings will be reported.
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, pulse oximetry measurements, 
body weight measurements, and blood pressure (systolic and diastolic) values and changes from baseline 
will be summarized at each scheduled time point. The percentage of subjects with values beyond 
clinically important limits will be summarized.
Abnormalities observed during the targeted nasal examinations at screening and post-baseline will be 
summarized and listed by treatment group.
Sedation data from the MOAA/S and dissociative symptoms data from the CADSS will be summarized 
descriptively at each scheduled visit by treatment group.
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JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
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Status: Approved, Date: 31 January 2018
TIME AND EVENTS SCHEDULE 
Phase
Screening
Double-blind Treatment
Follow Up
Visit Number
1
2
3
4b
5b
6b
7b
8b
9b
10b
-
-
-
11b
12b 13b 14a 15a 16a 17a
18a
-
Week
1
2
3
4
4
5
5
6
7
8
10
13
Day
-c
1
2ff
4
8
11
15
18
22
25
D/Cu DB 
ETd
DB 
RCd
28 
RCii 32
35 
RCii 39
46
53
67
90/ FU
ETdd
90 
RCdd
-
Pre
dose
0 
hr
40
min
1
hr
1.5 
hr
4
hree
Study Procedures
Setting
Emergency Room (ER) 
or other permitted setting e
X
X
X
X
X
X
Xf
Inpatient psychiatric unit g
X
X
Outpatient psychiatric unit
X
X
X
X
X
X
-
-
X
X
X
X
X
X
Screening/Administrative
Informed consent
X
Informed consent for optional 
genetic research samples
X
Inclusion/exclusion criteria
X
X
Medical history, psychiatric 
history, and demographics
X
Standard of care 
antidepressants assignment hh
X
X
Urine pregnancy test for 
women of childbearing 
potential i
X
X
X
Urine drug screen i
X
X
X
Mini International Psychiatric 
Interview (MINI) j
X
Question B3 and B10 from 
MINI (current status) j, k
X
Study Drug Administration
Practice session for use of 
intranasal device
X
Randomization
X
Study Drug Administration m
(intranasal esketamine or 
placebo)
X
X
X
X
X
X
X
X
Safety Assessments
Physical examination
X
X
X
X
Nasal examination
X
Xh
X
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
29
Status: Approved, Date: 31 January 2018
Phase
Screening
Double-blind Treatment
Follow Up
Visit Number
1
2
3
4b
5b
6b
7b
8b
9b
10b
-
-
-
11b
12b 13b 14a 15a 16a 17a
18a
-
Week
1
2
3
4
4
5
5
6
7
8
10
13
Day
-c
1
2ff
4
8
11
15
18
22
25
D/Cu DB 
ETd
DB 
RCd
28 
RCii 32
35 
RCii 39
46
53
67
90/ FU
ETdd
90 
RCdd
-
Pre
dose
0 
hr
40
min
1
hr
1.5 
hr
4
hree
Vital signs n
X
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
X
X
12-lead ECG
Xp
Xq
Xq
Xq
X
Pulse oximetry r
X (every 15 min)
X
X
X
X
X
X
X
Body weight
X
Xh
X
X
Height
X
Modified Observer's 
Assessment of 
Alertness/Sedation 
(MOAA/S) j, t
X (every 15 min)
X
X
X
X
X
X
X
Clinician Administered 
Dissociation States Scale 
(CADSS) j, s
X
X
X
X
X
X
X
X
X
X
Efficacy Assessments
Suicide Ideation and 
Behavior Assessment Tool 
(SIBAT) w
X
X
X
Xh
Xh
Xh
Xh
Xh
Xh
Xh
X
X
X
X
X
X
X
X
Montgomery Asberg 
Depression Rating Scale 
(MADRS) (Recall: 7 days) j
X
X
X
X
X
X
MADRS (Recall: since last 
assessment) j
Xh
Xh
Xh
Xh
Xh
Xh
Xh
X
X
X
X
X
X
X
MADRS (Recall: 4 hours) j, ee
Xv,z
Xv,z
MADRS (Recall: 24 hours) j
X
Beck Hopelessness Scale 
(BHS) (Recall: Last 7 days) l
X
Xh
X h
X
X
X
Quality of Life in Depression 
Scale (QLDS) l
X
X
Xh
Xh
X
X
X
EQ-5D-5L l
X
X
Xh
Xh
X
X
X
Treatment Satisfaction 
Questionnaire for Medication 
(TSQM-9) l
Xh
Xh
X
X
X
Clinical Laboratory Assessments
Hematology, Chemistry
Xx
Xh
X
Urinalysis
Xx
Xh
X
NCT03097133


JNJ54135419 (esketamine)
Clinical Protocol 54135419SUI3002 Amendment 2
30
Status: Approved, Date: 31 January 2018
Phase
Screening
Double-blind Treatment
Follow Up
Visit Number
1
2
3
4b
5b
6b
7b
8b
9b
10b
-
-
-
11b
12b 13b 14a 15a 16a 17a
18a
-
Week
1
2
3
4
4
5
5
6
7
8
10
13
Day
-c
1
2ff
4
8
11
15
18
22
25
D/Cu DB 
ETd
DB 
RCd
28 
RCii 32
35 
RCii 39
46
53
67
90/ FU
ETdd
90 
RCdd
-
Pre
dose
0 
hr
40
min
1
hr
1.5 
hr
4
hree
Medical Resource Utilization
Health Resource Use
Questionnaire (HRUQ) j
X
X
X
X
X
Biomarkers 
Blood sample collection 
(serum and plasma 
biomarkers) aa
X y
X
Xh, y
X
Blood sample collection 
(RNA biomarkers) gg
X
X
Xh
X
Pharmacogenomics (DNA/epigenetics) – Optional
Blood sample collection bb
X
X
Xh
X
Pharmacokinetics
Blood sample collection cc
X
X
Ongoing Subject Review
Prior and concomitant 
therapy
Continuous
X
Continuous
Adverse events
Continuous
X
X
X
X
Continuous
X
Abbreviations: BHS, Beck Hopelessness Scale; CADSS, Clinician Administered Dissociative States Scale; DB, double-blind; D/C, discharge; DNA, deoxyribonucleic acid; ECG, 
electrocardiogram; EQ-5D-5L, EuroQol-5 dimension- 5-level; ER, emergency room; ET, early termination; FU, follow-up; HRUQ, Health Resource Use Questionnaire; ICF, informed 
consent form; MADRS, Montgomery-Asberg Depression Rating Scale; MINI, Mini International Neuropsychiatric Interview; MOAA/S, Modified Observer’s Assessment of 
Alertness/Sedation; QLDS, Quality of Life in Depression Scale; RC, remote contact; RNA, ribonucleic acid; SIBAT, Suicide Ideation and Behavior Assessment Tool; SpO2, oxygen 
saturation; TSQM-9, Treatment Satisfaction Questionnaire for Medication
Footnotes:
a
Visit can be performed ±3days.
b
Visit can be performed ±1 day. Intranasal treatment sessions should not be given on consecutive days.
c
The subject should be screened (ie, starting with the signing of the informed consent form) within 48 hours prior to intranasal dosing on Day 1 (if possible, the subject should be 
screened within 24 hours prior to the Day 1 intranasal dose). 
d
Subjects who discontinue from the double-blind treatment phase prior to completion of the Day 25 visit will have an Early Termination (DB ET) visit conducted at the time of 
discontinuation. For subjects who discontinue from double-blind treatment with reasons other than lost to follow up, death, or withdrawal of consent, Remote Contact (RC) will be 
implemented 3 days after the last dose of intranasal study medication (if the date of the DB ET visit is less than 3 days after the last dose of intranasal study medication) and on Day 25 
for MADRS assessment and adverse event collection. The investigator must ensure the subject is appropriately transitioned/followed for any additional care required. 
e
Not applicable for subjects who have been admitted directly into the inpatient psychiatric unit due to imminent risk for suicide or for medical stabilization (following recent suicide 
attempt). These subjects will receive their first dose of study medication in the inpatient psychiatric unit. Other permitted setting is a non-ER setting that has appropriate staffing to 
manage acutely suicidal patients.
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f 
For subjects dosed in the ER or other permitted setting, it is recommended that subjects not be transferred from the ER to the inpatient psychiatric unit until after the 4 hour postdose 
assessments are completed. 
g 
Subjects can be admitted directly into the inpatient psychiatric unit due to imminent risk for suicide or for medical stabilization (following recent suicide attempt). These subjects will 
receive their first dose of study medication in the inpatient psychiatric unit. The recommended duration of inpatient hospitalization is 5 days, with shorter or longer hospitalizations 
permitted if clinically warranted per local standard of care by the investigator’s opinion. Discharge before 5 days must be discussed and approved by the sponsor’s medical monitor.
h
Performed predose.
i
In addition to the scheduled time points, additional pregnancy and drug screening can be performed at the investigator’s discretion during the study.
j 
Clinician-administered assessment.
k 
Subjects will be asked to respond to Questions B3 and B10 of the MINI relative to their current state. 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 Questions B3 and B10 of the MINI must be repeated prior to randomization to confirm 
eligibility.
1 
Subject-completed assessment.
m 
On each dosing day, subjects will self-administer 1 spray into each nostril (ie, 2 sprays per intranasal device) at each of the following 3 time points: t = 0, 5 minutes and 10 minutes, 
where time = 0 is defined as the time of the first 100-µL spray. After Day 1, a one-time decrease to intranasal esketamine 56 mg or intranasal placebo, in a blinded manner, will be 
permitted if a subject is unable to tolerate the intranasal esketamine 84 mg or placebo dose assigned at randomization. In this case, the subject would receive the decreased dose on all
remaining dosing days. Please see details about study drug administration in Section 6.2.
n 
Blood pressure, heart rate, respiratory rate, and temperature (tympanic recommended). 
o 
Blood pressure, heart rate, and respiratory rate at predose and at t = 40 minutes, 1 hour, and 1.5 hours postdose on each dosing day. Temperature at predose only on each dosing day.
p 
At screening, the ECG tracing will be sent to the central ECG laboratory but the investigator or sub-investigator is also required to review the ECG locally to determine subject 
eligibility.
q 
Performed 1 hour postdose. 
r
On each dosing day, pulse oximetry (SpO2) will be performed every 15 minutes from predose to 1.5 hour postdose (see Section 9.7 for further guidance on timing of pulse oximetry 
assessments). 
s
CADSS will be performed on dosing days predose and at 40 minutes and 1.5 hours postdose. If any CADSS items are scored zero at 40 minutes, these items will not be repeated at 
1.5 hours postdose.
t
MOAA/S will be performed every 15 minutes on dosing days from predose to 1.5 hour postdose, or longer, if necessary (see Section 9.7 for further guidance on MOAA/S 
assessments).
u 
Discharge (D/C) visit is performed on the actual day of discharge from initial hospitalization required at study entry. If the actual day of discharge coincides with another scheduled 
study visit, all study procedures for the scheduled visit should be completed and duplicate assessments are not required.
v 
MADRS performed at 4 hours postdose.
w 
The SIBAT has both clinician-administered and subject-reported modules; not all modules are completed at every visit. Refer to the SIBAT Time and Events Schedule for an outline of 
which module(s) will be performed at each scheduled time point.
x 
Samples will be collected for analysis by local laboratory (for eligibility) and central laboratory. If standard of care clinical laboratory tests are performed within 24 hours prior to the 
screening visit (ie, prior to signing of the ICF) the results for laboratory tests required per protocol at screening can be used for determination of subject eligibility. In this case, after the 
subject signs the ICF, a sample(s) for the local laboratory is not required, but samples for the central laboratory are still required. 
y
Menstrual cycle information will be collected on these visits.
z 
The sleep item will not be assessed at the 4-hour postdose time point on Day 1 and Day 25. The MADRS scores for the sleep item recorded predose on the same day will be carried forward.
aa
Approximately 20 mL serum and 10 mL plasma samples will be collected at each time point.
bb
A 6 mL whole blood sample will be collected at each time point.
cc
A 2 mL whole blood sample will be collected at each of the following postdose times: 30-50 minutes, 1.5 hour to 2.5 hours, and 4 hours to 12 hours.
dd
Subjects, who discontinue from the follow-up phase prior to completion of the Day 90 visit, will have an Early Termination (FU ET) visit conducted at the time of discontinuation. For 
subjects who discontinue with reasons other than lost to follow up, death, or withdrawal of consent, Remote Contact (RC) will be implemented on Day 90 for MADRS assessment and 
adverse event collection. Subjects who discontinue during the double-blind treatment phase prior to Day 25 will also have a Remote Contact on Day 90 for MADRS assessment and 
adverse event collection.
ee
The 4-hour assessments at the Day 1 and Day 25 visit should be performed within ±30 minutes of the 4-hour postdose time point.
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ff
The 24-hour assessments at the Day 2 visit should be performed within ±2 hours of the 24-hour postdose time point.
gg
A 2.5mL whole blood sample will be collected at each time point.
hh
The standard of care antidepressant treatment (antidepressant monotherapy or antidepressant plus augmentation therapy) will be determined by the treating physician(s) based on 
clinical judgment and practice guidelines prior to randomization, and the treatment will be initiated on Day 1. See Section 6.2 for further details.
ii
Remote contact will be implemented for MADRS assessment and adverse event collection.
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SIBAT TIME AND EVENTS SCHEDULE
Phase
Screening
Double-blind Treatment
Follow Up
Visit Number
1
2
3
4 b
5b
6b
7b
8b
9b
10b
-
-
-
11b
12b
13b
14a 15a 16a 17a
18a
-
Week
1
2
3
4
4
5
5
6
7
8
10
13
Day
-
1
2j
4c
8c
11c
15c 18c 22c
25c D/Cd DB
ETf
DB
RCf
28 
RCg
32
35 
RCg
39
46
53
67
90/ FU 
ETh
90 
RCh
-
Pre
dose
0 
hr
40 
min
1 
hr
1.5 
hr
4 
hri
SIBAT
Subject Completed Modules
Module 1 About me
X
Module 2 My Risk/ 
Protective Factors
X
X
X
X
X
X
X
Module 3 My Current 
Thinking
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Module 4 My Actions
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Module 5 My Risk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinician Completed Modules
Module 6. Clinician Semi-
Structured Interview
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Module 7. Clinical Global 
Impressions e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Module 8. Clinical 
Judgment of optimal 
Suicide Management
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: CGI-SR-I, Clinical Global Impression of Imminent Suicide Risk; CGI-SR-LT, Clinical Global Impression of Long-term Suicide Risk; CGI-SS-R, Clinical Global 
Impression of Severity of Suicidality – Revised; DB, double-blind; D/C, discharge; ET, early termination; FoST, frequency of suicidal thinking; FU, follow-up; RC, remote contact; 
SIBAT, Suicide Ideation and Behavior Assessment Tool
Footnotes:
a
Visit can be performed +/- 3days.
b
Visit can be performed +/- 1 day. Intranasal treatment sessions should not be given on consecutive days.
c
The SIBAT modules will be performed predose.
d
Discharge (D/C) visit is performed at on the actual day of discharge from inpatient hospitalization. If the actual day of discharge coincides with another scheduled study visit, the 
SIBAT modules will be performed according to the procedures under D/C column and duplicate assessments are not required.
e
Module 7 includes the Clinical Global Impression of Severity of Suicidality – Revised (CGI-SS-R), Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I), Clinical Global 
Impression of Long-term Suicide Risk (CGI-SR-LT), and assessment of frequency of suicidal thinking (FoST).
f
Subjects who discontinue from the double-blind treatment phase prior to completion of the Day 25 visit will have an Early Termination (DB ET) visit conducted at the time of 
discontinuation. For subjects who discontinue from double-blind treatment with reasons other than lost to follow up, death, or withdrawal of consent, Remote Contact (RC) will be 
implemented 3 days after the last dose of intranasal study medication (if the date of the DB ET visit is less than 3 days after the last dose of intranasal study medication) and on Day 25 
for MADRS assessment and adverse event collection. The investigator must ensure the subject is appropriately transitioned/followed for any additional care required.
g
Remote contact will be implemented for MADRS assessment and adverse event collection.
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h
Subjects, who discontinue from the follow-up phase prior to completion of the Day 90 visit, will have an Early Termination (FU ET) visit conducted at the time of discontinuation. For 
subjects who discontinue with reasons other than lost to follow up, death, or withdrawal of consent, Remote Contact (RC) will be implemented on Day 90 for MADRS assessment and 
adverse event collection. Subjects who discontinue during the double-blind treatment phase prior to Day 25 will also have a Remote Contact on Day 90 for MADRS assessment and 
adverse event collection.
i
The 4-hour assessments at the Day 1 visit should be performed within ±30 minutes of the 4-hour postdose time point.
j
The 24-hour assessments at the Day 2 visit should be performed within ±2 hours of the 24-hour postdose time point.
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ABBREVIATIONS
ANCOVA
analysis of covariance
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BDNF
brain-derived neurotrophic factor
BHS
Beck Hopelessness Scale
BUN
blood urea nitrogen
CADSS
Clinician Administered Dissociative States Scale
CGI-SR-I
Clinical Global Impression – Imminent Suicide Risk
CGI-SR-LT
Clinical Global Impression – Long-term Suicide Risk
CGI-SS
Clinical Global Impression – Severity of Suicidality
CGI-SS-R
Clinical Global Impression – Severity of Suicidality - Revised
CGJ-SR
Clinical Global Judgment of Suicide Risk
eCRF
electronic case report form(s)
CYP
hepatic cytochrome P450
DNA
deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders (5th edition)
ECG
electrocardiogram
ECT
electroconvulsive therapy
eDC
electronic data capture
EDTA
ethylenediaminetetraacetic acid
ER
Emergency Room
GCP
Good Clinical Practice
HPA
hypothalamic-pituitary-adrenal
HRUQ
Healthcare Resource Use Questionnaire
ICD-10
International Statistical Classification of Diseases and Related Health Problems - 10th revision
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IM
intramuscular
IRB
Institutional Review Board
ISST
InterSePT Scale for Suicidal Thinking
IV
Intravenous
IWRS
interactive web response system
LC-MS/MS
liquid chromatography/mass spectrometry/mass spectrometry
LSD
lysergic acid diethylamide
MADRS
Montgomery Asberg Depression Rating Scale
MADRS-SI
Montgomery Asberg Depression Rating Scale - Suicidal Thoughts Item
mAMP
methamphetamine
MDD
major depressive disorder
MDMA
3, 4-methylenedioxy-methamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MINI
Mini International Psychiatric Interview
miRNA
micro ribonucleic acid
MOAA/S
Modified Observer’s Assessment of Alertness/Sedation
mRNA
messenger ribonucleic acid
NMDA
N-methyl-D-aspartate
PCP
phencyclidine
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PQC
Product Quality Complaint
QTc
corrected QT
QTcB
QT corrected according to Bazett's formula
QTcF
QT corrected according to Fridericia's formula
RNA
ribonucleic acid
SAP
Statistical Analysis Plan
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SE
standard error
SIBAT
Suicide Ideation and Behavior Assessment Tool
SMQ
standardized Medical Dictionary for Regulatory Activities queries
SpO2
arterial oxygen saturation
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TRD
treatment-resistant depression
USP
United States Pharmacopeia
w/v
weight/volume
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1.
INTRODUCTION
Major depressive disorder (MDD) is the most prevalent mental health condition and the 
psychiatric diagnosis most commonly associated with suicide. 41,65 Epidemiology studies suggest 
that nearly 60% of those who die by suicide suffer from affective disorders, and at least one-half 
of people who complete suicide are depressed at the time of their deaths.2,13,17,51 Although MDD 
with imminent risk for suicide is a potentially lethal condition that requires immediate 
intervention, there is no approved treatment. The current standard of care is hospitalization and 
treatment with antidepressant medication. However, hospitalization is temporary and not 
completely effective, and the risk for suicide remains high in the weeks after discharge. As 
standard antidepressants may take up to 4-6 weeks to exert their full effect75,79, there is a 
significant unmet therapeutic need for effective drugs with rapid onset of effect.24
Ketamine and esketamine (the S-enantiomer of ketamine) are approved and widely used for the 
induction and maintenance of anesthesia via intramuscular (IM) or intravenous (IV) 
administration. The anesthetic effects of esketamine are attributed to the blockade of ionotropic 
N-methyl-D-aspartate (NMDA) glutamate receptors.78 Janssen Research & Development (JRD) 
is developing intranasal esketamine as an antidepressant therapy. The mechanism of action of 
esketamine is distinct from conventional monoaminergic antidepressant treatments, and 
esketamine profoundly affects fast excitatory glutamate transmission, increases brain-derived 
neurotrophic factor (BDNF) release, and stimulates synaptogenesis.26 In addition, a higher 
NMDA receptor binding affinity of esketamine compared to ketamine allows a lower volume of 
medication to be administered via the non-invasive and rapidly-absorbed intranasal route.
For the most comprehensive nonclinical and clinical information regarding esketamine
(JNJ-54135419), refer to the latest version of the Investigator's Brochure for esketamine.37
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
1.1.1.
Nonclinical Studies
Safety Pharmacology
The effects of ketamine on myocardial contractility and blood pressure varied with species and 
experimental conditions.37 In these studies, the dog was most predictive of the cardiovascular 
effects of ketamine in man. In dogs, ketamine produced increases in arterial blood pressure, heart 
rate and cardiac output as well as a decrease in total peripheral resistance.43 Results from animal 
studies suggest that the increase in blood pressure produced by ketamine is due to selective 
activation of central cardiac stimulating mechanisms leading to an increase in cardiac output.43
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Toxicology
Repeated-dose Toxicity:
Repeated-dose toxicity studies with intranasally administered 
esketamine were performed in rats for up to 6 months and in dogs for up to 9 months. Intranasal 
administration of esketamine was well tolerated in these studies. No adverse effects were noted 
in rats or dogs up to the highest dose tested.37
Neurotoxicity: The neurotoxic potential of intranasal esketamine has been investigated in rats in 
two single-dose studies and one 14-day study. No neuropathological lesions were noted in the 
esketamine-dosed rats at the highest dose tested in each study.37
Reproductive and Developmental Toxicity: In a rat fertility and early embryonic developmental 
study, no adverse effects of intranasal esketamine on the fertility and reproductive capacities of 
adult males and females were observed.37 Rat and rabbit embryo-fetal developmental toxicity 
studies with intranasally administered racemic ketamine did not reveal evidence of reproductive 
toxicity. 37 However, when monkey fetuses were exposed in utero to high dose levels of racemic 
ketamine, neurotoxicity was observed.37 Intranasal esketamine did not affect pre- and postnatal 
development in rats; however, high dose levels of racemic ketamine induced neurotoxicity in 
early postnatal rat pups.37
Genotoxicity: In vitro and in vivo genotoxicity studies have been performed with ketamine and 
esketamine, and the overall weight of evidence demonstrates the absence of significant genotoxic 
risk.37
Abuse potential: The results of self-administration and withdrawal experiments in several animal 
models suggest that esketamine would have abuse potential in humans. 7,20,21,46,57,83,84
1.1.2.
Clinical Studies
1.1.2.1.
Completed and Ongoing Clinical Studies with Intranasal Esketamine
A total of 9 Phase 1 studies with intranasal esketamine have been completed and reported, 
including 6 studies in healthy younger subjects, 2 studies in healthy elderly and younger subjects, 
and 1 study in subjects with a history of allergic rhinitis. In total, 263 subjects have been exposed 
to intranasal esketamine in the completed Phase 1 studies that have been reported.37 Three 
additional Phase 1 studies in healthy subjects have been completed but not reported, and a total 
of 6 Phase 1 studies are ongoing in healthy subjects, subjects with hepatic impairment, and 
subjects with renal impairment.
One Phase 2 study has been completed in subjects with MDD who are at imminent risk of 
suicide with 35 subjects exposed to intranasal esketamine.16 One Phase 2 study has been 
completed in subjects with treatment-resistant depression (TRD) with 107 subjects exposed to 
intranasal esketamine.37 In addition, one Phase 2 study in subjects with TRD is ongoing.
In the clinical development program for intranasal esketamine, 6 Phase 3 clinical studies are 
ongoing in subjects with TRD: 2 short-term double-blind, randomized, active-controlled studies, 
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1 maintenance-of-effect study, 2 long-term, open-label studies, and 1 short-term study in elderly 
subjects with TRD.
Further information about the completed and ongoing studies with esketamine is provided in the 
Investigator’s Brochure.37
1.1.2.2.
Human Pharmacokinetics and Product Metabolism
Metabolism and Excretion
Ketamine (and esketamine) undergoes extensive metabolism by human hepatic cytochrome P450 
(CYP). In humans, N-demethylation to the active metabolite norketamine is a major route of 
metabolism. Norketamine had a half-life in plasma of approximately 5 hours in humans.31 The 
major human hepatic cytochromes that catalyze ketamine N-demethylation in vitro were
CYP2B6 and CYP3A4,32,68,82 and those that were responsible for the formation of norketamine 
metabolites included
CYP2A6 and CYP2B6.68 Pharmacokinetic (PK) results after IV 
administration of racemic ketamine and esketamine to human subjects suggested that inversion 
of esketamine to arketamine (the R-enantiomer of ketamine) does not occur.29
Racemic ketamine and its metabolites have been shown to be predominantly excreted in the 
urine. An average of 91% of a dose of ketamine administered to healthy subjects was recovered 
in urine.18 Less than 3% of an administered dose was excreted in urine as parent drug.80
Pharmacokinetics of Intranasal Esketamine
The PK of intranasal esketamine have been characterized in healthy adult subjects (elderly and 
younger adults) as well as subjects with a history of allergic rhinitis, with TRD37, and with MDD 
at imminent risk for suicide. In healthy adult subjects, intranasally-administered esketamine (28 
to 112 mg) was rapidly absorbed with measurable concentrations at 7 minutes after the first 
spray; the plasma esketamine maximum concentration and area under the concentration-time 
curve increased in a dose-related manner following intranasal administration, and the mean 
terminal half-life of esketamine ranged from 5.86 to 9.83 hours (ESKETINTRD1001).37 When 
administered in healthy adult subjects via the intranasal route, esketamine was rapidly absorbed 
and had an absolute bioavailability of approximately 48% (ESKTINTRD1009).37 In a Phase 2 
study in subjects with TRD (ESKETINTRD2003), there was a dose-dependent increase in mean 
plasma esketamine concentrations from subjects in Panel A who were administered 28, 56, or 
84 mg doses of intranasal esketamine.37 Furthermore, the mean esketamine concentrations in 
plasma samples collected at corresponding timepoints on Days 1, 11, and 25 were similar 
suggesting that the PK was consistent after repeated intranasal administration.37 The PK results 
from subjects with MDD at imminent risk of suicide (ESKETINSUI2001) who received 84 mg 
doses of intranasal esketamine were consistent with the PK results in healthy adults and those 
with TRD.
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1.1.2.3.
Efficacy
Several small clinical studies and case reports suggested that subanesthetic doses of ketamine
could improve symptoms of depression within hours even in subjects who responded poorly to 
conventional antidepressants.50 Further results from Panel A (conducted in the United States and 
Belgium) in a Phase 2, 2-panel, double-blind, doubly-randomized, placebo-controlled clinical 
study in subjects with TRD (ESKETINTRD2003) demonstrated that treatment with intranasal 
esketamine (28, 56, and 84 mg) rapidly improved clinical symptoms of depression at 2 hours and 
24 hours after the first dose as assessed by the change in Montgomery-Asberg Depression Rating 
Scale (MADRS) total score from baseline.37 In addition, after 1 week of treatment the analysis 
showed that all 3 esketamine dose groups were statistically superior to the placebo group using a 
one-sided significance level of 0.05 (least squares mean differences [SE] between each 
esketamine group and the placebo group were: -4.2 [2.09], -6.3 [2.07], and -9.0 [2.13] for 
esketamine 28, 56, and 84 mg, respectively; p=0.021, p=0.001, and p<0.001 for esketamine 28, 
56, and 84 mg, respectively) and that there was a significant relationship between esketamine 
dose and change in MADRS total score (p<0.001).37 The major secondary analyses of results 
from Panel A provided preliminary evidence suggesting that improvements in depressive 
symptoms resulting from esketamine treatment could be sustained with repeated dosing for 
74 days, the duration of the study in Panel A.37 In Panel B (conducted in Japan), subjects were 
treated with placebo or 14 or 56 mg of intranasal esketamine for up to 25 days. Greater 
improvements in MADRS total score were observed in the esketamine 56-mg group compared 
with the placebo group using a one-sided significance level of 0.10 (mean difference [SE]: -3.7 
[2.81]; p=0.096), and a dose response was detected during the first week of treatment
(p=0.097).37 Although there was a statistically significant difference between the esketamine 
56-mg and placebo groups during the first week of treatment, the results from Panel B must be 
interpreted with caution due to a significant treatment by baseline MADRS total score interaction 
during the first week of treatment (p=0.052), where results favored the placebo group for 
subjects with higher baseline MADRS total scores and the esketamine groups for subjects with 
lower baseline MADRS total scores.37
Several pilot studies in subjects with MDD or bipolar depression also suggested that ketamine 
may reduce suicidal ideation within hours of administration25,47,71,72,85. In addition, three 
independent randomized, double-blind trials in subjects with MDD suggested that doses of IV 
ketamine could rapidly decrease suicidal ideation as evaluated by assessments such as the 
MADRS Suicidal Thoughts Item (MADRS-SI).5,38,63 Recently, a Phase 2, double-blind, 
randomized, placebo-controlled, proof-of-concept study (ESKETINSUI2001) evaluated the 
efficacy and safety of intranasal esketamine for the rapid reduction of the symptoms of MDD, 
including suicidal ideation. Subjects with a diagnosis of MDD assessed to be at imminent risk for 
suicide from the United States were randomly assigned to treatment with placebo (n=31) or 
esketamine 84 mg (n=35) for up to 25 days.16 All subjects received comprehensive standard of 
care treatment including initial hospitalization and optimized antidepressant medication. 
Esketamine 84 mg compared with placebo demonstrated a clinically meaningful and statistically 
significant reduction of depressive symptoms as assessed by changes from baseline in MADRS 
total score using a two-sided significance level of 0.20 at 4 hours after the first dose (primary 
endpoint; mean difference [SE] between esketamine 84 mg and placebo: -5.3 [2.10]; p=0.015)
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and at approximately 24 hours after the first dose (mean difference [SE]: -7.2 [2.85]; p=0.015), 
and esketamine 84 mg demonstrated evidence of a potential therapeutic effect on Day 25 (mean 
difference [SE]: -4.5 [3.14]; p=0.159).16 The changes from baseline in suicidal ideation based on 
the MADRS-SI score also favored esketamine 84 mg; the difference between the esketamine and 
placebo group was statistically significant at 4 hours after the first dose (p=0.002), and the 
differences between esketamine and placebo showed evidence of a potential therapeutic effect at 
approximately 24 hours after the first dose (p=0.129) and on Day 25 (p=0.143).16 Additionally, 
changes from baseline in the Clinical Global Judgment of Suicide Risk (CGJ-SR), which 
summarized the clinician’s overall judgment of suicide risk, provided evidence of a potential 
therapeutic effect of esketamine 84 mg compared with placebo at both 4 hours (p=0.112) and 
24 hours (p=0.150) after the first dose.16 The results from ESKETINSUI2001 support the 
hypothesis that esketamine, administered intranasally, is an efficacious treatment for the rapid 
reduction of the symptoms of MDD, including suicidal ideation, in subjects assessed to be at 
imminent risk for suicide. 
1.1.2.4.
Safety and Tolerability
Ketamine was first introduced as an anesthetic in 1963 and is considered to have an excellent 
medical safety profile.30,45,73,76 The following adverse reactions are listed as very common, 
common, or frequent occurrences for ketamine and esketamine when administered as an 
anesthetic: emergence or recovery reactions, elevated blood pressure and pulse rate, stimulation 
of respiration, nausea, and vomiting.44,78
Short-term Use of Intranasal Esketamine in Subjects with TRD
Subjects with TRD in Panel A in Study ESKETINTRD2003, received placebo or 28, 56, or 
84 mg of intranasal esketamine, and subjects in Panel B received placebo or 14 or 56 mg of 
esketamine. All doses of esketamine generally appeared to be tolerated, and no new safety 
concerns were raised during the study. There were no deaths during the double-blind or open-
label treatment phases. There was 1 death due to completed suicide in Panel B during the follow-
up phase of the study, 20 days after the subject received the last dose of study medication.37 A 
total of 4 non-fatal serious adverse events (SAEs) occurred in 3 subjects during the study; 
oesophagitis (during placebo treatment), ectopic pregnancy (during esketamine treatment, 
leading to treatment withdrawal), general physical health deterioration (follow-up phase) and 
confusional state (follow-up phase).37 The investigator assessed the SAE of confusional state as 
probably related to study medication and SAEs of esophagitis, ectopic pregnancy, and general 
physical health deterioration, and completed suicide as not related to study medication. In total, 
4 subjects experienced treatment-emergent adverse events (TEAEs) which led to withdrawal of 
study medication while receiving esketamine treatment (ectopic pregnancy [described above], 
syncope, headache, and dissociative disorder).37 The investigator assessed the events of headache 
and dissociative disorder as very likely related to study medication. The investigator considered 
the event of syncope possibly related to the study medication, and the sponsor considered the
event of syncope not related to the study medication based on the short half-life of esketamine 
and the onset of the event of syncope. 
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In Panels A and B combined, the common TEAEs (≥10% the total esketamine or placebo 
groups) that occurred more frequently in the total esketamine group compared with the placebo 
group during the double-blind phase were: dizziness, headache, dissociation, nausea, feeling 
abnormal, and hypoaesthesia.19 A majority of subjects in Panels A and B experienced elevations 
in blood pressure measurements after receiving esketamine doses; the maximum elevations from 
predose in blood pressure measurements on each dosing day were observed in most cases within 
1 hour post dose, with the majority returning within the normal range by 2 hours postdose.19 The 
blood pressure changes observed did not appear to attenuate over time with multiple doses. A 
majority of subjects in the esketamine treatment groups in Panels A and B experienced an 
increase in dissociative symptoms after dosing as assessed using the Clinician Administered 
Dissociative States Scale (CADSS). Dissociative symptoms peaked at approximately 40 minutes 
after dosing and typically resolved by 2 hours after dosing.19 The magnitude of postdose 
dissociative symptoms decreased over time with repeated consecutive doses for all esketamine 
doses.
Short-term Use of Intranasal Esketamine in Subjects with MDD at Imminent Risk for 
Suicide
In the Phase 2 study in subjects with MDD at imminent risk for suicide (ESKETINSUI2001), the 
TEAEs reported by esketamine-treated subjects were consistent with the safety profile of
esketamine observed in earlier studies. Esketamine 84 mg was generally tolerated, and no new 
safety signals emerged in this population. There were no deaths during the study. There were 
4 SAEs in the double-blind phase, all in the esketamine 84 mg group.16 Three of these events 
were related to re-hospitalization of subjects with re-emergence of suicidal ideation (n=2) or 
depression (n=1) in subjects who had improved and had been discharged from the hospital. In all 
3 instances, the subjects recovered and completed both the double-blind and follow-up phases. 
One subject experienced an event of increased agitation, and the study medication was 
withdrawn. With the exception of re-emergence of depressive symptoms, which was considered 
possibly related to study medication, none of the other SAEs were considered to be related to 
study medication by the investigator. During the follow-up phase, 5 subjects in the placebo group
experienced SAEs, including suicidal ideation (n=1) and attempted suicide (n=3) and cellulitis 
(n=1), compared with only 1 subject in the esketamine group, who experienced suicidal ideation.
One subject in the placebo group and 5 subjects in the esketamine 84 mg group discontinued 
from the double-blind phase due to TEAEs.16 Events leading to discontinuation in the esketamine 
group were dizziness, dysgeusia, ventricular extrasystole, nausea, and dyspnea, which were 
considered by the investigator to be probably or very likely related to study drug; and aggression 
and agitation, which were considered to be doubtfully and not related to study drug, respectively.
In total, 3 of 35 subjects in the esketamine group had dose reductions from 84 mg to 56 mg for 
intolerance.16
The most common (≥20%) individual TEAEs in the esketamine 84 mg group were nausea, 
dizziness, dysgeusia, headache, and dissociation and vomiting.16 A majority of subjects in the 
esketamine group experienced elevations in blood pressure measurements after dosing. The 
maximum increases in blood pressure occurred in the esketamine treated subjects at 
approximately 40 minutes postdose.16 A greater proportion of subjects in the esketamine group 
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reported dissociative symptoms as assessed by the CADSS compared with the placebo group. 
The dissociative symptoms observed in the esketamine group had an onset shortly after the start 
of the dose and generally resolved within 2 hours postdose.16 The dissociative symptoms 
attenuated with repeated dosing.
Adverse Events Associated with Chronic Use of Ketamine
Much of the literature on chronic ketamine use comes from data gathered from illegal use, rather 
than clinical studies. Several studies have examined cognitive function in ketamine users, 
23,58,60,64; overall, infrequent use did not appear to be associated with long-term cognitive 
impairment.64 The most robust findings were that frequent ketamine users (more than 5 times a 
week) exhibited impairments in both short- and long-term memory.60 Although dosages varied, 
the dosages reported by ketamine users in this study were much higher than the dosages of 
ketamine or equivalent doses of esketamine intended for use in treating MDD. The memory 
impairments were not found in ex-users who had been abstinent for at least a year, thus 
impairments may be reversible.61
Ketamine-induced ulcerative cystitis is also an identified complication.59 The most common 
symptoms are frequency and urgency of urination, dysuria, urge incontinence, and occasionally 
painful hematuria. Most cases were in near-daily recreational ketamine users; the majority of 
cases resolved after stopping ketamine use, and one-third remained static. The ketamine dose, 
dosing frequency, and duration of chronic ketamine use at which cystitis may develop are not 
known. Compared with the doses and dosing frequency of esketamine proposed in this study, the 
equivalent ketamine dose in published reports of interstitial cystitis and bladder-related 
symptoms was typically much higher; ketamine was dosed more frequently, and often there was
concomitant use of other substances.
Abuse Liability, Dependence and Withdrawal
There are reports of ketamine dependence in the literature but no large-scale studies. 35,39,56,59,66
One study found that ketamine users and ex-users expressed concerns about ketamine addiction, 
and the majority of frequent users reported using the drug without stopping until supplies ran out, 
so compulsive patterns of behavior are a concern.62 A few published reports describe craving and 
somatic and psychological aspects of anxiety as symptoms of withdrawal from ketamine; 
however, a specific ketamine withdrawal syndrome has not yet been described.22,48,59
1.2.
Overall Rationale for the Study
The current study is being conducted to evaluate the efficacy and safety of intranasal esketamine 
in addition to comprehensive standard of care in subjects with MDD who are at imminent risk 
for suicide as a pivotal Phase 3 study in support of regulatory agency requirements for 
registration of intranasal esketamine.
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2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objective
The primary objective is to evaluate the efficacy of intranasal esketamine 84 mg compared with 
intranasal placebo in addition to comprehensive standard of care in reducing the symptoms of 
MDD, including suicidal ideation, in subjects 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.
Key Secondary Objective
The key secondary objective is to assess the efficacy of intranasal esketamine compared with 
intranasal placebo in reducing severity of suicidality as measured by the clinical global 
impression of severity of suicidality revised version (CGI-SS-R) at 24 hours post first dose.
Other Secondary Objectives
The other secondary objectives are:

To evaluate the efficacy of intranasal esketamine compared with intranasal placebo in 
remission of MDD (defined as MADRS total score ≤12) at 4 hours and 24 hours post first 
dose, and through the end of the double-blind treatment phase (Day 25).

To evaluate the efficacy of intranasal esketamine compared with intranasal placebo in 
reducing symptoms of MDD as assessed by the MADRS total score at 4 hours post first 
dose on Day 1, and through the end of the double-blind treatment phase (Day 25).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in 
reducing severity of suicidality as measured by the CGI-SS-R at 4 hours post first dose on 
Day 1, and through the end of the double-blind treatment phase (Day 25).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in 
achieving resolution of suicidality as measured by the score of 0 (normal, not at all suicidal) 
or 1 (questionably suicidal) of the CGI-SS-R at 4 hours and 24 hours post first dose, and 
through the end of the double-blind treatment phase (Day 25).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in 
reducing imminent suicide risk as measured by the clinical global impression of imminent 
suicide risk (CGI-SR-I) at 4 hours and 24 hours post first dose, and through the end of the 
double-blind treatment phase (Day 25).

To assess the impact of intranasal esketamine compared with intranasal placebo on the 
following patient-relevant concepts through the end of the double-blind treatment phase 
(Day 25)

Hopelessness as measured by Beck Hopelessness Scale (BHS)
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
Health related quality of life and health status, using the European Quality of Life 
(EuroQol) Group, 5-Dimension, 5-Level (EQ-5D-5L)

Health related quality of life using the Quality of Life in Depression Scale (QLDS)

Treatment satisfaction using the Treatment Satisfaction Questionnaire for Medication 
(TSQM-9)

Patient-reported suicidality using the Suicidal Ideation and Behaviors Assessment Tool 
(SIBAT), including Module 5 My Risk, Question 3 (patient-reported frequency of 
suicidal thinking)

To assess the safety and tolerability of intranasal esketamine during the double-blind 
treatment phase and the follow-up phase, with special attention given to the following 
assessments:

Potential effects on suicidal ideation and behavior using the SIBAT

On dosing days:
o
Effect on heart rate, blood pressure, respiratory rate, and blood oxygen saturation 
o
Effect on alertness and sedation using the Modified Observer's Assessment of 
Alertness/Sedation (MOAA/S) scale
o
Treatment-emergent dissociative symptoms using the Clinician Administered 
Dissociative States Scale (CADSS)

To assess the pharmacokinetics of intranasal esketamine.
Exploratory Objectives
The exploratory objectives are:

To evaluate the efficacy of intranasal esketamine compared with intranasal placebo in 
reducing symptoms of MDD as assessed by the MADRS total score and remission rate 
through the end of the follow-up phase (Day 90).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in 
reducing severity of suicidality as measured by the CGI-SS-R through the end of the follow-
up phase (Day 90).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in 
reducing imminent suicide risk as measured by the CGI-SR-I through the end of the follow-
up phase (Day 90).

To assess the impact of intranasal esketamine compared with intranasal placebo through the 
end of the follow-up phase (Day 90) on the following patient-relevant concepts:

Hopelessness (BHS)

Health related quality of life and health status (EQ-5D-5L)

Health related quality of life (QLDS)

Subject treatment satisfaction (TSQM-9)
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
To assess the effect of intranasal esketamine compared with intranasal placebo on the 
SIBAT Module 3 My Current Thinking through the double-blind treatment (Day 25) and 
follow-up (Day 90) phases.

To assess medical resource utilization as measured by the Healthcare Resource Use 
Questionnaire (HRUQ) of intranasal esketamine compared with intranasal placebo through 
the end of the follow-up phase (Day 90), including 30-day and 60-day readmission, and 
emergency room visits related to MDD and suicidality.

To evaluate whether pretreatment concentrations or post-treatment change in MDD-related 
biomarkers (eg, hypothalamic-pituitary-adrenal [HPA] axis function, immune system 
activation, growth factors, metabolic markers) correlate with clinical response or non-
response as measured by the MADRS, following intranasal administration of esketamine.
2.1.2.
Endpoints
The primary efficacy endpoint will be the change from baseline (Day 1, predose) to 24 hours 
post first dose in depressive symptoms, as measured by the MADRS total score.
The key secondary efficacy endpoint will be the change from baseline (Day 1, predose) at 
24 hours post first dose in severity of suicidality, as measured by the CGI-SS-R.
The other secondary endpoints are:

MADRS

Remission rate (MADRS ≤12) at 4 hours and 24 hours post first dose, and through the 
end of the double-blind treatment phase (Day 25)

Change from baseline of MADRS total score at 4 hours post first dose and through the 
end of the double-blind treatment phase (Day 25)

CGI-SS-R

Change from baseline at 4 hours post first dose and through the end of the double-blind 
treatment phase (Day 25).

Proportion of subjects achieving resolution of suicidality (CGI-SS-R score of 0 or 1) at 
4 hours and 24 hours post first dose, and through the end of the double-blind treatment 
phase (Day 25)

CGI-SR-I: Change from baseline at 4 hours and 24 hours post first dose, and through the end 
of the double-blind treatment phase (Day 25)

BHS: Change from baseline through the end of the double-blind treatment phase (Day 25)

EQ-5D-5L: Change from baseline through the end of the double-blind treatment phase 
(Day 25)

QLDS: Change from baseline through the end of the double-blind treatment phase (Day 25)

TSQM-9: Scores through the end of the double-blind treatment phase (Day 25)

SIBAT: Change from baseline in Module 5 My Risk, Question 3 (patient-reported frequency 
of suicidal thinking), through the end of the double-blind treatment phase (Day 25)
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
Pharmacokinetics: Plasma esketamine and noresketamine concentrations will be 
summarized; plasma concentrations of esketamine (and noresketamine concentrations, if 
warranted) will be included in a population analysis

Safety endpoints will be evaluated throughout the study:

Monitoring of treatment emergent adverse events (TEAEs)

Clinical laboratory 
tests, 
physical examination, nasal examination, 12-lead 
electrocardiogram (ECG), and vital signs

SIBAT

On dosing days: MOAA/S, CADSS, and pulse oximetry
The exploratory endpoints include:

Change from baseline in MADRS, CGI-SS-R, CGI-SR-I, BHS, QLDS, and EQ-5D-5L
through the end of the follow-up phase (Day 90)

TSQM-9 scores, medical resource utilization, and biomarkers through the end of the follow-
up phase (Day 90)

SIBAT: Change from baseline in Module 3 My Current Thinking through the end of the 
double-blind (Day 25) and follow-up (Day 90) phases
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2.
Hypothesis
The primary hypothesis is that, in addition to comprehensive standard of care, intranasal 
esketamine 84 mg is superior to intranasal placebo in rapidly reducing the symptoms of MDD, 
including suicidal ideation, as assessed by the change from baseline in the MADRS total score at 
24 hours post first dose in subjects who are assessed to be at imminent risk for suicide.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind, placebo-controlled, multicenter study. A target of 224 male 
and female subjects, 18 to 64 years of age, with MDD presenting to an emergency room (ER) or 
other permitted setting and assessed to be at imminent risk for suicide will be enrolled in this 
study.
The study will consist of a screening evaluation performed within 48 hours prior to the Day 1 
intranasal dose (if possible, screening should occur within 24 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. 
On Day 1 of the double-blind treatment phase, approximately 224 subjects will be randomized in 
a 1:1 ratio to 1 of 2 treatments: intranasal esketamine 84 mg (n = 112) or intranasal placebo 
(n = 112), administered two times per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25). 
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Randomization will be stratified by study center and by the physician’s assessment of the 
subject’s need of standard of care antidepressant treatment (ie, antidepressant monotherapy or an 
antidepressant plus augmentation therapy); the standard of care will be determined prior to 
randomization on Day 1. 
The first dose of study medication will be administered in the ER or other permitted setting, 
including the inpatient psychiatric unit. All subjects will be treated in the context of 
comprehensive standard clinical care, including hospitalization and the initiation or optimization 
of antidepressant treatment, which will be determined by the treating physician(s). The standard 
of care antidepressant treatment will be initiated or optimized for all subjects on Day 1. 
After the first dose (ie, starting with the Day 4 dose or later), a one-time dose reduction to 
intranasal esketamine 56 mg or intranasal placebo is allowed if a subject is unable to tolerate the 
intranasal esketamine 84 mg or placebo dose assigned at randomization. No further dose 
adjustment is allowed during the double-blind treatment phase.
Dose titration/adjustments of newly initiated or optimized standard of care antidepressant 
treatment should occur during the first 2 weeks of double-blind treatment (ie, by Day 15), with 
doses remaining stable thereafter through the end of the double-blind phase (Day 25). During the 
follow-up phase, the antidepressant treatment will be managed based on clinician’s judgment.
Subjects will remain in the inpatient psychiatry unit for a recommended duration of 5 days, with 
shorter or longer hospitalizations permitted if clinically warranted per local standard of care. 
Discharge before 5 days must be discussed and approved by the sponsor’s medical monitor. 
Following discharge from the inpatient psychiatric unit, subsequent visits for the double-blind 
treatment phase will be conducted twice-weekly at an outpatient psychiatric facility through 
Day 25. During the follow-up phase, subjects will be monitored twice weekly for the first two 
weeks (Days 28, 32, 35, and 39) after study drug treatment. Subjects will then be followed up 
weekly for the next two weeks (Days 46 and 53) and every two weeks for the rest of the follow-
up period (Days 67 and 90).   
Efficacy, safety, pharmacokinetic, biomarker, and pharmacogenomic evaluations will be 
performed as described in the Time and Events Schedule. 

The primary efficacy evaluation is the MADRS, the key secondary evaluation is CGI-SS-R, 
and other efficacy evaluations include the SIBAT, BHS, EQ-5D-5L, QLDS, and TSQM-9.

Safety evaluations include monitoring and collection of adverse events and concomitant 
therapies, physical examination, nasal examination, body weight, height, vital signs, 12-lead 
ECG, pulse oximetry, respiratory rate, clinical laboratory tests, SIBAT, MOAA/S, and 
CADSS. 

Blood samples will be collected for measurement of plasma concentrations of esketamine, 
noresketamine, and other metabolites if warranted.

Blood samples will be collected for biomarker evaluations.
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
Pharmacogenomic blood samples will be collected from subjects who consent separately to 
this component of the study (where local regulations permit). Subject participation in 
pharmacogenomic research is optional.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study. Refer 
to Section 11.9, Data Monitoring Committee, for details.
A diagram of the study design is provided in Figure 1.
Figure 1:
Schematic Overview of the Study
3.2.
Study Design Rationale
3.2.1.
Study Population
This study will enroll adult subjects (18 to 64 years) with MDD presenting with suicidal ideation 
who are assessed to be at imminent risk for suicide. Subjects must meet Diagnostic and 
Statistical Manual of Mental Disorders - 5th edition (DSM-5) criteria for MDD (without 
psychosis), based on diagnostic assessment with the Mini International Psychiatric Interview 
(MINI), and subjects must have a MADRS total score >28 at baseline. By selecting for subjects 
with a MADRS total score of >28 (representing moderate to severe depression), the study may 
reduce placebo response and enhance signal detection.
MDD 
subjects 
assessed to 
be at 
imminent 
risk for 
suicide a
(n =224) 
Intranasal Esketamine 84 mg
on Day 1, 4, 8, 11, 15, 18, 22, 25 
+ 
Standard of Care antidepressant 
treatment b
(n = 112)
Emergency Room
(or other permitted setting) 
Inpatient 
Psychiatric Unit
(Recommended 5 days) d
Intranasal Placebo
on Day 1, 4, 8, 11, 15, 18, 22, 25 
+ 
Standard of Care antidepressant 
treatment b
Standard of Care antidepressant 
treatment
Screening
(within 48 hours c
prior to Day 1 dose)
Double-blind Treatment
(Day 1 to 25)
(Day 1, 4, 8, 11, 15, 18, 22, and 25) 
Follow Up
(Day 26 to 90)
(Day 28e, 32, 35e, 39, 46, 53, 67, and 90)
Outpatient Psychiatric Unit 
(n = 112)
a Randomization will be stratified by study center and by the physician’s assessment of the subject’s need of 
standard of care antidepressant treatment (ie, antidepressant monotherapy or an antidepressant plus
augmentation therapy); the standard of care will be determined prior to randomization on Day 1.
b Standard of care antidepressant treatment will be initiated or optimized on Day 1.
c If possible, screening should be performed within 24 hours prior the Day 1 intranasal dose.
d Discharge before 5 days must be discussed and approved by the sponsor’s medical monitor.
e Remote contact
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Enrolled subjects must also present with suicidal ideation with intent, operationalized by 
affirmative responses to MINI questions B3 (Think about harming/hurting/injuring yourself or 
about suicide?) and B10 (Intend to act on thoughts of killing yourself?). This generally 
corresponds with the level of severity of suicidal ideation that appears to predict suicidal 
behavior over the short term.69 Additionally, in the physician’s opinion, acute psychiatric 
hospitalization of the subject must be clinically warranted due to the subject’s imminent risk of 
suicide. By selecting for subjects with this degree of suicide risk, the possibility of a favorable 
benefit-risk balance for the experimental treatment is enhanced.
The age range of 18 to 64 years was selected as this Phase 3 study is designed to confirm the 
efficacy and safety of esketamine in subjects with MDD presenting with suicidal ideation using 
84 mg, the dose anticipated to offer the most rapid and sustained benefit in adults. As higher 
systemic bioavailability of intranasal esketamine has been previously observed in an elderly 
population (≥65 years) (Studies ESKETINTRD1003 and ESKETINTRD101237) and the efficacy 
and safety of esketamine in the elderly population with MDD is being further evaluated in other 
studies, elderly adult subjects will not be enrolled in this study.
Subjects with a recent history (<6 months) of moderate or severe substance or alcohol use 
disorders will be excluded to ensure the subject’s depression is not attributed to substance or 
alcohol use (ie, substance-induced depressive disorder). Subjects with a current diagnosis of 
bipolar or related disorders will be excluded to allow accurate assessment of efficacy and/or 
safety data of the study drug in the context of MDD.
3.2.2.
Treatment and Study Duration
Patients with MDD with suicidal thoughts and behaviors are at risk for increased suicidality both 
in the first several days after initiating treatment with a standard antidepressant40 and post-
hospitalization.12,79 Therefore, the dosing regimen in this study includes administration of 
esketamine twice weekly for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25). This duration of 
repeated dosing is consistent with the timeframe in which standard antidepressants take to exert 
their action, and will allow for the evaluation of depression and assessment of suicide risk during 
this period of increased vulnerability. The same dosing regimen and duration of treatment was 
used in the Phase 2 study ESKETINSUI2001. 
While Study ESKETINSUI2001 demonstrated a rapid onset of effect for esketamine in reducing 
the symptoms of depression and suicidality, it also suggested that continued dosing through 
Day 25 provided an additional therapeutic advantage. Indeed, esketamine showed greater 
improvement compared to placebo on the MADRS total score and on the MADRS-SI at the 
double-blind endpoint (Day 25).16 This result was further supported by response rates (at least 
50% improvement in MADRS total score from baseline) and remission rates (MADRS total 
score ≤12) on Day 25, 4 hours post dose. At that timepoint, 20 of 24 (83%) esketamine subjects, 
compared to 15 of 24 (63%) placebo subjects, were considered responders; similarly, 16 of 24 
(67%) esketamine subjects, compared to 12 of 24 (50%) placebo subjects were considered 
remitters.16 The improvements continued throughout the posttreatment follow-up phase; at 
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Day 81, remission rates were 63% in the esketamine group compared with 50% in the placebo 
group.16
The duration of follow-up in this study covers the period of greatest risk for recurrent suicidality 
post initial attempt and/or hospitalization.12,15 Specifically, the follow-up after the 25-day 
treatment period is through Day 90 and will allow for the exploration of the continued effects of 
esketamine on depression and suicidal symptoms. No intranasal study medication will be 
administered during the follow-up phase. Subjects will be monitored twice weekly for the first 
two weeks (Days 28, 32, 35, and 39) after study drug treatment. Subjects will then be followed 
up weekly for the next two weeks (Days 46 and 53) and every two weeks for the rest of the 
follow-up period (Days 67 and 90). The MADRS and CGI-SS-R will be completed at each of 
these visits. Additionally, throughout the follow-up period, suicide attempts, hospital re-
admissions for suicidality, and ER visits will be assessed. 
The short-term treatment course of esketamine in subjects with MDD at imminent risk for 
suicide is expected to provide antidepressant efficacy during the interval needed for the newly 
initiated or optimized oral antidepressants to become effective.
3.2.3.
Control, Randomization and Blinding
A placebo control will be used to establish the frequency and magnitude of changes in clinical
endpoints that may occur in the absence of active treatment.
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups. Randomization will be stratified by study 
center and by the physician’s assessment of the subject’s need of standard of care antidepressant 
treatment (ie, antidepressant monotherapy or an antidepressant plus augmentation therapy); the 
standard of care will be determined prior to randomization on Day 1. This stratification is aimed 
at balancing treatment groups within the standard of care antidepressant treatment to be initiated 
or optimized on Day 1, as antidepressant monotherapy and antidepressant plus augmentation 
therapy may be differentially effective. A similar stratification approach was used successfully in 
Study ESKETINSUI2001.
Blinded treatment will be used to reduce potential bias during data collection and evaluation of 
clinical endpoints. Administration of esketamine, however, is associated with a number of 
transient adverse events, including sedation, dissociative symptoms, and elevation of blood 
pressure. To minimize the risk of unblinding the treatment assignment, different raters will 
perform efficacy and safety assessments; clinicians who perform the MADRS and SIBAT 
assessments will be different from those who evaluate vital signs, MOAA/S, CADSS, and 
adverse events. Raters for the MADRS and SIBAT assessments will not be allowed to access or 
to review subject safety records; therefore, they will not provide clinical care for subjects. 
Clinical care of subjects will be performed by clinicians at the study site who are not MADRS 
and SIBAT raters. 
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3.2.4.
Dose
The currently available nonclinical safety studies support chronic intranasal administration of 
esketamine in human subjects up to a dose of 84 mg/day.37 The treatment groups in the double-
blind treatment phase of this study are esketamine 84 mg or placebo. The esketamine dose may 
be reduced at any time after the first dose to 56 mg for subsequent doses if a subject is unable to 
tolerate 84 mg. The same dosing regimen was used in the Phase 2 study ESKETINSUI2001.
The rationale for this dose selection is based on the fact that MDD with imminent risk for suicide 
is a psychiatric emergency requiring rapid and robust efficacy, and for which titration to an 
effective dose is not warranted. Study treatment will initially be administered in a hospital setting 
where any adverse effects can be closely monitored and managed. Finally, a course of treatment 
of esketamine for MDD with imminent risk for suicide is limited to 4 weeks. 
Given the benefit-risk assessment of treatment for a life-threatening condition, the 84 mg dose of 
esketamine (with an option to reduce to the 56 mg dose) was selected to provide the greatest 
opportunity for rapid onset of efficacy and longer durability of activity, with acceptable 
tolerability, in the context of a psychiatric emergency. 
Efficacy Findings Supporting the 84-mg Dose
Results from the Phase 2 placebo-controlled study ESKETINTSUI2001 provided evidence of 
efficacy of the esketamine 84 mg dose in MDD with imminent risk for suicide. At 4 hours and 
24 hours after the first dose and at the double-blind endpoint (Day 25), esketamine 84 mg 
demonstrated a rapid and statistically significant reduction in symptoms of depression (based on 
MADRS total score) and suicidal ideation (based on the MADRS-SI score) compared to placebo
(refer to Section 1.1.2.3 for details).Additionally, esketamine demonstrated evidence for a 
potential therapeutic effect based on the CGJ-SR, which summarized clinician overall judgment 
of suicide risk as derived from the SIBAT, at both 4 hours and 24 hours after the first dose.
Further support for the efficacy of the esketamine 84 mg dose comes from Panel A of the 
Phase 2 study ESKETINTRD2003 conducted in subjects with TRD; statistically significant 
reductions in the MADRS total score were observed in all esketamine groups (28, 56, 84 mg) 
compared with the placebo group after the first week of treatment, with a significant dose-
response relationship detected (refer to Section 1.1.2.3 for details).37 In addition, for those 
subjects in Panel A who received the same esketamine treatment for both periods and completed 
the double-blind phase, the greatest decrease in MADRS total score was seen with the 84-mg 
dose, followed by the 56-mg dose, whereas the 28 mg dose had the smallest decrease.37
Safety and Tolerability 
The dosing regimen in this study has a provision for reducing the esketamine dose to 56 mg after 
Day 1 for subsequent doses if a subject is unable to tolerate the assigned esketamine 84 mg dose.
In ESKETINSUI2001, more subjects in the esketamine 84 mg group than in the placebo group 
received all 8 scheduled doses of the study medication, and mean treatment durations were 
similar in the esketamine 84 mg group and in the placebo group. Furthermore, only 3 of the 
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35 subjects included in the safety analysis set had esketamine dose reductions from 84 mg to 
56 mg for intolerance. The most common (≥20%) TEAEs in the esketamine 84 mg group during 
the double-blind phase were nausea, dizziness, dysgeusia, headache, dissociation, and vomiting. 
The most common TEAE in the placebo group was headache. Dissociative symptoms, as 
measured on the CADSS, and transient blood pressure increases observed in the esketamine 
group were consistent with prior studies.
There were no deaths during Study ESKETINSUI2001. There were 4 SAEs in the double-blind
phase, all in the esketamine 84 mg group. Three of these events were related to re-hospitalization 
of subjects with re-emergence of suicidal ideation (n=2) or depression (n=1) in subjects who had 
improved and had been discharged from the hospital. In all 3 instances, the subjects recovered 
and completed both the double-blind and follow-up phases. One subject experienced an event of 
increased agitation, and the study medication was withdrawn. Six subjects experienced an SAE 
in the follow-up phase (5 in the placebo group and 1 in the esketamine 84 mg group;
see Section 1.1.2.4 for further details). The SAEs in the placebo group included 3 suicide 
attempts (non-fatal), 1 subject who experienced suicidal ideation, and 1 subject with cellulitis. 
The SAE in the subject from the esketamine group was suicidal ideation.
Six subjects (1 in the placebo group and 5 in the esketamine 84 mg group) discontinued from the 
double-blind phase due to TEAEs. In the esketamine group, events resulting in discontinuation 
were dizziness, dysgeusia, ventricular extrasystole, nausea and dyspnea, which were considered 
by the investigator to be probably or very likely related to study drug; and aggression and 
agitation, which were considered to be doubtfully and not related to study drug, respectively.
Overall, the safety profile of esketamine 84 mg in Study ESKETINSUI2001 was consistent with 
that observed in previous clinical studies of intranasal esketamine. No new safety signals were 
identified.
3.2.5.
Efficacy Measures
3.2.5.1.
Montgomery-Asberg Depression Rating Scale (MADRS)
The primary outcome measure in this study will be the MADRS (see Section 9.2.1). The 
MADRS is considered the gold standard to measure antidepressant treatment response and is 
acceptable to the regulatory health authorities for use as a primary endpoint to determine 
symptomatic improvement. Further, the MADRS is sensitive to rapid changes in depression 
symptoms and suicidal thoughts, and has been included as a key outcome parameter in published 
studies of ketamine for depression and suicidal ideation5,25,47,63,70,71 as well as in the sponsor’s 
Phase 2 studies of esketamine in MDD with imminent risk for suicide (ESKETINSUI2001) and 
in TRD (ESKETINTRD2003 and the Phase 3 studies of esketamine in TRD). 
This study is primarily aimed at evaluating the rapid reduction of symptoms of MDD, including 
suicidal ideation, in subjects who are assessed to be at imminent risk for suicide. Accordingly, 
the primary efficacy endpoint is the change from baseline (Day 1 predose) in the MADRS total 
score at 24 hours post first dose. Although therapeutic activity is observed with esketamine as 
early as 4 hours after administration, it appears that the full benefit is evident after 24 hours, and 
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evaluation of the primary efficacy endpoint at 24 hours after the first dose is expected to reflect 
the timeframe needed for esketamine to exert its full antidepressant effect. This timepoint is 
relevant to current clinical practice as patients at imminent risk for suicide are typically 
hospitalized for at least 24 hours. 
The MADRS also will be used to evaluate secondary objectives assessing the change from 
baseline in MADRS total score at 4 hours post first dose and through the end of the double-blind 
treatment phase and the remission rate at 4 hours and 24 hours post first dose and through the 
end of the double-blind treatment phase. In addition, the MADRS will be used to evaluate the 
exploratory objective assessing the change from baseline in MADRS total score and the 
remission rate through the end of the follow-up phase (Day 90).
3.2.5.2.
Suicide Ideation and Behavior Assessment Tool (SIBAT)
The development of treatments with the potential for rapid onset of efficacy as measured by 
diminished severity of suicidal thinking and reduced clinical perception of risk for suicide has 
driven the need for scales that can reliably measure these attributes. However, these requirements 
correspond with specific deficits in existing suicide assessment scales. To address these unmet 
needs, a new instrument, the SIBAT, has been developed by a team of experts in suicide and 
psychometrics. The SIBAT is a suicide assessment tool that captures suicidal ideation and 
behavior(s) as reported by patients and reviewed by clinicians permitting efficient collection and 
documentation of clinical impression of severity of suicidality and imminent and long-term 
suicide risk and treatment plans (see Section 9.2.2). 
The SIBAT is computerized and organized into 8 modules with branching logic to allow for 
efficient, comprehensive, and flexible data collection from a broad base of patients who may 
have a wide variety of demographic, cultural and demographic backgrounds. The 8 modules of 
the SIBAT are divided into patient-reported (Modules 1-5) and clinician-rated (Modules 6-8) 
sections. This modular structure allows for customization, and the administration of specific 
modules can be adjusted to meet clinical needs. Responses less susceptible to change (eg, 
demographics, medical history) are segregated into modules distinct from those responses more 
likely to fluctuate over shorter time intervals (eg, current suicidal ideation). In general, the 
patient-reported modules document information regarding the severity of suicidal ideation and 
risk and protective factors associated with suicide risk and specific suicidal behaviors. 
Information from the patient-reported modules, plus a brief semi-structured clinician interview in 
Module 6, represent a comprehensive profile for assessment of the Clinical Global Impressions 
in Module 7, which includes the Clinical Global Impression of Severity of Suicidality – Revised 
(CGI-SS-R), the Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I), the Clinical 
Global Impression of Long-Term Suicide Risk, and assessment of the frequency of suicidal 
thinking. An assessment of the Clinical Global Judgment of Optimal Suicide Management is 
included in Module 8.
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The SIBAT builds on prior work used to develop scales which are available for assessing 
suicidality; for example, the InterSePT Scale for Suicidal Thinking (ISST),49 a 12-item 
instrument designed for the assessment of current suicidal ideation in patients with schizophrenia 
and schizoaffective disorders, and the Clinical Global Impression of Severity of Suicidality 
(CGI-SS). Module 7 (Clinical Global Impressions) of the SIBAT includes a revised version of 
the CGI-SS (CGI-SS-R), which will be used to evaluate the key secondary objective in this study
(further details are provided below), as well as a Clinical Global Impression of Imminent Suicide 
Risk (CGI-SR-I), which will be used to evaluate secondary and exploratory objectives (further 
details are provided below). In addition, Question 3 (patient- reported frequency of suicidal 
thinking) in Module 5 (My Risk) from the SIBAT will be used to evaluate the secondary 
objective assessing patient-reported suicidality through the end of the double-blind treatment 
phase.
Formal testing of inter- and intra-rater reliability and assessments of construct validity and 
internal consistency are being conducted on the SIBAT.
Clinical Global Impression of Severity of Suicidality – Revised (CGI-SS-R)
The CGI-SS was initially created for the International Suicide Prevention Trial (InterSePT), a 
large-scale, long-term prospective study that evaluated the potential of clozapine and olanzapine 
to reduce suicidal behaviors in subjects with schizophrenia or schizoaffective disorder who are 
known to be at high risk for suicide. 1,49,53 The CGI-SS 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 patient’s illness. The CGI-SS provided an index to quantify an expert's impression 
of severity of suicidality that helped to confirm the validity ISST. 
A revised version of the CGI-SS (CGI-SS-R) will be used in this study (see Section 9.2.2). This 
revision is aligned with the standard CGI-S with which all clinicians are familiar, and has more 
severity levels than the original version, allowing for greater sensitivity.
The CGI-SS-R, assessed at 24 hours post initial dosing, will be used as the key secondary 
endpoint in this study. In addition, the CGI-SS-R will be used to evaluate secondary objectives 
assessing:

Change in severity of suicidality at 4 hours postdose on Day 1 and through the end of the 
double-blind treatment phase

Resolution of suicidality as measured by the score of 0 (normal, not at all suicidal) or 1 
(questionably suicidal) of the CGI-SS-R at 4 hours postdose on Day 1, 24 hours postdose on 
Day 2, and through the end of the double-blind treatment phase 
and exploratory objectives assessing:

Change in severity of suicidality through the end of the follow-up phase
Clinical Global Impression of Imminent Suicide Risk (CGI-SR-I)
The CGI-SR-I is a scale summarizing the clinician’s best assessment of the likelihood that the
subject will attempt suicide in the next 7 days (see Section 9.2.2).
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The CGI-SR-I will be used to evaluate secondary objectives assessing:

Change in imminent suicide risk at 4 hours postdose on Day 1, 24 hours postdose on Day 2,
and through the end of the double-blind treatment phase
and exploratory objectives assessing:

Change in imminent suicide risk through the end of the follow-up phase
3.2.5.3.
Beck Hopelessness Scale (BHS)
The Beck Hopelessness Scale (BHS) is a self-reported measure to assess the level of a subject’s 
negative expectations or pessimism regarding the future, and as such, is an important future 
predictor of suicide. Further information about the BHS is provided in Section 9.2.3.
3.2.5.4.
European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level 
(EQ-5D-5L)
The EQ-5D-5L is included as a standardized subject-completed instrument for use as a measure 
of health-related quality of life and health status.27,28 Further information about the EQ-5D-5L is 
provided in Section 9.2.4.
3.2.5.5.
Quality of Life in Depression Scale (QLDS)
The QLDS is a disease-specific patient-reported outcome designed to assess health related 
quality of life in patients with MDD.34,52,77 Further information about the QLDS is provided in 
Section 9.2.5.
3.2.5.6.
Treatment Satisfaction Questionnaire for Medication (TSQM-9)
The TSQM-9 is a 9-item generic patient reported outcome instrument to assess patients’ 
satisfaction with medication.4 It is derived from the longer TSQM Version 1.411 and covers 
domains of effectiveness, convenience and global satisfaction. Further information about the 
TSQM-9 is provided in Section 9.2.6.
3.2.6.
Safety Evaluations
Physical examination, nasal examination, body weight, vital signs (including measurement of 
blood pressure, heart rate, respiratory rate, and temperature), 12-lead ECG, pulse oximetry, 
clinical laboratory tests (hematology, chemistry, and urinalysis), pregnancy testing (for women 
of childbearing potential), urine drug screen, and evaluation of TEAEs and concomitant therapies 
will be performed during the study per the Time and Events Schedule to monitor subject safety. 
The TEAEs of special interest will be examined separately grouped in the following categories: 
drug abuse, dependence and withdrawal, transient dizziness/vertigo, impaired cognition, anxiety, 
cystitis, and suicidality. The adverse events of special interest will be further listed in the 
Statistical Analysis Plan (SAP).
Given the potential for treatment-emergent transient elevation in systolic and diastolic blood 
pressure, heart rate and blood pressure will be monitored throughout the study and at multiple 
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time points on dosing days. Specific guidance to be followed on intranasal dosing days is 
provided in Section 6.1.1.
The MOAA/S will be administered to assess the severity and duration of any sedation, and the
CADSS will be administered to assess treatment-emergent dissociative symptoms. Although the 
SIBAT will be an efficacy evaluation, it will also be used to inform safety evaluation to detect 
any worsening of suicidal ideation and behavior throughout the study.
On all outpatient intranasal dosing days, all subjects must remain at the clinical site until study 
procedures have been completed and the subject is ready for discharge per clinician’s 
assessment. The minimum time required for postdose monitoring is 1.5 hours. Subjects should be 
accompanied when released from the clinical study site. Subjects must not drive a car or work 
with machines for 24 hours after receiving study drug.
A list of prohibited therapies is provided in Attachment 1 for general guidance for the 
investigator; however, this list is not all-inclusive.
3.2.7.
Pharmacokinetic Assessments
Blood samples will be collected for measurement of plasma concentrations of esketamine, 
noresketamine, and other metabolites if warranted.
3.2.8.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) 
Evaluations
Blood samples may be collected for the analysis of one or more candidate genes and/or the 
analysis of genetic and epigenetic markers as well as RNA expression markers. In addition,
blood samples will be collected for the exploratory analysis of biomarkers related to immune 
system activity, HPA axis activation, neurotrophic and metabolic factors. 
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in drug distribution and response and can also serve as a marker for disease 
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to a drug. The goal of the pharmacogenomic component is to collect DNA to allow 
the identification of genetic and/or epigenetic factors that may influence the pharmacokinetics
(PK), pharmacodynamics (PD), efficacy, safety, or tolerability of esketamine and to identify 
genetic factors associated with MDD and suicidality. Specifically, genes and epigenetic changes 
in genes known to be in pathways relevant to depression (HPA axis, inflammation, growth 
factors, monoamine transporters, ion channels, circadian rhythm) will be evaluated. Expression 
analyses may include testing of known messenger RNA/microRNA (mRNA/miRNA) transcripts 
or transcriptome-wide analysis in relationship to antidepressant treatment response and MDD.
Increasingly, it is recognized that psychiatric disorders may be associated with altered 
immune/metabolic activation patterns. Blood samples will be collected to explore biomarkers 
related to immune system activity, HPA axis activation, and neurotropic factors (including but 
not limited to growth factors, inflammation, or endocrine markers). Biomarker samples (plasma, 
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serum, and RNA) will be collected to evaluate the mechanism of action of esketamine or help to 
explain interindividual variability in clinical outcomes or may help to identify population 
subgroups that respond differently to a drug. In addition, biomarker samples may be combined 
with samples collected from other sources to understand the biomarker correlates of suicidal 
behavior including but not limited to high ideation state versus low ideation state versus no 
ideation and to understand the MDD disease mechanism.
The DNA, RNA, protein, and metabolic biomarker samples may be used to help address 
emerging issues and to enable the development of safer, more effective, and ultimately 
individualized therapies.
3.2.9.
Medical Resource Utilization
Treatment of subjects with MDD at immediate risk of suicide with esketamine versus placebo 
may result in lower utilization of services (ie, outpatient visits, ER visits or hospitalization) as 
assessed using the Heath Resource Use Questionnaire (HRUQ). The HRUQ includes information 
regarding utilization of healthcare services, including the timing of services, enabling changes in 
level and quantity of services to be considered as a variable in economic models.
4.
SUBJECT POPULATION
Screening for eligible subjects should be performed within 48 hours prior to the first 
administration of intranasal study drug (if possible, screening should occur within 24 hours prior 
to the first administration of intranasal study drug). 
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
Subject must be a man or woman, 18 to 64 years of age, inclusive.
2.
Subject must meet Diagnostic and Statistical Manual of Mental Disorders (5th edition) 
(DSM-5) diagnostic criteria for MDD, without psychotic features, based upon clinical 
assessment and confirmed by the MINI.
3.
Subjects 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.
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4.
In the physician’s opinion, acute psychiatric hospitalization is clinically warranted due 
to subject’s imminent risk of suicide.
5.
Subject has a MADRS total score of >28 predose on Day 1.
6.
As part of standard of care treatment, subject 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).
7.
Subject is comfortable with self-administration of intranasal medication and able to 
follow instructions provided.
8.
Subject must be medically stable on the basis of physical examination, medical history, 
vital signs, and 12-lead ECG performed at screening. If there are abnormalities, the 
subject may be included only if the investigator judges the abnormalities to be not 
clinically significant. This determination must be recorded in the subject's source 
documents and initialed by the investigator.
Note: Subjects recovering from a recent suicide attempt may be eligible provided they 
are medically stable.
9.
Subject must be medically stable on the basis of clinical laboratory tests performed by 
the local laboratory at screening. If the results of the serum chemistry panel, 
hematology, or urinalysis are outside the normal reference ranges, the subject may be 
included only if the investigator judges the abnormalities or deviations from normal to 
be not clinically significant. This determination must be recorded in the subject's source 
documents and initialed by the investigator.

Incidental exclusionary laboratory values ("incidental" refers to duplicate 
results from a separate blood sample analyzed at the central laboratory that 
become available after the subject has satisfied the inclusion and exclusion 
criteria based on the local laboratory values) will be handled on a case-by-case 
basis to determine if the subject should be withdrawn from the study.
10.
Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for subject participating in clinical studies.
Before randomization, a woman must be either:
a.
Not of childbearing potential defined as:
o
postmenopausal (>45 years of age with amenorrhea for at least 
12 months), permanently sterilized (eg, bilateral tubal occlusion/ligation 
procedures, 
hysterectomy, 
bilateral 
salpingectomy, 
bilateral 
oophorectomy); or otherwise be incapable of pregnancy
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b.
Of childbearing potential and
o
practicing a highly effective method of contraception (failure rate of <1% 
per year when used consistently and correctly)
Examples of highly effective contraceptives include
- user-independent methods:
implantable progestogen-only hormone contraception associated with 
inhibition of ovulation; intrauterine device (IUD); intrauterine 
hormone-releasing system (IUS); vasectomized partner; sexual 
abstinence (sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study drug. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of 
the study and the preferred and usual lifestyle of the subject.)
- user-dependent methods:
combined (estrogen- and progestogen-containing ) hormonal 
contraception associated with inhibition of ovulation: oral, 
intravaginal, and transdermal; progestogen-only hormone 
contraception associated with inhibition of ovulation: oral and 
injectable
Typical use failure rates may differ from those when used consistently and 
correctly. Use should be consistent with local regulations regarding the 
use of contraceptive methods for subjects participating in clinical studies.
o
agrees to use a highly effective method throughout the study and for at 
least 6 weeks after the last dose of study drug.
Note: If the childbearing potential changes after start of the study or the risk of 
pregnancy changes (eg, a woman who is not heterosexually active becomes active), a 
woman must begin a highly effective method of contraception, as described throughout 
the inclusion criteria.
11.
A woman of childbearing potential must have a negative urine pregnancy test at 
screening.
12.
During the study (ie, from Day 1 of the double-blind phase) and for a minimum of 
1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose 
of study drug, a man who is sexually active with a woman of childbearing potential

must be practicing a highly effective method of contraception with his female 
partner from those listed above (see examples of highly effective methods of 
contraception provided for female subjects).

must use a condom if his partner is pregnant.

must agree not to donate sperm.
Note: If the childbearing potential changes after start of the study, a female partner of a 
male study subject must begin a highly effective method of birth control, as described 
above.
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13.
Subject must be willing and able to adhere to the prohibitions and restrictions specified 
in this protocol.
14.
Each subject must sign an informed consent form (ICF) indicating that he or she 
understands the purpose of and procedures required for the study and is willing to 
participate in the study.
Note: Subjects with acute alcohol intoxication should not be screened (but can be 
screened once sober).
15.
Each subject must sign a separate informed consent form if he or she agrees to provide 
an optional DNA sample for research (where local regulations permit). Refusal to give 
consent for the optional DNA research sample does not exclude a subject from 
participation in the study.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
Subject has a current DSM-5 diagnosis of bipolar (or related disorders), antisocial 
personality disorder, or obsessive compulsive disorder.
2.
Subject currently meets DSM-5 criteria for borderline personality disorder. 

Subjects not meeting full DSM-5 criteria for borderline personality disorder 
but exhibiting recurrent suicidal gestures, threats, or self-mutilating behaviors 
should also be excluded.
3.
Subject has a current clinical diagnosis of autism, dementia, or intellectual disability.
4.
Subject has a current or prior DSM-5 diagnosis of a psychotic disorder, or MDD with
psychotic features.
5.
  
Criterion modified per Amendment 1
5.1. Subject 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.
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6.
Criterion modified per Amendment 1
6.1. Subject has any of the following conditions: 

a history or current signs and symptoms of liver or renal insufficiency

clinically significant cardiac (including unstable coronary artery disease and 
congestive heart failure, tachyarrhythmias and recent myocardial infarction) or
vascular, pulmonary, gastrointestinal, endocrine
(including uncontrolled 
hyperthyroidism), neurologic (including current or past history of seizures 
except uncomplicated childhood febrile seizures with no sequelae), 
hematologic,
rheumatologic, 
or 
metabolic 
(including 
severe 
dehydration/hypovolemia) disease.
7.
Criterion modified per Amendment 1
7.1. Subject has uncontrolled hypertension (systolic blood pressure >140 mmHg or 
diastolic blood pressure >90 mmHg) despite diet, exercise or a stable dose of anti-
hypertensive treatment for at least 2 weeks at screening; or any past history of 
hypertensive crisis.

Subjects with conditions in which the elevation of blood pressure could be a 
serious risk (including unstable heart failure, severe cardiovascular disease, 
recent cerebral injury, increased intracranial pressure / intracranial mass lesion, 
intracranial bleeding or acute stroke, untreated glaucoma or perforating eye 
injury) are excluded.

An abnormal blood pressure value at screening can be repeated once after 
5 minutes of relaxation for subject eligibility. On Day 1 of the double-blind 
phase prior to randomization, a supine or semi-supine systolic blood pressure 
>140 mmHg or diastolic blood pressure >90 mmHg is exclusionary.
8.
Criterion modified per Amendment 1
8.1. Subject has a positive urine test result(s) for phencyclidine (PCP), cocaine, or 
amphetamines (inclusive of amphetamine, methamphetamine [mAMP], and 3, 4-
methylenedioxy-methamphetamine [MDMA]) at screening. 

Subjects who have a positive test due to the appropriate use of prescribed 
opiates, benzodiazepines, or barbiturates may be eligible for study participation 
per clinician judgment. In addition, subjects who have a positive test for 
opiates, benzodiazepines, or barbiturates used without a prescription, may be 
considered eligible per clinician judgment and in consultation with the 
sponsor’s medical monitor. Subjects known to be using heroin should be 
excluded from the study.

Subjects who have a positive test due to opiates, benzodiazepines, or 
barbiturates taken in a suicide attempt (eg, overdose) may be eligible for study 
participation per clinician judgment and in consultation with the sponsor’s 
medical monitor.
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8.2 Criterion modified per Amendment 2

Subjects, who have a positive test result at screening due to prescribed 
psychostimulants (eg. amphetamine, methylphenidate) that are permitted 
during the study in accordance with Attachment 1, are eligible for study 
participation.
9.
Subject has a history of malignancy within 5 years before screening (exceptions are 
squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or 
malignancy that in the opinion of the investigator, with concurrence with the sponsor's 
medical monitor, is considered to have minimal risk of recurrence).
10.
Subject has any anatomical or medical condition that, per the investigator’s clinical 
judgment based on assessment, may impede delivery or absorption of intranasal study 
drug.
11.
Subject has known allergies, hypersensitivity, intolerance or contraindications to
esketamine or ketamine or its excipients (refer to Investigator's Brochure for 
esketamine37,
Summary 
of 
Product 
Characteristics42,45,78, 
US 
prescribing 
information43,44).
12.
Subject has taken any disallowed therapy(ies) as noted in Section 8, Prestudy and 
Concomitant Therapy, and Attachment 1.
13.
  
Criterion modified per Amendment 1
13.1 Subject has received an investigational drug (including esketamine, ketamine, or 
investigational vaccines) or used an invasive investigational medical device within 
60 days before the planned first dose of study drug or is currently enrolled in an 
investigational study or was previously enrolled in this study or the Sponsor’s 
other studies in this population, 54135419SUI3001 and ESKETINSUI2001.
14.
Subject is a woman who is pregnant, breast-feeding, or planning to become pregnant 
while enrolled in this study or within 3 months after the last dose of study drug.
15.
Subject has any situation or condition for which, in the opinion of the investigator, 
participation would not be in the best interest of the subject (eg, compromise the well-
being) or that could prevent, limit, or confound the protocol-specified assessments.
16.
Subject is an employee of the investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study site, as 
well as family members of the employees or the investigator.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
Section 17.4, Source Documentation, describes the required documentation to support meeting 
the enrollment criteria.
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4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
Refer to Section 4.1, Inclusion Criteria, for information regarding contraception/birth 
control requirements and sperm donation restrictions.
2.
On all outpatient intranasal dosing days, all subjects must remain at the clinical site until 
study procedures have been completed and the subject is ready for discharge per 
clinician’s assessment. The minimum time required for postdose monitoring is 1.5 hours. 
Subjects should be accompanied when released from the clinical study site. Subjects must 
not drive a car or work with machines for 24 hours after study drug dosing.
3.
Refer to Section 8, Prestudy and Concomitant Therapy and Attachment 1 (Prohibited 
Therapies) for information regarding prohibited therapies.
4.
Subjects may not receive electroconvulsive therapy (ECT) during the study. ECT non-
responders at imminent risk for suicide may be included in the study. If an investigator 
were to enroll a subject currently receiving ECT, the investigator would have to 
document why it is clinically appropriate to discontinue the ECT treatments, and to 
ensure that treatment is not changed for the purpose of making the subject eligible.
5.
Food will be restricted for at least 2 hours before each administration of study medication. 
6.
Drinking of any fluids will be restricted at least 30 minutes before the first nasal spray
on each dosing day.
7.
Subjects should refrain from using alcohol within 24 hours before and after each 
intranasal treatment session. If a subject appears intoxicated, dosing should not occur 
(delayed per the permitted visit window; see the Time and Events Schedule).
8.
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation and Randomization
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups in a 1:1 ratio based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor. The randomization will be 
balanced by using randomly permuted blocks and will be stratified by study center and by the
physician’s assessment of the subject’s need of standard of care antidepressant treatment 
(ie, antidepressant monotherapy or an antidepressant plus augmentation therapy); the standard of 
care will be determined prior to randomization on Day 1. The interactive web response system 
(IWRS) will assign a unique treatment code, which will dictate the treatment assignment and 
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matching study drug kits for the subject. The requestor must use his or her own user 
identification and personal identification number when contacting the IWRS, and will then give 
the relevant subject details to uniquely identify the subject.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (eg, study drug plasma
concentrations, treatment allocation) will be handled with special care to ensure that the integrity 
of the blind is maintained and the potential for bias is minimized. This can include making 
special provisions, such as segregating the data in question from view by the investigators, 
clinical team, or others as appropriate until the time of database lock and unblinding. To
minimize the risk of unblinding the treatment assignment during the study, different raters will 
perform efficacy and safety assessments. Clinicians who perform MADRS and SIBAT will be 
different than those who evaluate vital signs, MOAA/S, CADSS, and adverse events. Raters for 
the MADRS and SIBAT assessment will not be allowed to access or to review subject safety 
records; therefore, they will not provide clinical care for subjects. Clinical care of subjects will 
be performed by clinicians at the study site who are not MADRS and CGI-SS-R/SIBAT raters. 
Adherence to this procedure will be monitored and enforced during the study.
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment/course of action would be dictated by knowing the treatment status of the 
subject. In such cases, the investigator may in an emergency determine the identity of the 
treatment by contacting the IWRS. It is recommended that the investigator contact the sponsor or 
its designee if possible to discuss the particular situation, before breaking the blind. Telephone 
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In 
the event the blind is broken, the sponsor must be informed as soon as possible. The date, time,
and reason for the unblinding must be documented in the appropriate section of the electronic 
case report form (eCRF), and in the source document. The documentation received from the 
IWRS indicating the code break must be retained with the subject's source documents in a secure 
manner.
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled early termination and follow-up contacts and visits.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. 
To maintain the blinding of intranasal study medication, the esketamine and placebo intranasal 
devices will be indistinguishable. Please refer to Section 14 (Study Drug Information) for 
information on the physical characteristics of the study drugs and devices.
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6.
DOSAGE AND ADMINISTRATION
6.1.
Intranasal Study Drug
All intranasal doses of study medication will be self-administered under the direct supervision of 
the investigator or designee. Instructions for use of the device will be provided as a separate 
document (see Section 15, Study-specific Materials). Details regarding study drug administration 
will be recorded in the source documents and the eCRF. On all intranasal treatment session days, 
a site staff member with training in cardiopulmonary resuscitation (eg, Basic Life Support course 
or equivalent course) that is up to date per local regulations must be present with the subject 
during the intranasal treatment session and the postdose observation period. In addition, 
equipment for supportive ventilation and resuscitation needs to be present. A physical 
description of the study drugs is provided in Section 14.1.
On Day 1, subjects will be randomized to treatment with either intranasal esketamine 84 mg or 
intranasal placebo, administered two times per week for 4 weeks. Intranasal treatment sessions 
should not take place on consecutive days.
Food will be restricted for at least 2 hours before each administration of study medication. 
Drinking of any fluids will be restricted at least 30 minutes before the first nasal spray on each 
dosing day. If the subject has nasal congestion on the dosing day, an intranasal decongestant can 
be used to reduce congestion, or with the exception of the Day 1 dose, the dosing day may be 
delayed (per the permitted visit window; see the Time and Events Schedule). If an intranasal 
decongestant is used to reduce congestion, it cannot be used within 1 hour prior to intranasal 
study drug dosing (see Attachment 1 for allowed intranasal decongestant).
The first dose of study medication will be administered in the ER or other permitted setting that 
has appropriate staffing to manage acutely suicidal subjects. If the first dose is administered in 
the ER, it is recommended that the subject not be transferred from the ER to the inpatient 
psychiatric unit after the 4-hour postdose assessments are completed. Subjects who have been 
admitted directly into the inpatient psychiatric unit due to imminent risk for suicide or transferred 
from a medical unit (following medical stabilization for recent suicide attempt) will receive their 
first dose of study medication in the inpatient psychiatric unit.
Subjects will remain in the inpatient psychiatry unit for a recommended duration of 5 days, with 
shorter or longer hospitalizations permitted if clinically warranted per local standard of care.
Following discharge from the inpatient psychiatric unit, subsequent visits for the double-blind 
treatment phase will be conducted twice-weekly at an outpatient psychiatric facility through 
Day 25.
On all outpatient intranasal dosing days, all subjects must remain at the clinical site until study 
procedures have been completed and the subject is ready for discharge per clinician’s 
assessment. The minimum time required for postdose monitoring is 1.5 hours. Subjects should be 
accompanied when released from the clinical study site. Subjects must not drive a car or work 
with machines for 24 hours after study drug dosing. Subjects should refrain from using alcohol 
within 24 hours before and after each intranasal treatment session. If a subject appears 
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intoxicated, dosing should not occur (delayed per the permitted visit window; see the Time and 
Events Schedule).
On each dosing day: Subjects will self-administer 1 spray into each nostril (ie, a total of 2 sprays 
using 1 intranasal device) at each of the following 3 time points: t = 0, 5 minutes and 10 minutes;
time = 0 is defined as the time of the first 100-μL spray. Subjects will use a separate intranasal 
device at each of these 3 time points (ie, a total of 3 devices). Sprays to each nostril should be 
delivered in rapid succession at the scheduled time points. Table 1 describes how esketamine 
84 mg or placebo will be administered in the double-blind treatment phase.
Table 1:
Dose Administration of Esketamine 84 mg or Placebo
Intranasal Treatment
Time of Intranasal Device Administration
0 a
5 minutes
10 minutes
Intranasal device b
1st
2nd
3rd
Placebo
1 spray of placebo to 
each nostril
1 spray of placebo to 
each nostril
1 spray of placebo to 
each nostril
Esketamine 84 mg
1 spray of esketamine to 
each nostril
1 spray of esketamine to 
each nostril
1 spray of esketamine to 
each nostril
a
Time 0 is defined as the time of administration of the first intranasal spray to one nostril from the first intranasal 
device. 
b
One device will be used at each time point. Each individual intranasal device contains 2 sprays. The intranasal 
devices containing esketamine deliver 14 mg per spray, for a total of 28 mg per individual device (ie, 2 sprays).
After the first dose (ie, starting with the Day 4 dose or later), if required due to tolerability issues, 
a one-time dose reduction to intranasal esketamine 56 mg or intranasal placebo is allowed for 
subsequent doses. No further dose adjustment is allowed during the double-blind treatment 
phase. The subject would receive the decreased dose at all remaining dosing days.
Table 2 describes how esketamine 56 mg or placebo will be administered in the double-blind 
treatment phase.
Table 2:
Dose Administration of Esketamine 56 mg or Placebo
Intranasal Treatment
Time of Intranasal Device Administration
0 a
5 minutes
10 minutes
Intranasal device b
1st
2nd
3rd
Placebo
1 spray of placebo to each 
nostril
1 spray of placebo to each 
nostril
1 spray of placebo to each 
nostril
Esketamine 56 mg 
1 spray of esketamine to 
each nostril 
1 spray of esketamine to 
each nostril
1 spray of placebo to each 
nostril
a
Time 0 is defined as the time of administration of the first intranasal spray to one nostril from the first intranasal 
device. 
b
One device will be used at each time point. Each individual intranasal device contains 2 sprays. The intranasal 
devices containing esketamine deliver 14 mg per spray, for a total of 28 mg per individual device (ie, 2 sprays).
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6.1.1.
Guidance on Blood Pressure Monitoring on Intranasal Treatment 
Session Days
Given the potential for treatment emergent transient elevation in systolic and diastolic blood 
pressure, the guidance shown in Table 3 should be followed on intranasal dosing days.
Table 3:
Guidance for Blood Pressure Monitoring
Timing of blood 
pressure 
measurement
Thresholds for elevated blood 
pressure that require further 
guidance
Guidance for dosing, blood pressure monitoring, or
follow-up assessment
Predose on 
Day 1
Refer to exclusion criterion #7 
(Section 4.2)

Refer to exclusion criterion #7 (Section 4.2).
Predose on any 
dosing day after 
Day 1
SBP: >140 mmHg
and/or
DBP: >90 mmHg

Blood pressure measurement should be repeated 
after the subject rests in a supine or semi-supine 
position to confirm measurement. 

If SBP and/or DBP remain higher than thresholds, 
dosing should be postponed and rescheduled on the 
following day or within the given visit window. 

If blood pressure elevation persists at the next visit, 
the subject will be scheduled for a consultation by 
cardiologist, other specialist, or primary care 
physician prior to further dosing.
At any postdose 
timepoint on any 
dosing day
SBP: ≥180 mmHg but <200 mmHg
and/or
DBP: ≥110 mmHg but <120 mmHg

Further intranasal dosing should be interrupted and 
the subject should be referred to a cardiologist, 
other specialist, or primary care physician for a 
follow-up assessment.

After the follow-up assessment, if recommended by 
the referring doctor and considered appropriate 
according to the clinical judgment for the subject to 
continue in the study, the subject may continue 
with intranasal dosing if the predose blood pressure 
at the next scheduled visit is within the acceptable 
range (see above).
At any postdose 
timepoint on any 
dosing day
SBP: ≥200 mmHg
and/or
DBP: ≥120 mmHg

Subject must discontinue from further dosing.

Subject should be referred to a cardiologist, other 
specialist, or primary care physician for a follow-up 
assessment.
At 90 minutes 
postdose on any 
dosing day
SBP: ≥160 mmHg
and/or
DBP: ≥100 mmHg

Blood pressure assessments should continue every 
30 minutes until:
o
SBP is <160 mmHg and DBP is <100 mmHg, 
or 
o
In the investigator’s clinical judgment, the 
subject is clinically stable and can be 
discharged from the study site, or 
o
The subject is referred for appropriate medical 
care, if clinically indicated.
At 120 minutes 
postdose on any 
dosing day
SBP: ≥180 mmHg
and/or
DBP: ≥120 mmHg

The subject should be referred for immediate 
medical treatment.
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure
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6.2.
Standard of Care Antidepressant Treatment
All subjects will be treated in the context of comprehensive standard clinical care, including 
hospitalization and the initiation or optimization of antidepressant treatment, which will be 
determined by the treating physician(s) based on clinical judgment and practice guidelines. The 
standard of care antidepressant treatment (antidepressant monotherapy or antidepressant plus 
augmentation therapy) will be initiated or optimized for all subjects at the time of randomization 
on Day 1. Subjects who are on antidepressant monotherapy from Day 1 should remain on 
antidepressant monotherapy through the end of double-blind phase (Day 25) whereas subjects 
who are on antidepressant plus augmentation therapy from Day 1 will remain on antidepressants 
plus augmentation therapy through the end of double-blind phase (Day 25). Eligible subjects 
may or may not be receiving antidepressants at the time of study entry. Dose 
titration/adjustments of newly initiated or optimized standard of care antidepressant treatment 
should occur during the first 2 weeks of double-blind treatment (ie, by Day 15), with doses 
remaining stable thereafter through the end of the double-blind phase (Day 25). Subjects who are 
currently taking a recently initiated antidepressant treatment at screening (initiated <2 weeks 
prior) may continue taking the antidepressant at the current dose or at an optimized dose (dose 
adjustment is allowed during the first 2 weeks of double-blind treatment) through the end of the 
double-blind phase (Day 25), if deemed clinically appropriate by the investigator. During the 
double-blind treatment phase, the investigator needs to consult with the sponsor’s medical 
monitor in advance if additional changes on antidepressant treatment are clinically indicated. 
During the follow-up phase, the antidepressant treatment will be managed based on the 
clinician’s judgment. 
7.
TREATMENT COMPLIANCE
All doses of study medication will be self-administered under the direct supervision of the 
investigator or designee.
The investigator or designated study-site personnel will maintain a log of all study drug 
dispensed and returned. Drug supplies for each subject will be inventoried and accounted for 
throughout the study.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy therapies administered up to 30 days before first dose of study drug should be recorded 
at screening. Concomitant therapies must be recorded throughout the study beginning with start 
of the first dose of study drug through the final visit. Concomitant therapies should also be 
recorded beyond this time only in conjunction with new or worsening adverse events, including 
serious adverse events that meet the criteria outlined in Section 12.3.2., Serious Adverse Events.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study drug must be recorded in the eCRF.
Modification of an effective preexisting therapy should not be made for the explicit purpose of 
entering a subject into the study.
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A list of prohibited therapies is provided in Attachment 1 as general guidance for the 
investigator; please note, however, this list is not all inclusive. Please contact the study team to 
discuss any questions or concerns regarding any specific concomitant therapies for a subject. 
Subjects must also adhere to the list of prohibitions and restrictions provided in Section 4.3.
Subjects may not receive ECT during the study. ECT non-responders at imminent risk for 
suicide may be included in the study. If an investigator were to enroll a subject currently 
receiving ECT, the investigator would have to document why it is clinically appropriate to 
discontinue the ECT treatments, and to ensure that treatment is not changed for the purpose of 
making the subject eligible.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, PK, biomarker,
pharmacogenomic/epigenetic, medical resource utilization, and safety measurements applicable 
to this study.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures 
be performed in the sequence provided by the sponsor (see Section 9.1.3). Actual dates and times 
of assessments will be recorded in the source documentation and eCRF.
Additional pregnancy tests may be performed, as determined necessary by the investigator or 
required by local regulation, to establish the absence of pregnancy at any time during the 
subject's participation in the study.
Additional drug tests may be performed as determined necessary by the investigator or required 
by local regulation.
Medical resource utilization data will be collected. Refer to Section 9.6, Medical Resource 
Utilization for details.
The total blood volume to be collected from each subject will be approximately 141 mL (see Table 
4).
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Table 4:
Approximate Volume of Blood to be Collected From Each Subject
Type of Sample
Volume (mL)
per sample
Number of Samples
per Subject
Total Volume of 
Blood (mL)a
Screening Phase
Serum chemistry
2.5
2 (1 local, 1 central) b
5
Hematology
2
2 (1 local, 1 central) b
4
Approximate total blood volume for screening phase
9
Double-Blind Treatment Phase
Serum chemistry 
2.5
1
2.5
Hematology
2
1
2
Pharmacokinetic evaluation
2
6
12
Blood for biomarker evaluation
30 c
3
90
Blood for RNA biomarker evaluation
2.5
3
7.5
Approximate total blood volume for double-blind treatment phase with biomarker samples
114
Pharmacogenomic/epigenetic evaluation d
6
3
18
Approximate total blood volume for double-blind treatment phase with biomarker and 
pharmacogenomic/epigenetic samples
132
Approximate total blood volume for study
141 mL
a 
Calculated as number of samples multiplied by amount of blood per sample.
b 
At screening, 2 samples will be collected for analysis – 1 sample each for the local laboratory (to have results 
prior to Day 1 dose) and the central laboratory (see Section 9.7 for further details).
c
Blood volume for biomarker samples represents volume of several tubes combined.
d
Blood sample(s) will be collected only from subjects who have consented to provide an optional sample for 
genetic research.
Note: If desired, an indwelling intravenous cannula may be used for blood sample collection.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
9.1.2.
Screening Phase
Prior to conducting any study procedure, the investigator (or designated study personnel) will 
review and explain the written ICF to each potential subject with MDD presenting to an ER or 
other permitted setting and assessed to be at imminent risk for suicide.
After signing the ICF, potential subjects will be screened under close supervision within 
48 hours of intranasal dosing on Day 1 to determine eligibility for study participation (if 
possible, potential subjects should be screened within 24 hours of intranasal dosing on Day 1). 
Subjects who have recently attempted suicide and are currently hospitalized for medical 
stabilization and continue to be at imminent risk for suicide, or subjects who have been admitted 
directly into the inpatient psychiatric unit due to imminent risk for suicide, may also be screened 
to determine eligibility. 
Subjects must meet DSM-5 diagnostic criteria for MDD, without psychotic features, based upon 
clinical assessment and confirmed by the MINI. In addition, the subject must have a MADRS 
total score of >28 predose on Day 1, and in the physician’s opinion, acute psychiatric 
hospitalization is clinically warranted due to the subject’s imminent risk of suicide. Refer to 
Section 4 (Subject Population) for all inclusion and exclusion criteria that will be used to 
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determine subject eligibility. Eligible subjects may or may not be receiving antidepressants at the 
time of study entry.
Refer to the Time and Events Schedule for a complete list of study procedures that will be 
performed at screening.
The clinician-administered assessments at screening can be performed in the order preferred by 
the clinical site: MINI, Question B3 and B10 from MINI (current status). If the screening phase 
is longer than 24 hours, Question B3 and B10 from MINI (current status) must be repeated prior 
to randomization to confirm eligibility.
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure (which may include contact for follow-up of safety).
9.1.3.
Double-Blind Treatment Phase
Following completion of all required screening procedures and confirmation of subject 
eligibility, subjects will enter the double-blind treatment phase.
On Day 1 of the double-blind treatment phase, approximately 224 subjects will be randomly 
assigned to 1 of 2 treatment groups in a 1:1 ratio (approximately 112 subjects per group): 
intranasal esketamine 84 mg or intranasal placebo. Study drug will be administered two times 
per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25). Intranasal treatment sessions should 
not take place on consecutive days.
Subjects will be admitted to and receive the first dose of study medication in the ER or other 
permitted setting; for example, subjects who have been admitted directly into the inpatient 
psychiatric unit due to imminent risk for suicide or transferred from a medical unit (following 
medical stabilization for recent suicide attempt) will receive their first dose of study medication 
in the inpatient psychiatric unit. If the first dose is administered in the ER, it is recommended 
that subjects not be transferred from the ER to the inpatient psychiatric unit until after the 
postdose assessments are completed (approximately 4 hours after study drug administration). 
Prior to the first intranasal dose on Day 1, subjects will practice spraying (into the air, not 
intranasally) a demonstration intranasal device that is filled with placebo solution. All subjects 
will self-administer the study medication under the direct supervision of the investigator or 
designee (Refer to Section 6, Dosage and Administration).
All subjects will be treated in the context of comprehensive standard clinical care, including 
hospitalization and the initiation or optimization of antidepressant treatment (antidepressant 
monotherapy or antidepressant plus augmentation therapy). On Day 1, all subjects will begin 
standard of care treatment and will continue, at least, this treatment through the duration of the 
double-blind treatment phase. The standard of care will be determined by the treating 
physician(s) based on clinical judgment and local practice at the time of randomization on Day 1.
Any changes to the standard of care treatment, that is different from what was planned at the 
time of randomization, should be clearly documented including the reason for the change.
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The 4-hour assessments at the Day 1 visit should be performed within ±30 minutes of the 4-hour 
postdose time point. The 24-hour assessments at the Day 2 visit should be performed ±2 hours of 
the 24-hour postdose time point.
Subjects will remain in the inpatient psychiatry unit for a recommended duration of 5 days, with 
shorter or longer hospitalizations permitted if clinically warranted per local standard of care. The 
discharge decision will be made based upon the investigator’s judgment that the subject is no 
longer imminently suicidal and meets standard discharge criteria per local practice. Discharge
before 5 days must be discussed and approved by the sponsor’s medical monitor. The 
investigator must discuss the need for continued hospitalization beyond 10 days and thereafter on 
a weekly basis with the sponsor’s medical monitor. Following discharge from the inpatient 
psychiatric unit, subsequent visits for the double-blind treatment phase will be conducted twice-
weekly at an outpatient psychiatric facility through Day 25.
Dose titration/adjustments of newly initiated or optimized standard of care antidepressant 
treatment should occur during the first 2 weeks of double-blind treatment (ie, by Day 15), with 
doses remaining stable thereafter through the end of the double-blind phase (Day 25). Subjects 
who are currently taking a recently initiated antidepressant treatment at screening (initiated 
<2 weeks prior) may continue taking the antidepressant at the current dose or at an optimized 
dose (dose adjustment is allowed during the first 2 weeks of double-blind treatment) through the 
end of the double-blind phase (Day 25), if deemed clinically appropriate by the investigator. The 
investigator needs to consult with the sponsor’s medical monitor in advance if additional changes 
to antidepressant treatment are clinically indicated. 
On all outpatient intranasal dosing days, all subjects must remain at the clinical site until study 
procedures have been completed and the subject is ready for discharge per clinician’s 
assessment. The minimum time required for postdose monitoring is 1.5 hours. Subjects should be 
accompanied when released from the clinical study site. Subjects must not drive a car or work 
with machines for 24 hours after study drug dose administration.
Efficacy, safety, pharmacokinetic, biomarker, pharmacogenomics, and medical resource 
utilization evaluations will be performed as described in the Time and Events Schedule. When 
multiple patient-reported outcomes and clinician-administered assessments are scheduled for the 
predose time point it is recommended they be performed in the following sequence:

SIBAT

MADRS

Patient-reported outcomes: BHS, QLDS, EQ-5D-5L, and TSQM-9
Clinicians who perform the MADRS and SIBAT assessments will be different from those who 
evaluate vital signs, MOAA/S, CADSS, and adverse events.
Subjects and site staff will complete the clinician-administered assessments and patient-reported 
outcomes using an electronic tablet device provided for this study or using a paper version (refer 
to Section 15, Study-Specific Materials).
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Early Withdrawal
Subjects who discontinue from the double-blind treatment phase prior to completion of the 
Day 25 visit will have an Early Termination visit conducted at the time of discontinuation. 
Subjects who discontinue with reasons other than withdrawal of consent, lost to follow up, or 
death will be contacted remotely at 3 days after the last dose of intranasal study medication (if 
the date of the Early Termination visit is less than 3 days after the last dose of intranasal study 
medication), on Day 25, and on Day 90 for MADRS assessment and adverse event collection.
For information obtained via telephone contact, written documentation of the communication 
must be available for review in the source documents. During telephone contact visits with the 
subject by site personnel, adverse event information will be obtained, and MADRS assessment
will be performed by appropriately qualified staff. In addition, the investigator must ensure the 
subject is appropriately transitioned/followed for any additional care required.
9.1.4.
Posttreatment Phase (Follow-Up)
During the follow-up phase, subjects will be monitored twice weekly for the first two weeks 
(Days 28, 32, 35, and 39) after study drug treatment. Subjects will then be followed up weekly 
for the next two weeks (Days 46 and 53) and every two weeks for the rest of the follow-up 
period (Days 67 and 90).
During the follow-up phase, the antidepressant treatment will be managed based on the 
clinician’s judgment. 
Efficacy, safety, and medical resource utilization evaluations will be performed as described in 
the Time and Events Schedule. When multiple patient-reported outcomes and clinician-
administered assessments are scheduled for the same time point it is recommended they be 
performed in the following sequence:

SIBAT

MADRS

Patient-reported outcomes: BHS, QLDS, EQ-5D-5L, and TSQM-9
Clinicians who perform the MADRS and SIBAT assessments will be different from those who 
evaluate vital signs, and adverse events.
Subjects and site staff will complete the clinician-administered assessments and patient-reported 
outcomes electronically using a device provided for this study or using a paper version (refer to 
Section 15, Study-Specific Materials).
Any clinically significant abnormalities persisting at the end of the study will be followed by the 
investigator until resolution or until a clinically stable endpoint is reached. All adverse events 
and special reporting situations, whether serious or non-serious, will be reported until completion 
of the subject's last study-related procedure (which may include contact for follow-up of safety).
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Early Withdrawal
Subjects who discontinue from the follow-up phase prior to completion of the Day 90 visit will 
have an Early Termination visit conducted at the time of discontinuation. Subjects who 
discontinue with reasons other than withdrawal of consent, lost to follow up, or death will be 
contacted remotely on Day 90 for MADRS assessment and adverse event collection. For 
information obtained via telephone contact, written documentation of the communication must 
be available for review in the source documents. During telephone contact visits with the subject 
by site personnel, adverse event information will be obtained, and MADRS assessment will be 
performed by appropriately qualified staff. In addition, the investigator must ensure the subject is 
appropriately transitioned/followed for any additional care required.
9.2.
Efficacy Evaluations
9.2.1.
Montgomery-Asberg Depression Rating Scale
The primary efficacy evaluation will be the MADRS total score. The MADRS will be performed 
using the Structured Interview Guide for the Montgomery Asberg Depression Rating Scale.81
The MADRS is a clinician-rated scale designed to be used in subjects with MDD to measure 
depression severity and detect changes due to antidepressant treatment.54,55 The test consists of 
10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous 
presence of the symptoms), for a total possible score of 60. Higher scores represent a more 
severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, 
sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal 
thoughts. The test exhibits high inter-rater reliability. 
The typical recall period for the MADRS is 7 days. In this study, the MADRS will also be 
administered using a since last assessment recall, a 4-hour recall on Day 1 and Day 25 postdose,
and a 24-hour recall on Day 2. For the MADRS performed at 4 hours postdose on Days 1 and 25, 
the MADRS scores for the sleep item recorded predose on the same day will be carried forward.
Whenever possible, all efforts should be made to use the same raters for the MADRS at each site 
to assess the same subjects throughout the study. If this is not possible, review of the appropriate 
prior assessments and communication with prior raters should be conducted as needed.
9.2.2.
Suicide Ideation and Behavior Assessment Tool
The SIBAT has two major divisions: a patient-rated section and a clinician-rated section. The 
patient-rated section has modules of demographics and suicide history, risk/protective factors, 
suicidal thinking, suicide behavior, and suicide risk. The information generated in this section 
will be summarized and used to support the clinical decision-making of the second section. The 
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. 
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The SIBAT will be provided in an electronic format for use by the subject and study staff during 
the study. Refer to the SIBAT Time and Events Schedule for an outline of which modules will be 
performed at each scheduled time point. 
One module of the SIBAT includes a revised version of the Clinical Global Impression –
Severity of Suicidality. 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 patients) and will be based on the totality of 
information available to the clinician, including information from the SIBAT. The CGI-SS-R 
summarizes the clinician’s overall impression of severity of suicidality and will be used to assess 
the key secondary endpoint in this study (see Section 2.1.2). This rating operates like numerous 
other CGI-severity scales that have been used in other psychiatric studies. These instruments 
have shown clinical validity and sensitivity to change.
The CGI-SR-I summarizes the clinician’s best assessment of the likelihood that a patient will 
attempt suicide in the next 7 days.
Whenever possible, all efforts should be made to use the same raters for the SIBAT at each site 
to assess the same subjects throughout the study. If this is not possible, review of the appropriate 
prior assessments and communication with prior raters should be conducted as needed.
9.2.3.
Beck Hopelessness Scale
The BHS is a self-reported measure to assess one’s level of negative expectations or pessimism 
regarding the future. It consists of 20 true-false items that examine the respondent’s attitude over 
the past week by either endorsing a pessimistic statement or denying an optimistic statement; 
9 are keyed false and 11 are keyed true. These items fall within 3 domains: (1) feelings about the 
future; (2) loss of motivation; and (3) future expectations. For every statement, each response is 
assigned a score of 0 or 1. The total BHS score is a sum of item responses and can range from 
0 to 20, with a higher score representing a higher level of hopelessness. Total scores that range 
from 0 to 3 are considered within the normal range, scores 4 to 8 identify mild hopelessness, 
scores 9 to 14 identify moderate hopelessness, and scores greater than 14 identify severe 
hopelessness. 
BHS scores of ≥9 have been found to be predictive of eventual suicide in depressed suicide 
ideators who were followed for 5-10 years after discharge from a hospital.8 Among a group of 
72 subjects with single-episode MDD, the scale was found to have a high degree of internal 
consistency (0.92); the same value of internal consistency was found among a group of 
134 subjects with recurrent-episode MDD.9 Among a group of hospitalized MDD subjects, the 
scale showed a relatively high correlation with clinical ratings of hopelessness and other self-
administered measures of hopelessness. Test-retest scores of 0.69 and 0.66 have been reported.9
The scale has been found to have concurrent and discriminant validity among subjects with MDD.9
Further, the scale was found to be sensitive to change in the subject’s state of depression over 
time.10 The measure is designed for use in adults aged 17 to 80 years and takes 5 to 10 minutes to 
complete. A scoring manual and scoring platform is available from the licensee holder.
The BHS will be administered using a recall period of the last 7 days.
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9.2.4.
EuroQol 5-Dimension 5-Level
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily 
designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and 
the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L descriptive system comprises the 
following 
5 
dimensions: 
Mobility, 
self-care, 
usual 
activities, 
pain/discomfort 
and 
anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems 
(Level 1 indicating no problem, Level 2 indicating slight problems, Level 3 indicating moderate 
problems, Level 4 indicating severe problems, and Level 5 indicating extreme problems).27,28
The subject selects an answer for each of the 5 dimensions considering the response that best 
matches his or her health “today.” The descriptive system can be represented as a health state. 
The EQ-VAS self-rating records the respondent’s own assessment of his or her overall health 
status at the time of completion, on a scale of 0 to 100. 
The time taken to complete the questionnaire varies with age, health status, and setting but is 
likely to be approximately 1 minute.
9.2.5.
Quality of Life in Depression Scale
The QLDS is a disease specific patient-reported outcome designed to assess health related quality 
of life in patients with MDD, ie, it captures the impact of depression and its treatment from the 
patient’s perspective.34,52,77 The instrument has a recall period of "at the moment", contains 34-
items with "yes"/"no" or “true”/“not true” response options and takes approximately 5-10 minutes 
to complete. The score range is from 0 (good quality of life) to 34 (very poor quality of life). It has 
been shown to have acceptable psychometric properties and sensitivity to change.
9.2.6.
Treatment Satisfaction Questionnaires for Medication
The Treatment Satisfaction Questionnaire for Medication (TSQM-9)4 is a 9-item generic patient 
reported outcome instrument to assess patients’ satisfaction with medication. It is derived from 
the longer TSQM Version 1.411 and covers domains of effectiveness, convenience and global 
satisfaction. The instrument is scored by domain with scores ranging from 0-100 where a lower 
score indicates lower satisfaction. The recall period is “the last 2-3 weeks”. It takes 
approximately 5 minutes to complete.
9.3.
Pharmacokinetics
Whole blood samples will be used to evaluate the PK of esketamine. Plasma collected for PK 
may additionally be used to evaluate safety or efficacy aspects that address concerns arising 
during or after the study period. Genetic analyses will not be performed on these plasma 
samples. Subject confidentiality will be maintained.
9.3.1.
Evaluations
Venous blood samples of approximately 2 mL will be collected for measurement of plasma
concentrations of esketamine, noresketamine, and other metabolites if warranted at the time 
points specified in the Time and Events Schedule. The exact dates and times and 
pharmacokinetic blood sampling must be recorded.
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9.3.2.
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of esketamine and noresketamine 
using a validated, specific, and sensitive achiral liquid chromatography/mass spectrometry/mass 
spectrometry (LC-MS/MS) method by or under the supervision of the sponsor.
If required, some plasma samples may be analyzed to document the presence of circulating 
metabolites using a qualified research method. In addition, plasma PK samples may be stored for
future analysis of the metabolite profile.
The bioanalytical report, including a description of the assay and a summary of the assay 
performance data, will be included in the final study report as an addendum.
9.3.3.
Pharmacokinetic Parameters
The plasma concentration-time data of esketamine (and noresketamine, if warranted) will be 
analyzed using population PK modeling. If conducted, the results of population PK analyses may 
be reported separately.
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations
The relationship between MADRS total score (and possibly selected adverse events and 
additional pharmacodynamic parameters), and PK metrics of esketamine may be evaluated. The 
results of such analyses may be reported separately.
9.5.
Biomarker and Pharmacogenomic (DNA) Evaluations
Biomarker Evaluations
Blood samples will be collected as indicated in the Time and Events Schedule for exploratory 
analysis of biomarkers (protein, metabolites, and RNA) related to immune system activity, HPA 
axis activation, neurotrophic and metabolic factors. Exploratory analyses may be performed for 
additional biomarkers as well. Results may be presented in a separate biomarkers report.
Biomarkers may be added or deleted based on scientific information or technical innovations 
under the condition that the total volume of blood collected will not be increased. 
All biomarker data obtained during this study may be included in ongoing cross-study analyses 
to investigate the relationship between depression severity and phenotypes and biomarkers.
Information on menstrual cycle (date of first day of last period, average length of cycle) will be 
recorded on Day 1 (predose) and Day 25 when blood samples for biomarker analysis are 
collected.
Pharmacogenomic Evaluations
Subject participation in pharmacogenomic/epigenetic evaluations is optional. A whole blood 
sample for DNA analyses will be collected from all subjects who provide consent for 
pharmacogenomic research at the time points indicated in the Time and Events Schedule.
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DNA samples will be analyzed for the assessment of genetic and epigenetic variation in genes in 
pathways relevant to MDD and suicidality. Additional analyses may be conducted if it is 
hypothesized that this may help resolve issues with the clinical data.
DNA samples will be used for research related to esketamine or MDD. They may also be used to 
develop tests/assays related to esketamine and MDD. Pharmacogenomic research may consist of 
the analysis of one or more candidate genes or of the analysis of genetic and epigenetic markers 
throughout the genome (as appropriate) in relation to esketamine or MDD clinical endpoints.
9.6.
Medical Resource Utilization
Medical resource utilization data, associated with medical encounters, will be collected using the 
Healthcare Resource Use Questionnaire (HRUQ) on an ongoing basis whenever an encounter 
occurs and will be reviewed as indicated in the Time and Events Schedule. The HRUQ includes 
information regarding utilization of healthcare services (including the timing and type of serves), 
enabling changes in level and quantity of services to be considered as a variable in economic 
models.
9.7.
Safety Evaluations
Details regarding the Independent Data Monitoring Committee are provided in Section 11.9.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule:
Adverse Events
Adverse events will be reported by the subject for the duration of the study. Adverse events will 
be followed by the investigator as specified in Section 12, Adverse Event Reporting.
The TEAEs of special interest will be examined separately (refer to Sections 3.2.6 and 11.8 for 
further details).
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis
will be collected. The investigator must review the laboratory results, document this review, and 
record any clinically relevant changes occurring during the study in the adverse event section of 
the eCRF. The laboratory reports must be filed with the source documents.
A local laboratory will be used at screening to ensure results are available in enough time to 
determine subject eligibility. If standard of care clinical laboratory tests are performed within 
24 hours prior to the screening visit (ie, signing of the ICF), results for those laboratory tests 
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required per protocol at screening can be used for determination of subject eligibility. In this 
situation, following signing of the ICF, sample(s) for the local laboratory are not required, but 
sample(s) must be obtained and sent to the central laboratory (see below). A local laboratory can 
also be used in any instance where safety follow up is time-critical and the central laboratory 
results are not expected to be available before actions need to be taken for safety reasons.
A central laboratory will be used at screening and during the study.
The following tests will be performed:

Hematology Panel
-hemoglobin
-platelet count
-hematocrit
-red blood cell (RBC) count
-white blood cell (WBC) count with differential

Serum Chemistry Panel
-sodium
-alkaline phosphatase
-potassium
-creatine phosphokinase (CPK)
-chloride
-lactic acid dehydrogenase (LDH)
-bicarbonate
-uric acid
-blood urea nitrogen (BUN)
-calcium
-creatinine
- phosphate
-glucose
-albumin
-aspartate aminotransferase (AST)
-total protein
-alanine aminotransferase (ALT)
-gamma-glutamyltransferase (GGT)
-total bilirubin

Urinalysis
Dipstick
Sediment (if dipstick result is
-specific gravity
abnormal)
-pH
-red blood cells
-glucose
-white blood cells
-protein
-epithelial cells
-blood
-crystals
-ketones
-casts
-bilirubin
-bacteria
-urobilinogen
-nitrite
-leukocyte esterase
If dipstick result is abnormal, flow cytometry will be used to measure sediment. In case of
discordance between the dipstick results and the flow cytometric results, the sediment will 
be examined microscopically.
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Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, and urobilinogen will be 
determined using a dipstick. Red blood cells, white blood cells, epithelial cells, crystals, casts, 
and bacteria will be measured using flow cytometry. If there is discordance between the dipstick 
results and the flow cytometric results, the sediment will be examined microscopically.
The following additional clinical laboratory assessments will be performed on-site:

Urine Pregnancy Testing (for women of childbearing potential only)

Urine Drug Screen
-
barbiturates, opiates, cocaine, PCP, amphetamines, and 
benzodiazepines
Electrocardiogram (ECG)
A single, 12-lead ECG will be performed at each time point specified in the Time and Events 
Schedule.
During the collection of ECGs, subjects should be in a quiet setting without distractions 
(eg, television, cell phones). Subjects should rest in a supine or semi-supine position for at least 
5 minutes before ECG collection and should refrain from talking or moving arms or legs. 
All ECG tracings will be sent to a central ECG laboratory. The ECGs will be read at the
scheduled time points and summarized by a central ECG laboratory. The central ECG laboratory 
will send the sponsor an electronic copy of the data for inclusion in the clinical database. In 
addition, the investigator or sub-investigator is required to review all ECGs at the study visit to 
assess for any potential safety concerns or evidence exclusionary conditions prior to dosing.
At screening, the ECG tracing will be sent to the central ECG laboratory but the investigator or 
sub-investigator is also required to review the ECG locally to determine subject eligibility.
Vital Signs (Temperature, Pulse/Heart Rate, Respiratory Rate, Blood Pressure)
Vital signs will be performed per the Time and Events Schedule. Blood pressure and pulse/heart 
rate measurements will be assessed with a completely automated device. Manual techniques will 
be used only if an automated device is not available.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of 
rest in a quiet setting without distractions (eg, television, cell phones).
For further details regarding blood pressure monitoring, please see Guidance on Blood Pressure 
Monitoring on Intranasal Treatment Session Days (Section 6.1.1).
Tympanic temperature is recommended. The method used for obtaining temperature should be 
documented.
Physical Examination, Body Weight, and Height
Physical examinations and measurement of body weight and height will be performed per the 
Time and Events Schedule.
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Nasal Examination
Targeted nasal examinations (including the upper respiratory tract/throat) will be conducted per 
the Time and Events Schedule. The objective of the examination at screening is to rule out any 
subjects with anatomical or medical conditions that may impede drug delivery or absorption. 
Subsequent examination will consist of a visual inspection of the nostrils, nasal mucosa, and 
throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption and epistaxis and 
will be graded as follows: none, mild, moderate, or severe. 
Dosing Day Assessments
Pulse Oximetry
Pulse oximetry will be used to measure arterial oxygen saturation (SpO2). On each dosing day, 
the device will be attached to the finger, toe, or ear, and SpO2 will be monitored and documented 
every 15 minutes from predose to 1.5 hours postdose. If oxygen saturation levels are <93% at 
any time during the 1.5 hour postdose interval, pulse oximetry will be recorded every 5 minutes 
until levels return to 93% or until the subject is referred for appropriate medical care, if 
clinically indicated.
Modified Observer's Assessment of Alertness/Sedation (MOAA/S)
The MOAA/S will be used to measure treatment-emergent sedation with correlation to levels of 
sedation defined by the American Society of Anesthesiologists (ASA) continuum.67 The 
MOAA/S scores range from 0 (no response to painful stimulus; ASA continuum = general 
anesthesia) to 5 (readily responds to name spoken in normal tone [awake]; ASA continuum = 
minimal sedation).
On each intranasal dosing day, the MOAA/S will be performed every 15 minutes from predose
to 1.5 hours postdose.
If the score is ≤3 at any time during the 90 minute postdose interval, the MOAA/S will be 
performed every 5 minutes until a score of 4 is reached (at which point a frequency of every 
15 minutes can be resumed until t = 90 minutes postdose). 
If a subject does not have a score of at least 5 at t = 90 minutes postdose, the subject should 
continue to be monitored. For subjects with a score of 4, the assessment should be repeated every 
15 minutes. And for subjects with a score of ≤3, the assessment should be repeated every 
5 minutes until the score returns to 5 or the subject is referred for appropriate medical care, if 
clinically indicated.
Clinician-Administered Dissociative States Scale (CADSS)
The CADSS is an instrument for the measurement of present-state dissociative symptoms14 and 
will be administered to assess treatment-emergent dissociative symptoms. On each dosing day, 
the CADSS will be performed predose, and at 40 minutes and 1.5 hours postdose.
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The CADSS consists of 23 subjective items, divided into 3 components: depersonalization 
(items 3 to 7, 20, and 23), derealization (items 1, 2, 8 to 13, 16 to 19, and 21) and amnesia 
(items 14, 15, and 22). The subject’s responses are coded on a 5-point scale (from 0=not at all to 
4=extremely). The CADSS has excellent inter-rater reliability and internal consistency.
If any CADSS items are scored zero at 40 minutes, these items will not need to be repeated at 
1.5 hours postdose.
9.8.
Other Evaluations
Mini-International Neuropsychiatric Interview (MINI)
The MINI is a short, structured diagnostic interview developed for the fifth edition of the 
Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and 10th revision of the 
International Statistical Classification of Diseases and Related Health Problems (ICD-10) 
psychiatric disorders. It has an administration time of approximately 15 to 30 minutes and 
provides an accurate structured psychiatric interview for multicenter clinical trials. The MINI is 
used to confirm the diagnosis of MDD with current suicidal ideation and to determine if there are 
other psychiatric conditions present.
Questions B3 and B10 from the MINI
Current suicidal ideation with intent will be evaluated at screening using 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?) from the MINI. Subjects will 
be asked to answer these questions (Yes or No) relative to their current status. The response to 
B3 must refer to the present, whereas the response to B10 may reflect the past 24 hours. If the 
screening phase is longer than 24 hours, Question B3 and B10 from MINI (current status) must 
be repeated prior to randomization to confirm eligibility.
9.9.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. If blood samples are collected via an indwelling cannula, an appropriate 
amount (1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock 
will be removed from the cannula and discarded before each blood sample is taken. After blood 
sample collection, the cannula will be flushed with 0.9% sodium chloride, United States 
Pharmacopeia (USP) (or equivalent) and charged with a volume equal to the dead space volume 
of the lock.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
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10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed treatment if he or she has completed assessments 
up to and including Day 25 of the double-blind treatment phase. Subjects who prematurely 
discontinue study treatment for any reason before completion of the double-blind phase will not 
be considered to have completed the study treatment.
A subject will be considered to have completed the study if he or she has completed assessments 
up to and including Day 90.
10.2.
Discontinuation of Study Treatment/Withdrawal From the Study
Discontinuation of Study Treatment During the Double-blind Phase
A subject will not be automatically withdrawn from the study if he or she has to discontinue 
treatment before the end of the double-blind treatment phase.
A subject's study treatment will be discontinued for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death

Lack of efficacy, per the investigator’s judgment

The investigator believes that for safety reasons or tolerability reasons (eg, adverse event or 
worsening of underlying condition) it is in the best interest of the subject to discontinue 
study treatment

The subject becomes pregnant during the double-blind treatment phase

Blind is broken 

Violation of protocol procedures, per the investigator’s judgment and in consultation with 
the sponsor

Change in the in-patient hospitalization status from voluntary to involuntary as a result of a 
judicial or other legal administrative order
If a subject discontinues study treatment for any reason other than lost to follow up, death, or 
withdrawal of consent before the end of the double-blind treatment phase, an Early Termination 
visit will be conducted at the time of discontinuation and the subject will be contacted remotely 
at 3 days after the last dose of intranasal study medication (if the date of the Early Termination 
visit is less than 3 days after the last dose of intranasal study medication), on Day 25 and on Day 
90 for MADRS assessment and adverse event collection. No further planned assessments will be 
conducted. In addition, the investigator must ensure the subject is appropriately transitioned 
and/or followed for any additional care required.
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Withdrawal From the Study During the Follow-up Phase
A subject will be withdrawn from the study during the follow-up phase for any of the following 
reasons:

Lost to follow-up

Withdrawal of consent

Death

Violation of protocol procedures, per the investigator’s judgment and in consultation with 
the sponsor
If a subject withdraws from the study after the double-blind phase but before the end of the 
follow-up phase for reasons other than lost to follow up, death, or withdrawal of consent, an 
Early Termination visit will be conducted at the time of discontinuation and the subject will be 
contacted remotely on Day 90 for MADRS assessment and adverse event collection. No further 
planned assessments will be conducted. In addition, the investigator must ensure the subject is 
appropriately transitioned and/or followed for any additional care required.
If a subject is lost to follow up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. This should 
include at least 3 telephone calls, certified letters, email requests, etc. To ensure access to follow-
up subjects, the study sites should attempt to obtain both primary and secondary telephone 
contact numbers (eg, home, work, and mobile phone numbers) as well as other contact 
information (eg, email addresses) from subjects before randomization. In addition, the study site 
should emphasize the importance of follow-up information to the subject before randomization. 
The measures taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. 
Withdrawal of Consent
Every effort will be made in the study to ensure withdrawal of consent is not selected as a reason 
for discontinuation when in fact the subject withdrew for an identifiable reason (eg, due to an 
adverse event or lack of efficacy). 
Subjects who wish to withdraw from the study should be asked if they are agreeable to continue 
to an Early Termination visit and to be contacted remotely to collect follow-up information at 
3 days after the last dose of intranasal study medication (if the subject discontinued during the 
double-blind phase and the date of the Early Termination visit is less than 3 days after the last 
dose of intranasal study medication), on Day 25 (if the subject discontinued during the double-
blind phase) and on Day 90. Subjects who are not agreeable to remote follow-up contact will be 
withdrawn from the study as “withdrawal of consent.” Subjects who no longer wish to take study 
drug but agree to provide follow-up information will be withdrawn from the double-blind phase 
with the reason noted as “Other” and will specify the reason why.
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For a subject who withdraws consent, it is recommended that the subject withdraw consent in 
writing; if the subject refuses or is physically unavailable, the study site should document and 
sign the reason for the subject’s failure to withdraw consent in writing and maintain it with the 
subject’s source records. 
The investigator will be responsible for making all required notifications to the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC).
10.3.
Withdrawal From the Use of Research Samples
A subject who withdraws from the study will have the following options regarding the optional
research sample:

The collected sample will be retained and used in accordance with the subject's original 
separate informed consent for optional research samples.

The subject may withdraw consent for optional research sample, in which case the sample 
will be destroyed and no further testing will take place. To initiate the sample destruction 
process, the investigator must notify the sponsor study site contact of withdrawal of consent 
for the optional research samples and to request sample destruction. The sponsor study site 
contact will, in turn, contact the biomarker representative to execute sample destruction. If 
requested, the investigator will receive written confirmation from the sponsor that the 
sample has been destroyed.
Withdrawal From the Optional Research Samples While Remaining in the Main Study
The subject may withdraw consent for optional research samples while remaining in the study. In 
such a case, the optional research sample will be destroyed. The sample destruction process will 
proceed as described above.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, Long-
Term Retention of Samples for Additional Future Research). In such a case, samples will be 
destroyed after they are no longer needed for the clinical study. Details of the sample retention
for research are presented in the main ICF and in the separate ICF for optional research samples.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the SAP.
11.1.
Subject Information
The primary efficacy and safety analysis sets are defined below.

Full analysis set: The full analysis set will include all randomized subjects who have 
received at least one dose of double-blind study medication and have both a baseline and a 
post dose evaluation for the MADRS total score.
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
Safety analysis set: The safety analysis set will include all randomized subjects who receive 
at least one dose of double-blind study medication.
11.2.
Sample Size Determination
The maximum sample size for this study was calculated assuming an effect size of 0.45 for the 
MADRS total score at 24 hours post first dose (Day 2), a one-sided significance level of 0.025, 
and a drop-out rate at 24 hours of 5%. Approximately 112 subjects will need to be randomized to 
each treatment group to achieve 90% power. The effect size used in this calculation was based 
on results of the ESKETINSUI2001 study where the effect size for the change from baseline to 
Day 2 was 0.65 (mean difference between treatment groups of -7.2 and a pooled SD of 11.02) for 
MADRS total score. Given that the ESKETINSUI2001 study was a Phase 2 study carried out in 
only one country, the maximum sample size for this Phase 3 study was determined using a 
smaller effect size of 0.45 to allow for greater variability that can be expected for a study 
conducted globally.
11.3.
Efficacy Analyses 
Primary Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is 
defined by the following 3 components:

Population: subjects with MDD who are at imminent risk of suicide

Endpoint: change from baseline to 24 hours post first dose (Day 2) in the MADRS total 
score 

Measure of Intervention: the effect of the initially randomized treatment that would have 
been observed had all subjects remained on their treatment until Day 2 of the double-blind 
phase. 
The primary analysis will be based on the full analysis set and the MADRS total scores collected 
at Day 2.
Primary Efficacy Endpoint
The primary efficacy variable, change from baseline in MADRS total score at 24 hours post first 
dose (Day 2), will be analyzed using an analysis of covariance (ANCOVA) model. The model 
will include factors for treatment, center, standard of care antidepressant treatment (ie, 
antidepressant monotherapy or an antidepressant plus augmentation therapy), and baseline 
MADRS total score as a covariate. A point estimate and 95% confidence interval for the 
treatment difference will be provided. Since subjects are hospitalized at the time of the primary 
endpoint, it is anticipated that missing data will be infrequent. However, if a subject has a 
MADRS total score at a time earlier than 24 hours post first dose but does not have the 24 hour 
value, the earlier value will be used for the primary efficacy analysis. In addition, descriptive 
statistics (N, mean, standard deviation, median, minimum and maximum) of the primary efficacy 
variable will be provided by study center.
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Secondary Efficacy Endpoints
The analysis of the key secondary efficacy endpoint, change from baseline for CGI-SS-R at 
24 hours post first dose (Day 2), will be performed using an ANCOVA model on the ranks of 
change with factors for treatment, center, standard of care antidepressant treatment (ie, 
antidepressant monotherapy or an antidepressant plus augmentation therapy) and baseline 
CGI-SS-R (unranked) as a covariate. The treatment difference will be estimated using the 
Hodges-Lehmann estimate, which is the median of all possible paired differences for the change 
from baseline for CGI-SS-R at 24 hours.
The multiplicity with regard to testing multiple endpoints (the primary and the key secondary) 
will be controlled by a fixed sequence testing procedure, ie, the key secondary hypothesis will be 
tested only after the null hypothesis for the primary endpoint is rejected.
The secondary efficacy endpoints, proportion of subjects with remission (MADRS total score 
≤12) and the proportion of subjects achieving resolution of suicidality (CGI-SS-R score of 0 or 
1) at each visit during the double-blind phase will be analyzed using a Cochran-Mantel-Haenszel 
chi-square test adjusting for center and standard of care antidepressant treatment (ie, 
antidepressant monotherapy or antidepressant plus augmentation therapy). Subjects who 
discontinue treatment prior to the particular visit of the double-blind phase will not be considered 
to have remission or resolution of suicidality.
Changes from baseline over time in MADRS total score, BHS, and QLDS total scores will be 
analyzed based on last observation carried forward (LOCF) data using an ANCOVA model with 
treatment, center, and standard of care antidepressant treatment (ie, antidepressant monotherapy 
or an antidepressant plus augmentation therapy) as factors and baseline value as a covariate. 
Additionally, the change from baseline in MADRS total score at Day 25 will be analyzed using a 
mixed model for repeated measures (MMRM) analysis with baseline MADRS total score as a 
covariate, and treatment, center, standard of care antidepressant treatment (ie, antidepressant 
monotherapy or antidepressant plus augmentation therapy), day, and
day-by-treatment
interaction as fixed effects, and a random subject effect. Comparison of esketamine versus 
placebo will be performed using the appropriate contrast. Point estimates and 95% confidence 
intervals for the treatment differences will be provided.  Missing data will be closely monitored 
and additional sensitivity analyses will be specified in the SAP, if necessary.
Ranks of changes from baseline over time for CGI-SS-R and CGI-SR-I will be analyzed based 
on LOCF data using an ANCOVA model with treatment, center, and standard of care
antidepressant treatment (ie, antidepressant monotherapy or an antidepressant plus augmentation 
therapy) as factors and baseline value (unranked) as a covariate.
SIBAT Module 5 My Risk, Question 3 (patient reported frequency of suicidal thinking), TSQM-
9, dimension scores of EQ-5D-5L data, and health status index will be summarized over time.
Additionally, scores of all efficacy endpoints will be summarized for all visits. Descriptive 
statistics (N, mean, standard deviation, median, minimum and maximum) will be provided for 
continuous variables and frequency distributions will be provided for categorical variables.
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Details regarding the other secondary and exploratory analyses will be provided in the Statistical 
Analysis Plan.
11.4.
Pharmacokinetic Analyses
Plasma esketamine and noresketamine concentrations will be listed for all subjects. All 
concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All subjects and samples excluded from the analysis will be 
clearly documented in the study report.
Population PK analysis of plasma concentration-time data of esketamine may be performed 
using nonlinear mixed-effects modeling. Data may be combined with those of other selected 
studies to support a relevant structural model. Available baseline subject characteristics 
(demographics, laboratory variables, genotypes, race, etc.) will be tested as potential covariates 
affecting PK parameters. For the parameter estimates, the standard error and 95% confidence 
interval will be provided. This will be determined after the population pharmacokinetic modeling 
of the data is completed. Details will be given in a population PK analysis plan and the results of 
the population PK analysis will be presented in a separate report.
11.5.
Pharmacokinetic/Pharmacodynamic Analyses
The relationship between MADRS total score (and possibly selected adverse events and 
additional pharmacodynamic parameters), and PK metrics of esketamine may be evaluated. The 
results of the PK/PD analyses may be reported separately.
11.6.
Biomarker and Pharmacogenomic Analyses
Biomarkers will be tabulated by treatment and summary statistics will be calculated. 
Posttreatment changes in biomarkers over time will be summarized by treatment group. 
Associations between baseline levels and changes from baseline in selected biomarkers and 
clinical endpoints will be explored. Exploratory analyses may include comparison of biomarker 
measures between the treatment groups and correlation with baseline and change from baseline 
biomarker values in the efficacy and other measures. Exploratory analyses may be performed for 
additional biomarkers. In addition, all biomarker data obtained from this study may also be 
included in an ongoing cross-study analysis to investigate the relationship between depression 
severity, phenotypes, and biomarkers.
Pharmacogenomic analyses may include candidate gene analyses or genome-wide association 
analyses in relation to treatment response, non-response, and MDD. Expression analyses may 
include testing of known mRNA/miRNA transcripts or transcriptome-wide analysis in 
relationship to antidepressant treatment response and MDD. Additional exploratory analyses 
may be performed.
Details of the analysis plan and summary of results from both biomarker and pharmacogenomic 
analyses will be reported separately.
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11.7.
Medical Resource Utilization Analyses 
Medical resource utilization data will be descriptively summarized by treatment group.
11.8.
Safety Analyses
Safety data will be analyzed for the double-blind phase using the safety analysis set. The safety 
data from the follow-up phase will be summarized separately.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events 
with onset during each phase (ie, treatment-emergent adverse events, and adverse events that 
have worsened since baseline) will be included in the analysis. For each adverse event, the 
percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized by treatment group. 
The TEAEs of special interest will be examined separately (refer to Section 3.2.6 for further 
details); adverse events of special interest will be further listed in the SAP. Subjects who die, 
who discontinue treatment due to an adverse event, or who experience a serious adverse event
will be summarized separately.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Markedly abnormal results 
(specified in the SAP) will be used in the summary of laboratory data. Descriptive statistics will
be calculated for each laboratory analyte at baseline and for observed values and changes from 
baseline at each scheduled time point. Frequency tabulations of the abnormalities will be 
provided. A listing of subjects with any markedly abnormal laboratory results will also be 
provided. 
Electrocardiogram (ECG)
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. These tables will include observed values and changes from baseline 
values.
Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will be 
calculated at baseline and for observed values and changes from baseline at each scheduled time 
point. Frequency tabulations of the abnormalities will be made.
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, 
and corrected QT (QTc) interval using the following correction methods: QT corrected according 
to Bazett's formula (QTcB), QT corrected according to Fridericia's formula (QTcF). 6,33,36,74
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each 
scheduled time point. The percentage of subjects with QTc interval >450 milliseconds, 
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>480 milliseconds, or >500 milliseconds will be summarized, as will the percentage of subjects 
with QTc interval increases from baseline >30 milliseconds or >60 milliseconds.
All clinically relevant abnormalities in ECG waveform that are changes from the baseline 
readings will be reported (eg, changes in T-wave morphology or the occurrence of U-waves.
Vital Signs, Pulse Oximetry and Body Weight
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, pulse oximetry 
measurements, body weight measurements, and blood pressure (systolic and diastolic) values
and changes from baseline will be summarized at each scheduled time point. The percentage of 
subjects with values beyond clinically important limits will be summarized.
Nasal Examination
Abnormalities observed during the targeted nasal examinations at screening and post-baseline 
will be summarized and listed by treatment group.
MOAA/S and CADSS
Sedation data from the MOAA/S and dissociative symptoms data from the CADSS will be 
summarized descriptively at each scheduled visit by treatment group.
11.9.
Independent Data Monitoring Committee
An external Independent Data Monitoring Committee will be established to monitor data on an 
ongoing basis to ensure the continuing safety of the subjects enrolled in this study. The 
committee will meet every 6 months to review safety data. After the reviews, the IDMC will 
make recommendations regarding the continuation of the study. The details will be provided in a 
separate IDMC charter.
The IDMC will consist of at least one medical expert in the relevant therapeutic area and at least 
one statistician. The IDMC responsibilities, authorities, and procedures will be documented in its 
charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
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12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event 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. (Definition per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
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be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For esketamine, the expectedness of an adverse 
event will be determined by whether or not it is listed in the Investigator's Brochure. 
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2, Attribution Definitions.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
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Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Accidental or occupational exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)

Exposure to a sponsor study drug from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure, which may include contact for follow-up of safety, with the exception 
of pregnancy which will be reported up to 6 weeks after the last dose of study medication 
(females) or 90 days after the last dose of study medication (partners of male subjects). Serious 
adverse events, including those spontaneously reported to the investigator from the time a signed 
and dated ICF is obtained until completion of the subject's last study-related procedure, must be 
reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. Anticipated events will be 
recorded and reported as described in Attachment 2.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the eCRF their opinion concerning the 
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relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate IEC/IRB that 
approved the protocol unless otherwise required and documented by the IEC/IRB. A SUSAR will 
be reported to regulatory authorities unblinded. Participating investigators and IEC/IRB will 
receive a blinded SUSAR summary, unless otherwise specified.
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct
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
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Inpatient hospitalizations that extend beyond the protocol-recommended 5 days (not due to 
adverse event, ie, clinical worsening)

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.
The cause of death of a subject in a study from the time a signed and dated ICF is obtained until 
completion of the subject's last study-related procedure, whether or not the event is expected or 
associated with the study drug, is considered a serious adverse event.
12.3.3.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious 
adverse events and must be reported using the Serious Adverse Event Form. Any subject who 
becomes pregnant during the study must promptly discontinue further study treatment. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
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durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
The esketamine supplied for this study is available as a clear, colorless intranasal solution of 
esketamine hydrochloride (16.14% weight/volume [w/v]; equivalent to 14% w/v of esketamine 
base) in a nasal spray pump. The solution will consist of 161.4 mg/mL esketamine hydrochloride 
(equivalent to 140 mg of esketamine base) formulated in 0.12 mg/mL EDTA and 1.5 mg/mL 
citric acid at pH of 4.5. It is provided in a nasal spray pump, which delivers 16.14 mg esketamine 
hydrochloride (14 mg esketamine base) per 100 μL spray. Each individual nasal spray pump 
(device) contains a total of 28 mg (ie, 2 sprays).
The placebo solution will be provided as a clear, colorless intranasal solution of water for 
injection with a bittering agent (denatonium benzoate [Bitrex®] at a final concentration of 
0.001 mg/mL) added to simulate the taste of the intranasal solution with active drug. The placebo 
solution will be provided in matching nasal spray pump devices. Benzalkonium chloride is added 
as a preservative at a concentration of 0.3 mg/mL. Each individual nasal spray pump (device) 
contains 2 sprays.
Study drug will be manufactured and provided under the responsibility of the sponsor. Refer to 
the Investigator's Brochure for a list of excipients.37
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14.2.
Packaging
Study drug (ie, intranasal esketamine and placebo solution) will be supplied by the sponsor in a 
bi-dose nasal spray device. The devices will contain 230 µL (of which ~30 µL is the residual 
volume). Each device delivers 16.14 mg esketamine hydrochloride (14 mg esketamine base) or 
0.1 µg of denatonium benzoate per 100 µL spray.
Each nasal spray device will be individually packaged in a blister tray and subsequently put into a 
carton box. Each carton box constitutes a non-child-resistant subject kit, labeled with a unique 
medication kit number.
Device for Practicing Intranasal Study Drug Administration
The demonstration intranasal device will also be supplied by the sponsor and will contain placebo 
solution. Subjects will practice spraying into the air and will not spray intranasally.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
Study drug will be stored at the study site in a secure area with restricted access until dispensed 
to the subjects.
All study drug must be stored at controlled temperatures as indicated on the product specific 
labeling.
Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study drug preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects must be instructed to return all original containers, whether empty 
or containing study drug. All study drug will be stored and disposed of according to the sponsor's 
instructions. Study-site personnel must not combine contents of the study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the drug return form. When the study site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form.
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Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator's Brochure for esketamine

Pharmacy manual/study site investigational product and procedures manual

Study medication “Instructions for Use” documents for subject and clinical site staff

Practice/demonstration intranasal devices and ancillary supplies

Central laboratory manual and materials

ECG manuals and materials

Clinician-administered and subject-completed/patient-reported outcome assessments 

Paper versions if applicable

Electronic devices and associated materials

IWRS Manual

Electronic data capture (eDC) manual

Information for clinician regarding dosing, switching, and augmenting antidepressant 
treatments

Guidance for minimum requirements for site staff and equipment on dosing days

Study awareness and support materials (ie, to facilitate subject identification and retention)
Any updates to these documents that occur during the study will also be provided.
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Clinical Study in Subjects with MDD Assessed to be at Imminent Risk of Suicide
Major depressive disorder is the most prevalent mental health condition and the psychiatric 
diagnosis most commonly associated with suicide.41,65Epidemiology studies suggest that nearly 
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60% of those who die by suicide suffer from affective disorders, and at least one-half of people
who complete suicide are depressed at the time of their deaths.2,13,17,51
There is no approved treatment for patients with MDD assessed to be at imminent risk for 
suicide. The current standard of care is hospitalization and initiation or optimization of treatment 
with antidepressant medication. 
Pilot studies in subjects with MDD or bipolar depression suggest that ketamine may have a 
significant effect on reducing suicidal ideation within hours of administration.25,47,71,72,85
Furthermore, a Phase 2 study (ESKETINSUI2001) recently completed by the sponsor suggested 
that intranasal esketamine rapidly reduced symptoms of depression and suicidality in subjects 
with MDD at imminent risk for suicide and that intranasal esketamine was tolerated in this 
population.
Selection of Subjects
The primary aim of the study is to evaluate the efficacy of intranasal esketamine for the rapid 
reduction of the symptoms of major depressive disorder, including suicidal ideation, in subjects 
assessed to be at imminent risk for suicide. Thus, the study cannot be completed in healthy 
subjects or depressed patients who are not at imminent risk for suicide.
While a patient’s decisional capacity can be impacted by severe depression and suicidality, this 
becomes an ethical concern when the patient refuses medically necessary treatment. However, 
the subjects in this trial will be providing voluntary consent to participate in the study of a 
potentially efficacious treatment, given in the context of standard of care treatment (ie, 
hospitalization and antidepressant treatment). Subjects may participate in the study only if they 
have adequate capacity to give consent and after fully understanding the potential risks, benefits, 
and potential adverse events of the study. Determination of a subject’s decisional capacity will 
be made by the study investigator. Thus, ethical concerns regarding subjects’ decision to 
participate are minimal.
Justification for Using Placebo
Assessment of the potential efficacy of a new compound for the treatment of major depression 
requires adequate and well-controlled clinical studies. As there are no approved treatments for 
the rapid reduction of symptoms of MDD, including suicidal ideation, a placebo controlled study 
conducted in the context of comprehensive standard of care treatment (ie, acute psychiatric 
hospitalization, the initiation of optimization standard of care antidepressant treatment, and close 
outpatient follow up) is ethically appropriate. Subjects will remain hospitalized for a 
recommended period of 5 days, which is consistent with the typical length of stay for MDD 
patients who are hospitalized due to imminent risk of suicide, and may stay shorter or longer if 
clinically warranted. 
Precautions to Ensure Subject Safety in the Study
Subjects may participate in the study only if they have adequate capacity to give consent and 
after fully understanding the potential risks and giving an informed consent. Determination of 
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capacity will be made by the study investigator. Subjects may discontinue the study at any time. 
The probability of receiving placebo and the concept of random assignment will be explained to 
the subject. Potential disadvantages and adverse events of participating in the study and 
alternative treatment options will be discussed. 
Importantly, the study will be conducted in the context of standard clinical care, including 
hospitalization the initiation or optimization of antidepressant treatment, and close outpatient 
follow up. Subjects will remain hospitalized for a recommended period of 5 days, which is 
consistent with the typical length of stay for MDD patients who are hospitalized due to imminent 
risk of suicide, and may stay longer if clinically warranted. Subjects will receive standard of care
antidepressant treatment beginning on Day 1. 
For subjects who do not respond during the study and are not willing or able to receive additional 
study drug treatment, clinical care will be arranged between the study investigator and or their 
physician.
Compensation for any procedure will be fair per local standards and approved by the IECs/IRBs
for participating sites in order to not offer any undue incentive to participate in the study.
The investigator will ensure that subjects who withdraw from the study prior to completion are 
appropriately followed and/or transitioned for any additional care required.
Only qualified and experienced investigators will participate in the study.
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected is considered to be an acceptable amount of blood to be 
collected over this time period from the population in this study and will be less than a Red Cross 
blood donation.3
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
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study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
Approval for the collection of optional samples for research and for the corresponding ICF must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda
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
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-
related activity. The ICF(s) that is/are used must be approved by both the sponsor and by the 
reviewing IEC/IRB and be in a language that the subject can read and understand. The informed 
consent should be in accordance with principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his or her disease. Finally, they will be 
told that the investigator will maintain a subject identification register for the purposes of long-
term follow up if needed and that their records may be accessed by health authorities and 
authorized sponsor personnel without violating the confidentiality of the subject, to the extent 
permitted by the applicable law(s) or regulations. By signing the ICF the subject is authorizing 
such access, which includes permission to obtain information about his or her survival status. It 
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also denotes that the subject agrees to allow his or her study physician to recontact the subject for 
the purpose of obtaining consent for additional safety evaluations, and subsequent disease-related 
treatments, if needed.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject.
Subjects will be asked for consent to provide optional samples for research (where local 
regulations permit). After informed consent for the study is appropriately obtained, the subject
will be asked to sign and personally date a separate ICF indicating agreement to participate in the 
optional research component. Refusal to participate in the optional research will not result in 
ineligibility for the study. A copy of this signed ICF will be given to the subject.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory DNA, biomarker, and PK research is not conducted under standards appropriate for 
the return of data to subjects. In addition, the sponsor cannot make decisions as to the 
significance of any findings resulting from exploratory research. Therefore, exploratory research 
data will not be returned to subjects or investigators, unless required by law or local regulations. 
Privacy and confidentiality of data generated in the future on stored samples will be protected by 
the same standards applicable to all other clinical data.
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16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand esketamine, to 
understand depression, to understand differential drug responders, and to develop tests/assays 
related to esketamine and depression. The research may begin at any time during the study or the 
post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal From the Use of Samples in Future 
Research.
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 16.1, Study-Specific Design 
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
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17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
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17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
drug receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as
the clinical study-specific data fields as determined by the protocol. This data is electronically 
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extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the eCRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the eCRF. Data in this system 
may be considered source documentation.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
All eCRF entries, corrections, and alterations must be made by the investigator or authorized 
study-site personnel. The investigator must verify that all data entries in the eCRF are accurate 
and correct.
Electronic data capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an eCRF, and transmitted in a secure 
manner to the sponsor within the timeframe agreed upon between the sponsor and the study site. 
The electronic file will be considered to be the eCRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into 
eCRF in English. The eCRF must be completed as soon as possible after a subject visit and the 
forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, scale information or other questionnaires) should be completed 
by the same individual who made the initial baseline determinations whenever possible.
The investigator must verify that all data entries in the eCRFs are accurate and correct. All eCRF 
entries, corrections, and alterations must be made by the investigator or other authorized study-
site personnel. If necessary, queries will be generated in the eDC tool. If corrections to a eCRF
are needed after the initial entry into the eCRF, this can be done in either of the following ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
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The sponsor will review eCRF for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources. 
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare data entered into the eCRF
with the source documents
(eg, 
hospital/clinic/physician’s office medical records); a sample may be reviewed. The nature and 
location of all source documents will be identified to ensure that all sources of original data 
required to complete the eCRF are known to the sponsor and study-site personnel and are 
accessible for verification by the sponsor study-site contact. If electronic records are maintained 
at the study site, the method of verification must be discussed with the study-site personnel. 
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Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review will be discussed with the study-site personnel. The sponsor expects that, during 
monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site. 
Central monitoring will take place for data identified by the sponsor as requiring central review.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed with the last study assessment for the last subject 
participating in the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject assessment at that study site, in the time frame 
specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
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respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding esketamine or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomic or exploratory biomarker
research data, generated as a result of this study, are considered confidential and remain the sole 
property of the sponsor. The investigator agrees to maintain this information in confidence and 
use this information only to accomplish this study, and will not use it for other purposes without 
the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of esketamine, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information 
derived from the clinical studies to be used, the investigator is obligated to provide the sponsor 
with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomic or
exploratory biomarker analyses performed after the Clinical Study Report has been issued will 
be reported in a separate report and will not require a revision of the Clinical Study Report. 
Study subject identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the sponsor as author and owner of copyright in such work.
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Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from 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. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.
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Attachment 1: Prohibited Therapies
The table below is intended for general guidance, please contact the study team to discuss any 
questions or concerns regarding any specific concomitant therapies for a subject. 
The pharmacotherapies listed below are permitted (Y) or excluded (N) due to potential impact on efficacy 
evaluation and/or subject safety or because they are indicated for exclusionary conditions.
Except where specifically noted in the protocol, the prohibited therapies listed in this table are prohibited 
from screening until at least 1 day (24 hours) after the last dose of intranasal study medication.
Drug Class
Episodic Use
(PRN)
Continuous 
Use
Comments
ADHD medications (eg, 
atomoxetine, guanfacine)
N
Y
See also “Psychostimulants” row
Amantadine
N
N
Anorexiants (eg, 
phenteramine)
N
N
Anticonvulsants
N
N
Subjects with seizures are excluded. 
Anticonvulsants used for other indications may be 
allowed (eg, valproate for migraine, lamotrigine 
for mood disorder). Approval for use can be 
discussed on a case-by-case basis with the 
sponsor’s medical monitor.
Antidepressants (except
monoamine oxidase 
inhibitors)
N
Y
While continuous use of tricyclic antidepressants 
(TCAs) is not prohibited, given the target 
population (patients at imminent risk for suicide) 
and the known risk of lethality in TCA overdose, 
caution should be used if they are prescribed.
Episodic use (PRN) of trazodone is permitted but 
should not be used within 8 hours prior to the start 
of each intranasal study drug administration.
Antidepressants: 
Monoamine oxidase 
inhibitors
N
N
Prohibited within the past 2 weeks prior to 
intranasal study drug administration on Day 1 and 
are not permitted throughout the study.
Antipsychotics
Y (for sleep 
only)
Y
Use of antipsychotics (except clozapine) for 
treatment of depression is not excluded. It would 
be excluded if being used for psychotic symptoms.
Episodic use (PRN) of antipsychotics (except 
clozapine) for sleep is permitted but should not be 
used within 8 hours prior to the start of each 
intranasal study drug administration.
Benzodiazepines (at 
dosages equal to or less 
than the equivalent of 6 
mg/day lorazepam)
Y
Y
Prohibited within 8 hours prior to the start of each 
intranasal study drug administration. Additionally, 
no benzodiazepines should be used within 4 hours 
after the first intranasal study administration on 
Day 1 and within 8 hours of Day 2 assessments.
Chloral hydrate
N
N
Clonidine
Y
Y
Prohibited within 8 hours prior to the start of each 
intranasal study drug administration.
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Drug Class
Episodic Use
(PRN)
Continuous 
Use
Comments
Corticosteriods 
Y
N
Inhaled, intranasal, topical, and ophthalmic 
steroids are not prohibited.
Intermittent IM/IV corticosteroids are permitted 
(chronic use prohibited). Episodic or continuous
oral use can be discussed on a case-by-case basis 
with sponsor’s medical monitor.
Cough/Cold/Allergy 
preparations (except those 
containing 
dextromethorphan)
Y
Y
Intranasally-administered decongestants 
(vasoconstrictors) should not be used from 1 hour 
prior to each intranasal study medication 
administration. 
Pseudoephedrine- containing products should not 
be used within 12 hours prior to an intranasal 
treatment session.
Dextromethorphan
N
N
DHEA
Y
Y
Diphenhydramine
Y
N
PRN use is permitted, but should not be used 
within 8 hours prior to the start of each intranasal 
study drug administration.
Hypnotics 
(Non-benzodiazepine 
only)
Y
Y
Do not use within 8 hours prior to the start of each 
intranasal study drug administration.
Ketanserin
N
N
Lithium
N
Y
Patients with bipolar disorder (ie, lithium use for 
bipolar disorder) are excluded. Lithium use for 
another indication (eg, augmentation treatment for 
treatment-resistant depression) is permitted.
Methyldopa
N
N
Metyrosine
N
N
Opioids
Y
Y
Prescription opioid medication(s) can be 
continued, per clinician’s judgment
Non-vitamin K antagonist 
oral anticoagulation 
agents (eg, dabigatran, 
rivaroxaban, apixaban)
N
N
Psychostimulants 
(eg, amphetamines, 
methylphenidate, and 
modafinil, armodafinil)
N
Y
The use of amphetamines (including prescribed 
amphetamines) can be continued but must not be 
taken within 12 hours prior to the intranasal 
treatment session or for 2 hours after the intranasal 
treatment session. 
Reserpine
N
N
Scopolamine
N
N
St. John’s Wort
N
N
Thyroid hormone 
supplement
N
Y
Subjects needing supplements must be on a stable 
thyroid supplement dose for at least 4 weeks prior 
to Day 1 of the double-blind treatment phase.
Warfarin
N
N
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; DHEA, dehydroepiandrosterone ; IM, 
intramuscular; IV, intravenous; PRN, episodic use; TCA, tricyclic antidepressant 
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Attachment 2: Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease related) or background regimen.
For the purposes of this study the following events will be considered anticipated events37 for esketamine 
and major depressive disorder (MDD) (based on DSM-5): 

Suicidal thinking, ideation, and behavior

Sleep changes, difficulty sleeping, reduced sleep, abnormal sleep, tiredness, fatigue, and reduced 
energy

Difficulty in sexual desire, performance or satisfaction

Reduced appetite and weight changes (loss or increase)

Activation or hypomania/ mania

Irritability, anger, and impulsive behavior

Agitation, tension, panic attacks, and phobia
Reporting of Anticipated Events
All adverse events will be recorded in the eCRF regardless of whether considered to be anticipated events 
and will be reported to the sponsor as described in Section 12.3.1, All Adverse Events. Any anticipated 
event that meets serious adverse event criteria will be reported to the sponsor as described in 
Section 12.3.2, Serious Adverse Events. These anticipated events are exempt from expedited reporting as 
individual single cases to Health Authorities. However if based on an aggregate review, it is determined 
that an anticipated event is possibly related to study drug, the sponsor will report these events in an 
expedited manner.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of pre-specified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).
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Status: Approved, Date: 31 January 2018
INVESTIGATOR AGREEMENT
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SAP_001.pdf: 
1
Approved, Date: 3 May 2019
Janssen Research & Development 
Statistical Analysis Plan
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
Protocol 54135419SUI3002; Phase 3
JNJ54135419 (esketamine)
Status:
Approved
Date:
3 May 2019
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-ERI-183077645, 2.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 5
LIST OF IN-TEXT FIGURES ........................................................................................................................ 5
AMENDMENT HISTORY.............................................................................................................................. 6
ABBREVIATIONS ........................................................................................................................................ 7
1.
INTRODUCTION.................................................................................................................................. 8
1.1.
Trial Objectives ................................................................................................................................ 8
1.2.
Trial Design .................................................................................................................................... 10
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 11
1.4.
Sample Size Justification ............................................................................................................... 12
1.5.
Randomization and Blinding .......................................................................................................... 12
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 13
2.1.
Pooling Algorithm for Analysis Centers.......................................................................................... 13
2.2.
Analysis Phases............................................................................................................................. 13
2.2.1.
Analysis Phase Start and End Dates.......................................................................................... 13
2.2.2.
Study Reference Start and End Dates ....................................................................................... 14
2.2.3.
Study Day and Relative Day....................................................................................................... 14
2.3.
Baseline and End Point.................................................................................................................. 14
2.4.
Visit Windows................................................................................................................................. 14
2.5.
Analysis Sets.................................................................................................................................. 19
2.5.1.
All Randomized Analysis Set...................................................................................................... 19
2.5.2.
Full Efficacy Analysis Set............................................................................................................ 19
2.5.3.
Safety Analysis Set..................................................................................................................... 19
2.5.4.
Follow-up Analysis Set ............................................................................................................... 19
2.6.
Definition of Subgroups.................................................................................................................. 19
2.7.
Incomplete/Missing Dates for Adverse Events .............................................................................. 20
2.8.
Imputation Rules for Missing AE Time of Onset/Resolution.......................................................... 21
3.
DATA MONITORING COMMITTEE REVIEW................................................................................... 21
3.1.
Independent Data Monitoring Committee ...................................................................................... 21
4.
SUBJECT INFORMATION................................................................................................................ 21
4.1.
Demographics and Baseline Characteristics ................................................................................. 21
4.2.
Disposition Information................................................................................................................... 22
4.3.
Extent of Exposure......................................................................................................................... 23
4.4.
Protocol Deviations ........................................................................................................................ 23
4.5.
Prior and Concomitant Medications ............................................................................................... 23
5.
EFFICACY ......................................................................................................................................... 23
5.1.
Analysis Specifications................................................................................................................... 25
5.1.1.
Level of Significance................................................................................................................... 25
5.1.2.
Data Handling Rules................................................................................................................... 25
5.1.3.
Imputation Methods for Missing Items........................................................................................ 26
5.1.4.
Change from Baseline ................................................................................................................ 26
5.2.
Primary Efficacy Endpoint.............................................................................................................. 26
5.2.1.
Definition..................................................................................................................................... 26
5.2.2.
Primary Estimand ....................................................................................................................... 26
5.2.3.
Analysis Methods........................................................................................................................ 27
5.3.
Key Secondary Endpoint................................................................................................................ 29
5.3.1.
Definition..................................................................................................................................... 29
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5.3.2.
Analysis Methods........................................................................................................................ 29
5.4.
Other Secondary and Exploratory Variables.................................................................................. 32
5.4.1.
Remission of MDD...................................................................................................................... 32
5.4.1.1.
Definition.................................................................................................................................. 32
5.4.1.2.
Analysis Methods .................................................................................................................... 33
5.4.2.
Responder .................................................................................................................................. 33
5.4.2.1.
Definition.................................................................................................................................. 33
5.4.2.2.
Analysis Methods .................................................................................................................... 33
5.4.3.
Resolution of Suicidality.............................................................................................................. 33
5.4.3.1.
Definition.................................................................................................................................. 33
5.4.3.2.
Analysis Methods .................................................................................................................... 33
5.4.4.
CGI-SR-I ..................................................................................................................................... 33
5.4.4.1.
Definition.................................................................................................................................. 33
5.4.4.2.
Analysis Methods .................................................................................................................... 34
5.4.5.
BHS............................................................................................................................................. 34
5.4.5.1.
Definition.................................................................................................................................. 34
5.4.5.2.
Analysis Methods .................................................................................................................... 34
5.4.6.
EuroQol Group; 5 Dimension; 5 Level (EQ-5D-5L) .................................................................... 35
5.4.6.1.
Definition.................................................................................................................................. 35
5.4.6.2.
Analysis Methods .................................................................................................................... 35
5.4.7.
QLDS .......................................................................................................................................... 36
5.4.7.1.
Definition.................................................................................................................................. 36
5.4.7.2.
Analysis Methods .................................................................................................................... 36
5.4.8.
TSQM-9 ...................................................................................................................................... 36
5.4.8.1.
Definition.................................................................................................................................. 36
5.4.8.2.
Analysis Methods .................................................................................................................... 36
5.4.9.
SIBAT – Module 2 (My Risk/Protective Factors), Module 3 (My Current Thinking), 
Module 5 (My Risk) Questions 1,2, 3, and 4, Module 7 (Global Clinical Impression) 
FoST, CGI-SR-LT, and Module 8 (Clinical Judgment of Optimal Suicide Management) .......... 37
5.4.9.1.
Definition.................................................................................................................................. 37
5.4.9.2.
Analysis Methods .................................................................................................................... 37
6.
SAFETY............................................................................................................................................. 38
6.1.
Adverse Events .............................................................................................................................. 38
6.2.
Clinical Laboratory Tests................................................................................................................ 40
6.3.
Vital Signs, Weight, and BMI ......................................................................................................... 40
6.4.
Nasal Examination ......................................................................................................................... 41
6.5.
Electrocardiogram.......................................................................................................................... 41
6.6.
Other Safety Parameters ............................................................................................................... 43
6.6.1.
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) .......................................... 43
6.6.2.
Clinician Administered Dissociative States Scale (CADSS)....................................................... 43
6.6.3.
Columbia Classification Algorithm for Suicide Assessment (C-CASA)...................................... 44
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 45
8.
BIOMARKER/PHARMACOGENOMIC ANALYSES......................................................................... 45
9.
HEALTH ECONOMICS ..................................................................................................................... 46
9.1.
Healthcare Resource Use Questionnaire (HRUQ) ........................................................................ 46
10.
RELATIONSHIP BETWEEN CGI-SS-R AND OTHER RELEVANT CLINICAL ENDPOINTS......... 46
REFERENCES............................................................................................................................................ 47
ATTACHMENTS......................................................................................................................................... 48
Attachment 1:
Criteria of Markedly Abnormal Laboratory Values ..................................................... 48
Attachment 2:
Beck Hopelessness Scale Scoring............................................................................. 49
Attachment 3:
SIBAT Module 2 and Module 3 Scoring ..................................................................... 50
Attachment 4:
SIBAT Mapping to the C-CASA 2012 Plus................................................................. 53
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Attachment 5:
Bayesian Estimation of Treatment Effect in Ordinal Rating Scale Outcome: 
An Application to Clinical Global Impression Scoring ................................................ 59
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LIST OF IN-TEXT TABLES
Table 1:
Analysis Visits ........................................................................................................................... 16
Table 2:
Demographic Variables and Baseline Characteristics.............................................................. 22
Table 3:
Psychiatric History at Baseline Variables ................................................................................. 22
Table 4:
Efficacy Variables ..................................................................................................................... 24
Table 5:
Treatment-Emergent Abnormality Categories for Vital Signs................................................... 41
Table 6:
Limits for HR, PR, QRS and QT Interval Abnormality .............................................................. 42
Table 7:
Criteria for Abnormal QTc Values and Changes From Baseline.............................................. 42
LIST OF IN-TEXT FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 11
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AMENDMENT HISTORY
The SAP, originally approved on 4 April 2019 has been revised. The following is a list of changes made 
to the SAP, along with the rational for each change:
1) Section 4.1 Demographics and Baseline Characteristics (Table 3): changed variable name from 
“Baseline SIBAT: Patient Reported Global Assessment of Suicide Risk” to “Baseline SIBAT: Patient 
Reported Frequency of Suicidal Thinking”
2) Section 5.2.3 Analysis Methods Baseline Observation Carried Forward (BOCF) Imputation: To assess 
the sensitivity of the results of the ANCOVA (LOCF) model for the primary efficacy endpoint, a BOCF 
imputation will be applied. The change from Baseline (Day 1, predose) to 24 hours post first dose (Day 2) 
in MADRS total score, will be analyzed using an ANCOVA (BOCF) model, with factors for treatment 
(placebo or esketamine 84 mg), analysis center, standard of care antidepressant treatment as randomized 
(antidepressant monotherapy or antidepressant plus augmentation therapy), and baseline MADRS total 
score as a continuous covariate. The treatment effects will be estimated using least square means. A point 
estimate and 95% confidence interval for the treatment difference.
3) Section 5.3.2 Analysis Methods (BOCF): To assess the sensitivity of the results of models for the key 
secondary endpoint (change from baseline for CGI-SS-R at 24 hours post first dose), a BOCF imputation 
will be applied. The treatment difference will be estimated using the Hodges-Lehmann estimate with 
BOCF data. The Hodges-Lehmann estimate and the corresponding 95% CI for the treatment difference 
will be provided. The treatment difference will also be estimated by least square means based on an 
ANCOVA (BOCF) model on the actual change with factors for treatment, analysis center, standard of 
care antidepressant treatment as randomized (ie, antidepressant monotherapy or an antidepressant plus 
augmentation therapy) and baseline CGI-SS-R (unranked) as a covariate. A point estimate and 95% 
confidence interval for the treatment difference will be provided. In addition, item response modeling will 
be used on BOCF data to estimate treatment difference. Posterior median treatment effect estimate and 
95% credible interval of the odds ratio will be provided.
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ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ASA
American Society of Anesthesiologists
AST
aspartate aminotransferase
BHS
Beck Hopelessness Scale
BMI
BOCF
body mass index
baseline observation carried forward
BP
Blood Pressure
CADSS
Clinician Administered Dissociative States Scale
C-CASA
Columbia Classification Algorithm for Suicide Assessment
CGI-SR-I
Clinical Global Impression – Imminent Suicide Risk
CGI-SR-LT
Clinical Global Impression – Long-term Suicide Risk
CGI
Clinical Global Impression 
CGI-SS-R
Clinical Global Impression – Severity of Suicidality - Revised
CI
confidence interval
DB
Double-blind
ECG
electrocardiogram
ER
Emergency Room
EQ-5D-5L
EuroQol Group; 5 dimension; 5 level
EQ-VAS
EuroQol Group: visual analogue scale
FDA
Food and Drug Administration
FoST
frequency of suicidal thinking
F/U
Follow-up
GCP
Good Clinical Practice
HPA
hypothalamic-pituitary-adrenal
HR
heart rate
HRUQ
Healthcare Resource Use Questionnaire
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IWRS
interactive web response system
LOCF
last observation carried forward
MADRS
Montgomery Asberg Depression Rating Scale
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MINI
Mini International Psychiatric Interview
MMRM
Mixed-effects model using repeated measures
MOAA/S
Modified Observer’s Assessment of Alertness/Sedation
NDE
natural direct effect
NIE
natural indirect effect 
PR
pulse rate
QLDS
Quality of Life in Depression Scale
QTc
corrected QT
QTcB
QT corrected according to Bazett's formula
QTcF
QT corrected according to Fridericia's formula
RC
Remote contact
RR
respiratory rate
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SE
standard error
SIBAT
Suicide Ideation and Behavior Assessment Tool
TEAE
treatment-emergent adverse event
TEMA
treatment-emergent markedly abnormal
TSQM-9
treatment satisfaction questionnaire for medication
ULN
upper limit of normal
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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analyses for Study 54135419SUI3002.
1.1.
Trial Objectives
Primary Objective
The primary objective is to evaluate the efficacy of intranasal esketamine 84 mg compared with 
intranasal placebo in addition to comprehensive standard of care in reducing the symptoms of 
MDD, including suicidal ideation, in subjects 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.
Key Secondary Objective
The key secondary objective is to assess the efficacy of intranasal esketamine compared with 
intranasal placebo in reducing severity of suicidality as measured by the clinical global 
impression of severity of suicidality revised version (CGI-SS-R) at 24 hours post first dose.
Other Secondary Objectives
The other secondary objectives are:

To evaluate the efficacy of intranasal esketamine compared with intranasal placebo in 
remission of MDD (defined as MADRS total score ≤12) at 4 hours and 24 hours post first 
dose, and through the end of the double-blind treatment phase (Day 25).

To evaluate the efficacy of intranasal esketamine compared with intranasal placebo in 
reducing symptoms of MDD as assessed by the MADRS total score at 4 hours post first 
dose on Day 1, and through the end of the double-blind treatment phase (Day 25).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in 
reducing severity of suicidality as measured by the CGI-SS-R at 4 hours post first dose on 
Day 1, and through the end of the double-blind treatment phase (Day 25).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in 
achieving resolution of suicidality as measured by the score of 0 (normal, not at all suicidal) 
or 1 (questionably suicidal) of the CGI-SS-R at 4 hours and 24 hours post first dose, and 
through the end of the double-blind treatment phase (Day 25).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in 
reducing imminent suicide risk as measured by the clinical global impression of imminent 
suicide risk (CGI-SR-I) at 4 hours and 24 hours post first dose, and through the end of the 
double-blind treatment phase (Day 25).

To assess the impact of intranasal esketamine compared with intranasal placebo on the 
following patient-relevant concepts through the end of the double-blind treatment phase 
(Day 25)

Hopelessness as measured by Beck Hopelessness Scale (BHS)
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
Health related quality of life and health status, using the European Quality of Life 
(EuroQol) Group, 5-Dimension, 5-Level (EQ-5D-5L)

Health related quality of life using the Quality of Life in Depression Scale (QLDS)

Treatment satisfaction using the Treatment Satisfaction Questionnaire for Medication 
(TSQM-9)

Patient-reported suicidality using the Suicidal Ideation and Behaviors Assessment Tool 
(SIBAT), including Module 5 My Risk, Question 3 (patient-reported frequency of 
suicidal thinking)

To assess the safety and tolerability of intranasal esketamine during the double-blind 
treatment phase and the follow-up phase, with special attention given to the following 
assessments:

Potential effects on suicidal ideation and behavior using the SIBAT

On dosing days:
o
Effect on heart rate, blood pressure, respiratory rate, and blood oxygen saturation 
o
Effect on alertness and sedation using the Modified Observer's Assessment of 
Alertness/Sedation (MOAA/S) scale
o
Treatment-emergent dissociative symptoms using the Clinician Administered 
Dissociative States Scale (CADSS)

To assess the pharmacokinetics of intranasal esketamine.
Exploratory Objectives
The exploratory objectives are:

To evaluate the efficacy of intranasal esketamine compared with intranasal placebo in 
reducing symptoms of MDD as assessed by the MADRS total score and remission rate 
through the end of the follow-up phase (Day 90).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in 
reducing severity of suicidality as measured by the CGI-SS-R and resolution of suicidality
through the end of the follow-up phase (Day 90).

To assess the efficacy of intranasal esketamine compared with intranasal placebo in 
reducing imminent suicide risk as measured by the CGI-SR-I through the end of the follow-
up phase (Day 90).

To assess the impact of intranasal esketamine compared with intranasal placebo through the 
end of the follow-up phase (Day 90) on the following patient-relevant concepts:

Hopelessness (BHS)

Health related quality of life and health status (EQ-5D-5L)

Health related quality of life (QLDS)

Subject treatment satisfaction (TSQM-9)
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
To assess the effect of intranasal esketamine compared with intranasal placebo on the 
SIBAT Module 3 My Current Thinking through the double-blind treatment (Day 25) and 
follow-up (Day 90) phases.

To assess medical resource utilization as measured by the Healthcare Resource Use 
Questionnaire (HRUQ) of intranasal esketamine compared with intranasal placebo through 
the end of the follow-up phase (Day 90), including 30-day and 60-day readmission, and 
emergency room visits related to MDD and suicidality.

To evaluate whether pretreatment concentrations or post-treatment change in MDD-related 
biomarkers (eg, hypothalamic-pituitary-adrenal [HPA] axis function, immune system 
activation, growth factors, metabolic markers) correlate with clinical response or non-
response as measured by the MADRS, following intranasal administration of esketamine.
1.2.
Trial Design
This is a randomized, double-blind, placebo-controlled, multicenter study. A target of 224 male 
and female subjects, 18 to 64 years of age, with MDD presenting to an emergency room (ER) or 
other permitted setting and assessed to be at imminent risk for suicide will be enrolled in this 
study.
The study will consist of a screening evaluation performed within 48 hours prior to the Day 1 
intranasal dose (if possible, screening should occur within 24 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. 
On Day 1 of the double-blind treatment phase, approximately 224 subjects will be randomized in 
a 1:1 ratio to 1 of 2 treatments: intranasal esketamine 84 mg (n = 112) or intranasal placebo 
(n = 112), administered two times per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25). 
Randomization will be stratified by study center and by the physician’s assessment of the 
subject’s need of standard of care antidepressant treatment (ie, antidepressant monotherapy or an 
antidepressant plus augmentation therapy); the standard of care will be determined prior to 
randomization on Day 1. 
The first dose of study medication will be administered in the ER or other permitted setting, 
including the inpatient psychiatric unit. All subjects will be treated in the context of 
comprehensive standard clinical care, including hospitalization and the initiation or optimization 
of antidepressant treatment, which will be determined by the treating physician(s). The standard 
of care antidepressant treatment will be initiated or optimized for all subjects on Day 1. 
After the first dose (ie, starting with the Day 4 dose or later), a one-time dose reduction to 
intranasal esketamine 56 mg or intranasal placebo is allowed if a subject is unable to tolerate the 
intranasal esketamine 84 mg or placebo dose assigned at randomization. No further dose 
adjustment is allowed during the double-blind treatment phase.
Dose titration/adjustments of newly initiated or optimized standard of care antidepressant 
treatment should occur during the first 2 weeks of double-blind treatment (ie, by Day 15), with 
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doses remaining stable thereafter through the end of the double-blind phase (Day 25). During the 
follow-up phase, the antidepressant treatment will be managed based on clinician’s judgment.
Subjects will remain in the inpatient psychiatry unit for a recommended duration of 5 days, with 
shorter or longer hospitalizations permitted if clinically warranted per local standard of care. 
Discharge before 5 days must be discussed and approved by the sponsor’s medical monitor. 
Following discharge from the inpatient psychiatric unit, subsequent visits for the double-blind 
treatment phase will be conducted twice-weekly at an outpatient psychiatric facility through 
Day 25. During the follow-up phase, subjects will be monitored twice weekly for the first two 
weeks (Days 28, 32, 35, and 39) after study drug treatment. Subjects will then be followed up 
weekly for the next two weeks (Days 46 and 53) and every two weeks for the rest of the follow-
up period (Days 67 and 90).
A diagram of the study design is provided in Figure 1.
Figure 1:
Schematic Overview of the Study
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis is that, in addition to comprehensive standard of care, intranasal 
esketamine 84 mg is superior to intranasal placebo in rapidly reducing the symptoms of MDD, 
including suicidal ideation, as assessed by the change from baseline in the MADRS total score at 
24 hours post first dose in subjects who are assessed to be at imminent risk for suicide.
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1.4.
Sample Size Justification
The maximum sample size for this study was calculated assuming an effect size of 0.45 for the 
MADRS total score at 24 hours post first dose (Day 2), a two-sided significance level of 0.050, 
and a drop-out rate at 24 hours of 5%. Approximately 112 subjects will need to be randomized to 
each treatment group to achieve 90% power. The effect size used in this calculation was based 
on results of the ESKETINSUI2001 study where the effect size for the change from baseline to 
Day 2 was 0.65 (mean difference between treatment groups of -7.2 and a pooled SD of 11.02) for 
MADRS total score. Given that the ESKETINSUI2001 study was a Phase 2 study carried out in 
only one country, the maximum sample size for this Phase 3 study was determined using a 
smaller effect size of 0.45 to allow for greater variability that can be expected for a study 
conducted globally.
1.5.
Randomization and Blinding
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups.
Central randomization will be implemented in this study. Subjects will be randomly assigned 
to 1 of 2 treatment groups in a 1:1 ratio based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor. The randomization will be 
balanced by using randomly permuted blocks and will be stratified by study center and by the 
physician’s assessment of the subject’s need of standard of care antidepressant treatment (ie, 
antidepressant monotherapy or an antidepressant plus augmentation therapy); the standard of 
care will be determined prior to randomization on Day 1. This stratification is aimed at balancing 
treatment groups within the standard of care antidepressant treatment to be initiated or optimized 
on Day 1, as antidepressant monotherapy and antidepressant plus augmentation therapy may be 
differentially effective. The interactive web response system (IWRS) will assign a unique 
treatment code, which will dictate the treatment assignment and matching study drug kits for the 
subject. The requestor must use his or her own user identification and personal identification 
number when contacting the IWRS, and will then give the relevant subject details to uniquely 
identify the subject.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (eg, study drug plasma 
concentrations, treatment allocation) will be handled with special care to ensure that the integrity 
of the blind is maintained and the potential for bias is minimized. This can include making 
special provisions, such as segregating the data in question from view by the investigators, 
clinical team, or others as appropriate until the time of database lock and unblinding. To 
minimize the risk of unblinding the treatment assignment during the study, different raters will 
perform efficacy and safety assessments. Clinicians who perform MADRS and SIBAT will be 
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different than those who evaluate vital signs, MOAA/S, CADSS, and adverse events. Raters for 
the MADRS and SIBAT assessment will not be allowed to access or to review subject safety 
records; therefore, they will not provide clinical care for subjects. Clinical care of subjects will 
be performed by clinicians at the study site who are not MADRS and CGI-SS-R/SIBAT raters. 
Adherence to this procedure will be monitored and enforced during the study.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed.
To maintain the blinding of intranasal study medication, the esketamine and placebo intranasal 
devices will be indistinguishable.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Pooling Algorithm for Analysis Centers
Pooling may be conducted only for randomized subjects only if a sufficient number of subjects 
are not randomized to a site. If necessary, within each region (North America, Europe, South 
America) small study centers with fewer than 4 randomized subjects will be combined for the 
purpose of analysis. These small centers will be ordered according to the total number of subjects 
and then sequentially using the center number. The pooling will be carried out sequentially 
beginning with the smallest center. The size of any pooled analysis center should be as large as 
possible and not be larger than the size of the largest center in the region. If the number of small 
centers is large, and one pooled analysis center cannot include all small centers, then the second 
(or more) pooled analysis center(s) will be formed after the first one is filled with as many small 
centers as possible. Pooled sites as described are called analysis centers and will be used in the 
analyses as center effect.
2.2.
Analysis Phases
There are 2 analysis phases defined in this study: Double-blind and Follow-up (post treatment). 
Each analysis phase has its own analysis reference start date.
2.2.1.
Analysis Phase Start and End Dates
Double-Blind Phase
The DB start date is the date of the first dose of double-blind medication. The DB end date is the
maximum of the date of the last visit (excluding remote contact visit) in the double-blind phase 
and the date of early treatment termination. For randomized subjects who did not receive any
medication in the double-blind phase, both the DB start date and end date are missing.
Follow-up Phase
Start and end dates for the F/U phase are only defined for subjects who completed the DB phase 
and continued into the F/U phase (including a visit in the F/U phase or an adverse event in the 
F/U phase). The analysis reference start date of the follow-up analysis phase is the day after the
reference end date for the double-blind analysis phase. The analysis reference end date is the date 
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of the last visit (excluding remote contact visit) in the follow-up phase for subjects who 
discontinued in F/U phase but had remote contact on Day 90. Otherwise, it is the maximum of 
the last follow-up visit date and the end of trial date.
2.2.2.
Study Reference Start and End Dates
The overall reference start date for the study is defined as the date of the first dose of DB 
medication (the date is missing for screened subjects who did not receive a dose of DB 
medication). The overall reference end date for the study is the end of trial date including the last 
follow-up visit.
2.2.3.
Study Day and Relative Day
Study day is calculated relative to the overall reference start date for the study. Relative day is 
calculated relative to the analysis reference start date of the analysis phase in which the data are 
captured.
Study day for an event on or after the start of the study is calculated as:
Event date-study start date+1.
Study day for an event prior to the start of the study is calculated as:
Event date-study start date
Relative day for an event on or after a reference start date is calculated as:
Event date - reference start date + 1.
Relative day for an event prior to a reference start date is calculated as:
Event date - reference start date.
2.3.
Baseline and End Point
The double-blind baseline value will be the last observation before receiving the first dose of the 
study drug in the double-blind phase.
The double-blind end point value will be the final post baseline value assessed during the 
double-blind phase.
2.4.
Visit Windows
As subjects do not always adhere to the protocol visit schedule (including permitted visit 
windows), the following rules are applied to assign actual visits to protocol visits. Listed below 
are the visit windows for analysis and the target days for each visit. The reference day is Study 
Day 1 (which is the first day that any study drug was taken in the double-blind phase).
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If a subject has 2 or more scheduled or unscheduled visits in one visit window, the visit closest to 
the target day will be used as the protocol visit for that visit window. If 2 actual visits are 
equidistant from the target day within a visit window, the later visit is used. 
All assignments will be made in chronological order. Once a visit is assigned to a visit window, 
it will no longer be used for a later time point except for the end point. Listed below are the visit 
windows and the target days (if applicable) for each visit defined in the protocol for all phases 
(Table 1).
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Table 1:
Analysis Visits
Parameter
Analysis
Phase
Scheduled Day
Time Interval
(label on output)
Time Interval
(Day)
Target
Time Point
(Relative 
Day)
MADRS
DB
1
Baseline (DB)
≤1; pre-dose
1
1
Day 1 (DB): 4H
1
1
2
Day 2 (DB)
2
2
4
Day 4 (DB)
3 - 6
4
8
Day 8 (DB)
7 - 9
8
11
Day 11 (DB)
10 - 12
11
15
Day 15 (DB)
13 - 16
15
18
Day 18 (DB)
17 - 19
18
22
Day 22 (DB)
20 - 23
22
25
Day 25 (DB): Predose
24 - end of DB
25
25
Day 25 (DB): 4H
24 - end of DB
25
DB final visit 
End Point (DB)
Day 1 (DB): 4H - end of DB
Day 25 RCa
Day 25 (RC)
use Day 25 RC visit
25
F/U
28
Day 28 (F/U)
Day 1 (F/U) - 4
3
32
Day 32 (F/U)
5 - 10
7
39
Day 39 (F/U)
11 - 17
14
46
Day 46 (F/U)
18 - 24
21
53
Day 53 (F/U)
25 - 34
28
67
Day 67 (F/U)
35 - 53
42
90
Day 90 (F/U)
54 - end of F/U
65
F/U final visit
End Point (F/U)
Day 1 (F/U) - end of F/U
Day 90 RCa
Day 90 (RC)
use Day 90 RC visit
65
SIBAT Module 1
DB
1
Baseline (DB)
≤1; pre-dose
1
SIBAT (Modules 3, 
5, 6 and 7)
DB
1
Baseline (DB)
≤1; pre-dose
1
1
Day 1 (DB): 4H
1
1
2
Day 2 (DB)
2
2
4
Day 4 (DB)
3 - 6
4
8
Day 8 (DB)
7 - 9
8
11
Day 11 (DB)
10 - 12
11
15
Day 15 (DB)
13 - 16
15
18
Day 18 (DB)
17 - 19
18
22
Day 22 (DB)
20 - 23
22
25
Day 25 (DB)
24 - end of DB
25
DB final visit 
End Point (DB)
Day 1 (DB): 4H - end of DB
F/U
32
Day 32 (F/U)
Day 1 (F/U) - 10
7
39
Day 39 (F/U)
11 - 17
14
46
Day 46 (F/U)
18 - 24
21
53
Day 53 (F/U)
25 - 34
28
67
Day 67 (F/U)
35 - 53
42
90
Day 90 (F/U)
54 - end of F/U
65
F/U final visit
End Point (F/U)
Day 1 (F/U) - end of F/U
SIBAT Module 4
DB
8
Day 8 (DB)
1 - 9
8
11
Day 11 (DB)
10 - 12
11
15
Day 15 (DB)
13 - 16
15
18
Day 18 (DB)
17 - 19
18
22
Day 22 (DB)
20 - 23
22
25
Day 25 (DB)
24 - end of DB
25
DB final visit
End Point (DB)
Day 8 (DB) - end of DB
F/U
32
Day 32 (F/U)
Day 1 (F/U) - 10
7
39
Day 39 (F/U)
11 - 17
14
46
Day 46 (F/U)
18 - 24
21
53
Day 53 (F/U)
25 - 34
28
67
Day 67 (F/U)
35 - 53
42
90
Day 90 (F/U)
54 - end of F/U
65
F/U final visit
End Point (F/U)
Day 1 (F/U) - end of F/U
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Table 1:
Analysis Visits
Parameter
Analysis
Phase
Scheduled Day
Time Interval
(label on output)
Time Interval
(Day)
Target
Time Point
(Relative 
Day)
SIBAT (Module 8)
DB
1
Baseline (DB)
≤1; pre-dose
1
2
Day 2 (DB)
2
2
8
Day 8 (DB)
3 - 10
8
15
Day 15 (DB)
11 - 19
15
25
Day 25 (DB)
20 - end of DB
25
DB final visit 
End Point (DB)
2 - end of DB
F/U
32
Day 32 (F/U)
Day 1 (F/U) - 13
7
46
Day 46 (F/U)
14 - 29
21
67
Day 67 (F/U)
30 - 53
42
90
Day 90 (F/U)
54 - end of F/U
65
F/U final visit
End Point (F/U)
Day 1 (F/U) - end of F/U
SIBAT (Module 2)
DB
1
Baseline (DB)
≤1; pre-dose
1
8
Day 8 (DB)
2 - 10
8
15
Day 15 (DB)
11 - 19
15
25
Day 25 (DB)
20 - end of DB
25
DB final visit 
End Point (DB)
2 - end of DB
F/U
90
Day 90 (F/U)
Day 1 (F/U) - end of F/U
65
BHS
DB
1
Baseline (DB)
≤1
1
8
Day 8 (DB)
2 - 16
8
25
Day 25 (DB)
17 - end of DB
25
DB final visit 
End Point (DB)
2 - end of DB
F/U
46
Day 46 (F/U)
Day 1 (F/U) - 42
21
90
Day 90 (F/U)
43 - end of F/U
65
F/U final visit
End Point (F/U)
Day 1 (F/U) - end of F/U
QLDS/
EQ-5D-5L
DB
1
Baseline (DB)
1
1
2
Day 2 (DB)
2
2
11
Day 11 (DB)
3 - 17
11
25
Day 25 (DB)
18 - end of DB
25
DB final visit 
End Point (DB)
2 - end of DB
F/U
46
Day 46 (F/U)
Day 1 (F/U) - 42
21
90
Day 90 (F/U)
43 - end of F/U
65
F/U final visit
End Point (F/U)
Day 1 (F/U) - end of F/U
TSQM-9
DB
11
Day 11 (DB)
1 - 17
11
25
Day 25 (DB)
18 - end of DB
25
DB final visit 
End Point (DB)
1 - end of DB
F/U
46
Day 46 (F/U)
Day 1 (F/U) - 42
21
90
Day 90 (F/U)
43 - end of F/U
65
F/U final visit
End Point (F/U)
Day 1 (F/U) - end of F/U
Nasal examination
DB
Screening
Baseline (DB)
≤1
≤1
25
Day 25 (DB)
2 - end of DB
25
DB final visit 
End Point (DB)
2 - end of DB
Vital signs
DB
Screening
Screening
≤1; pre-dose
≤1
1
Baseline (DB)
≤1; pre-dose
1
1
Day 1 (DB): Predose
Day 1 (DB): 40M
Day 1 (DB): 1H
Day 1 (DB): 1.5H
1
1
4
Day 4 (DB): Predose
Day 4 (DB): 40M
Day 4 (DB): 1H
Day 4 (DB): 1.5H
2 - 5
4
8
Day 8 (DB): Predose
Day 8 (DB): 40M
Day 8 (DB): 1H
Day 8 (DB): 1.5H
6 - 9
8
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Table 1:
Analysis Visits
Parameter
Analysis
Phase
Scheduled Day
Time Interval
(label on output)
Time Interval
(Day)
Target
Time Point
(Relative 
Day)
11
Day 11 (DB): Predose
Day 11 (DB): 40M
Day 11 (DB): 1H
Day 11 (DB): 1.5H
10 - 12
11
15
Day 15 (DB): Predose
Day 15 (DB): 40M
Day 15 (DB): 1H
Day 15 (DB): 1.5H
13 - 16
15
18
Day 18 (DB): Predose
Day 18 (DB): 40M
Day 18 (DB): 1H
Day 18 (DB): 1.5H
17 - 19
18
22
Day 22 (DB): Predose
Day 22 (DB): 40M
Day 22 (DB): 1H
Day 22 (DB): 1.5H
20 - 23
22
25
Day 25 (DB): Predose
Day 25 (DB): 40M
Day 25 (DB): 1H
Day 25 (DB): 1.5H
24 - end of DB
25
DB final visit 
End Point (DB)
Day 1 (DB): 40M - end of 
DB
F/U
90
Day 90 (F/U)
Day 1 (F/U) - end of F/U
65
ECG
DB
Screening
Baseline (DB)
≤1; pre-dose
≤1
1
Day 1 (DB): 1H
1
1
8
Day 8 (DB): 1H
2 - 16
8
25
Day 25 (DB): 1H
17 - end of DB
25
Maximum (DB)
Maximum (DB)
Day 1 (DB): 1H - end of DB
DB final visit 
End Point (DB)
Day 1 (DB): 1H - end of DB
Pulse oximetryb
MOAA/Sc (predose 
and every 
15 minutes to 1.5H)
CADSS (predose, 
40M, 1.5H)
DB
1
Day 1
1
1
4
Day 4
2 - 5
4
8
Day 8
6 - 9
8
11
Day 11
10 - 12
11
15
Day 15
13 - 16
15
18
Day 18
17 - 19
18
22
Day 22
20 - 23
22
25
Day 25
24 - end of DB
25
Body weight
DB
Screening
Baseline (DB)
≤1
≤1
25
Day 25 (DB)
2 - end of DB
25
DB final visit 
End Point (DB)
2 - end of DB
F/U
90
Day 90 (F/U)
Day 1 (F/U) - end of F/U
65
Height
DB
Screening
Baseline (DB)
≤1
≤1
Hematology, 
Chemistry, 
Urinalysis
DB
Screening
Baseline (DB)
≤1
≤1
25
Day 25 (DB)
2 - end of DB
25
DB final visit 
End Point (DB)
2 - end of DB
a
Subjects who discontinue with reasons other than withdrawal of consent, lost to follow up, or death will be contacted 
remotely at 3 days after the last dose of intranasal study medication (if the date of the Early Termination visit is less than 
3 days after the last dose of intranasal study medication) and on Day 25 for MADRS assessment. Day 25 remote contact (RC) 
will only be used as part of sensitivity analysis for MADRS total score at Day 25
b
If oxygen saturation levels are <93% at any time during the 1.5 hour postdose interval, pulse oximetry will be recorded every 
5 minutes until levels return to ≥93% or until the subject is referred for appropriate medical care, if clinically indicated.
c
If the MOAA/S score is ≤3 at any time during the 1.5 hour postdose interval, the MOAA/S will be performed every 
5 minutes until a score of 4 is reached (at which point a frequency of every 15 minutes can be resumed until t=+1.5 hours 
post dose).
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2.5.
Analysis Sets
Subjects will be classified into the following analysis sets: all randomized, full, safety and 
follow-up.
For each analysis set described below subjects who received an incorrect treatment will be 
analyzed under the planned treatment.
2.5.1.
All Randomized Analysis Set
This analysis set will include all subjects who were randomized (i.e., subjects who reported a 
randomization date, or were assigned a randomization number) regardless of whether treatment 
was received. This analysis set will be used for summarizing the overall study 
completion/withdrawal information.
2.5.2.
Full Efficacy Analysis Set
The efficacy analyses of data in the double-blind phase will be based on the full efficacy analysis 
set. The full efficacy analysis set is defined as all randomized subjects who received at least 1 
dose of double-blind study medication and have both a baseline and a post-baseline evaluation 
for the MADRS total score or CGI-SS-R.
2.5.3.
Safety Analysis Set
Safety analyses for the double-blind phase will be performed on the Safety analysis set. It will 
include all randomized subjects who received at least 1 dose of study drug in the double-blind 
phase. 
Screen failures and randomized subjects who received no double-blind study medication will be 
excluded from the safety analysis set.
2.5.4.
Follow-up Analysis Set
The Follow-up analysis set is defined as all subjects who entered the follow-up phase or had 
provided adverse event data after the double-blind phase. This analysis set will be used for both 
efficacy and safety analyses.
2.6.
Definition of Subgroups
Analyses will be provided for the primary endpoint, change from baseline in MADRS total 
score, and the key secondary endpoint, change from baseline in CGI-SS-R using the following 
subgroups.

Sex

Race (White, Black, Other)

Age Group (18-34 years, 35-54 years, 55-64 years)

Region: North America (includes United States and Canada), Europe (includes Austria, 
Belgium, Czech Republic, France, Lithuania, Poland, Spain, Turkey), and South America
(includes Argentina and Brazil)
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
Country (Argentina, Austria, Belgium, Brazil, Canada, Czech Republic, France, Lithuania, 
Poland, Spain, Turkey, United States)

Baseline MADRS total score (≤/> median)

Standard of care antidepressant treatment as randomized (antidepressant monotherapy, or 
antidepressant plus augmentation therapy)

Baseline SIBAT: Prior Suicide Attempt (Yes, No) (Module 1: “I have made one or more 
attempts to end my life”)

Baseline Suicide attempt within the last month (Yes, No)
2.7.
Incomplete/Missing Dates for Adverse Events
Treatment-emergent adverse events (TEAEs) for the double-blind phase are those events with an 
onset date/time on or after the start of double-blind study medication and occurred on or before 
the end of the double-blind phase. Adverse events (AEs) for the follow-up phase are those events 
with an onset date on or after the start of the follow-up phase and occurred on or before the end 
of the follow-up phase. A conservative approach will be used to handle the missing dates for 
AEs.
Onset Date
If the onset date of an adverse event is missing day only, it will be set to:
i)
First day of the month that the AE occurred, if month/year of the onset of AE is
different than the month/year of DB start date
ii)
The day of DB start date, if the month/year of the onset of AE is the same as 
month/year of the DB start date and month/year of the AE resolution date is different
iii)
The day of DB start date or day of AE resolution date, whichever is earliest, if
month/year of the onset of AE and month/year of the DB start date and month/year of
the AE resolution date are the same.
If the onset date of an adverse event is missing both day and month, it will be set to the earliest 
of: 
i)
January 1 of the year of onset, as long as this date is after the DB start date.
ii)
DB start date, if this date is the same year that the AE occurred.
A completely missing onset date of an adverse event will be set to the DB start date.
Resolution Date
The missing day of resolution of an adverse event will be set to the last day of the month of
resolution.
If the resolution date of an adverse event is missing both day and month, it will be set to the
earlier of the date of withdrawal, study completion, or December 31 of the year.
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A completely missing resolution date of an adverse event that is not recorded as ongoing will be
set to the date of withdrawal or study completion.
2.8.
Imputation Rules for Missing AE Time of Onset/Resolution
If the time of onset is missing, it will be imputed as follows:
i)
00:00 if the date of onset is after DB start date
ii)
The time of intranasal medication start in the double-blind treatment phase, if the date 
is the same as DB start date.
If the time of resolution is missing, it will be set to 23:59.
If a missing time is associated with a partial or missing date, the date will be imputed first prior
to imputing the time.
3.
DATA MONITORING COMMITTEE REVIEW
3.1.
Independent Data Monitoring Committee
An external Independent Data Monitoring Committee (IDMC) will be established and will 
provide recommendations about stopping or continuing the study based on safety. The IDMC 
will monitor data on an ongoing basis to ensure the continuing safety of the subjects enrolled in 
this study. The committee will meet every 6 months to review safety data. After the reviews, the 
IDMC will make recommendations regarding the continuation of the study. The details of the 
safety analysis for the IDMC are provided in a separate IDMC SAP for Safety Monitoring. Roles 
and responsibilities for the IDMC are detailed a separate IDMC charter.
The IDMC will consist of at least one medical expert in the relevant therapeutic area and at least 
one statistician. The IDMC responsibilities, authorities, and procedures will be documented in its 
charter.
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Demographic and baseline characteristics (Table 2) and psychiatric history at baseline (Table 3) 
will be summarized by treatment group for the Safety and Full Efficacy analysis sets. Continuous
variables will be summarized using descriptive statistics (N, mean, standard deviation [SD], 
median, minimum, and maximum). Categorical variables will be summarized using a frequency 
distribution with the number and percentage of subjects in each category.
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Table 2:
Demographic Variables and Baseline Characteristics
Continuous Variables:

Age (years)

Baseline weight (kg)

Baseline height (cm)

Baseline BMI (kg/m2) calculated as Weight (kg)/[Height (m)]2
Categorical Variables:

Age (18-34 years, 35-54 years, 55-64 years)

Sex (male, female)

Racea (White, Black or African American, Asian, American Indian or Alaskan native, Native Hawaiian or 
other Pacific islander, other)

Ethnicity (Hispanic or Latino, not Hispanic or Latino)

Baseline BMI (underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, overweight 25-<30 kg/m2, obese ≥30 
kg/m2)

Standard of Care Antidepressant Treatment as Randomized (monotherapy, augmentation)

Standard of Care Antidepressant Treatment as Actually Received (monotherapy, augmentation, initial 
monotherapy followed by augmentation therapy)

Country
a If multiple race categories are indicated, then Race is recorded as “Multiple”.
Table 3:
Psychiatric History at Baseline Variables
Continuous Variables:

Baseline MADRS total score

Duration of current depressive episode (month): derived from the MADRS euthymic baseline

Baseline MADRS item 10 (suicide)

Baseline BHS total score

Last hospitalization discharge prior to screening ([month] in the subjects with hospitalization due to 
depression or suicidality in the past 12 months)a
Categorical Variables:

Baseline CGI-SS-R

Baseline CGI-SR-I

Baseline MINI (B3 and B10 Current Status): think about suicide (Y/N), frequency (occasionally, often, very 
often) and intensity (mild, moderate, severe); Intend to act on thoughts of killing yourself (Y/N)

Number of episodes of depression in life time: 1, 2 – 5, 6 – 10, >10

Hospitalization due to depression or suicidality in the past 12 months (Y/N)

Last hospitalization discharge prior to screening ([months] in subjects with hospitalization due to depression 
or suicidality in the past 12 months)a: 0 – 1, 2 – 3, 4 – 6, 7 – 12

Baseline SIBAT: Prior Suicide Attempt (Yes, No) (Module 1: “I have made one or more attempts to end my 
life”)

Baseline SIBAT: Patient Reported Frequency of Suicidal Thinking (Module 5, Question 3: “Which of the 
following ratings best describes your thinking about suicide right now”)

Baseline Suicide attempt within the last month (Y/N)

Baseline MINI: make a suicide attempt in your lifetime
a This is missing for subjects without hospitalization due to depression or suicidality in the past 12 months.
4.2.
Disposition Information
The distribution of the number of subjects who are randomized, receive double-blind treatment, 
and complete the double-blind phase will be presented by treatment group. In addition, the 
distribution of treatment termination reasons will be presented. These summaries will be 
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provided for the All Randomized and Safety analysis sets. A subject will be considered to have 
completed the double-blind phase if he or she has completed assessments through Day 25. 
The distribution of the number of subjects who completed the study, including the follow-up 
phase, will be presented by treatment group. The reasons for discontinuation will be summarized.
4.3.
Extent of Exposure
The total duration of the double-blind phase is defined as time between the first and the last day 
of study medication in the double-blind phase.
Descriptive statistics (N, mean, SD, median, and range) of total duration will be presented by 
treatment group for the Full and Safety analysis sets. A frequency distribution showing the 
number of days a subject was dosed during the double-blind phase will be provided. In addition, 
the number and percent of subjects who decreased their dose during the double-blind phase will 
be provided.
4.4.
Protocol Deviations
Deviations that occurred during the study will be tabulated for the All Randomized analysis set 
by treatment group. Major deviations will be tabulated as they are grouped prior to unblinding in 
the following categories: Entered but did not satisfy criteria; Received a disallowed concomitant 
treatment; Received wrong treatment or incorrect dose; Developed withdrawal criteria but not 
withdrawn; Other. More categories may be included depending on the nature of the protocol 
deviation.
4.5.
Prior and Concomitant Medications
The number and percent of subjects receiving prior antidepressant and antipsychotic medications 
will be summarized by treatment group for the Safety analysis set.
The number and percent of subjects who receive concomitant therapies will be summarized by 
treatment group using the generic term of the medication for the Safety analysis set and for the 
Follow-up analysis set. The use of benzodiazepines and lithium during the double-blind phase 
and the follow-up phase will be summarized separately. The standard of care antidepressant 
treatment during the double-blind phase and the follow-up phase will also be summarized. 
5.
EFFICACY
The efficacy variables for this study are listed in Table 4.
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Table 4:
Efficacy Variables
Efficacy Variable
Endpoint
MADRS

Change in MADRS total score from Baseline to 24 hours post
first dose
Primary

Remission of MDD (MADRS total score ≤12) at 4 hours and 
24 hours post first dose, and through the end of the DB 
treatment phase (Day 25)
Secondary

Change in MADRS total score from Baseline to 4 hours post 
first dose and through the end of the DB treatment phase 
(Day 25) 
Secondary

Change in MADRS total score from Baseline through the end 
of the follow-up phase (Day 90)
Exploratory

Remission of MDD (MADRS ≤12) through the end of the 
follow-up phase (Day 90)
Exploratory

Response rates (at least 50% improvement from baseline) at 
4 hours and 24 hours post first dose, and through the end of 
the DB treatment (Day 25) and follow-up phases (Day 90)
Exploratory

Change in MADRS individual item from Baseline through 
the end of the DB treatment (Day 25) and follow-up phases
(Day 90)
Exploratory
SIBAT –
CGI-SS-R

Change in CGI-SS-R from Baseline to 24 hours post first 
dose
Key Secondary

Change in CGI-SS-R from Baseline to 4 hours post first dose
and through the end of the DB treatment phase (Day 25)
Secondary

Resolution of suicidality (CGI-SS-R score of 0 or 1) at 4 
hours and 24 hours post first dose, and through the end of the 
DB treatment phase (Day 25) 
Secondary

Change in CGI-SS-R from Baseline through the end of the 
follow-up phase (Day 90)
Exploratory

Resolution of suicidality (CGI-SS-R score of 0 or 1) through 
the end of the follow-up phase (Day 90)
Exploratory
SIBAT –
CGI-SR-I

Change in CGI-SR-I from Baseline to 4 hours and 24 hours
post first dose, and through the end of the DB treatment phase 
(Day 25)
Secondary

Change in CGI-SR-I from Baseline through end of the 
follow-up phase (Day 90)
Exploratory
BHS

Change in BHS total score from Baseline through the end of 
the DB treatment phase (Day 25)
Secondary

Change in BHS total score from Baseline through the end of 
the follow-up phase (Day 90)
Exploratory
EQ-5D-5L, EQ-VAS, and 
health status index

Change in EQ-5D-5L dimension scores, the sum score, EQ-
VAS and health status index from Baseline through the end of 
the DB treatment phase (Day 25)
Secondary

Change in EQ-5D-5L dimension scores, the sum score, EQ-
VAS, health status index from Baseline through the end of 
the follow-up phase (Day 90)
Exploratory
QLDS

Change in QLDS from Baseline through the end of the DB
treatment phase (Day 25)
Secondary

Change in QLDS from Baseline through the end of the 
follow-up phase (Day 90)
Exploratory
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Table 4:
Efficacy Variables
Efficacy Variable
Endpoint
TSQM-9

TSQM-9 score of effectiveness, convenience and global 
satisfaction domains through the end of the DB treatment 
phase (Day 25)
Secondary

TSQM-9 score through the end of the follow-up phase 
(Day 90)
Exploratory
SIBAT – Module 3 (My 
Current Thinking)

Change in SIBAT– Module 3 (My Current Thinking) from 
Baseline through the end of the DB treatment (Day 25) and 
follow-up (Day 90) phases
Exploratory
SIBAT – Module 5 (My 
Risk) Questions 1,2,3,4

Change in SIBAT – Module 5 (My Risk) Question 1,2,3,4
from Baseline through the end of the DB treatment phase 
(Day 25)
Secondary
Exploratory
SIBAT – Module 7 (Global 
Clinical Impression) FoST

Change in SIBAT – Module 7 (Global Clinical Impression) 
FoST from Baseline through the end of the DB treatment 
phase (Day 25)

Change in SIBAT – Module 7 (Global Clinical Impression) 
FoST from Baseline through the end of the follow-up (Day 
90) phase
Secondary
Exploratory
SIBAT – CGI-SR-LT

Change in CGI-SR-LT from Baseline through the end of the 
DB treatment (Day 25) and follow-up (Day 90) phases
Exploratory
SIBAT – Module 8 
(Clinical Judgment of 
Optimal Suicide 
Management)

Change in SIBAT – Module 8 (Clinical Judgment of Optimal 
Suicide Management) from Baseline through the end of the 
DB treatment (Day 25) and follow-up (Day 90) phases
Exploratory
SIBAT - Module 2 (My 
Risk/Protective Factors)

Change in SIBAT - Module 2 (My Risk/Protective Factors)
from Baseline through the end of the DB treatment phase 
(Day 25)
Exploratory
5.1.
Analysis Specifications
5.1.1.
Level of Significance
Statistical analysis tests will be conducted at a two-sided 0.050 level of significance unless 
specified otherwise.
The multiplicity, with regard to testing multiple endpoints (the primary and the key secondary),
will be controlled by a fixed sequence testing procedure, ie, the key secondary hypothesis will be 
tested only after the null hypothesis for the primary endpoint is rejected.
Two-sided p-values will only be presented for the primary and key secondary endpoint (provided 
primary endpoint is significant). Point estimates of the treatment differences and 95% CIs will be 
presented for all other endpoints.
5.1.2.
Data Handling Rules
For endpoints using analysis of covariance (ANCOVA), the last observation carried forward 
(LOCF) method will be applied to the MADRS, CGI-SS-R, CGI-SR-I, BHS, and QLDS score
for the double-blind and follow-up phases. If a subject does not enter the follow-up phase, 
double-blind observations will not be carried forward into the follow-up phase. 
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The last post baseline observation during the double-blind phase will be carried forward as the 
“End Point” for the double-blind phase. The last post baseline observation in the follow-up phase 
will be carried forward as the “End Point” for the follow-up phase. Besides the observed cases 
and the end point assessment, the LOCF values will be created for intermediate post-baseline 
time points as well. These imputed time points will be labeled ‘DAY X (DB) LOCF’ or ‘Day X 
(F/U) LOCF’.
5.1.3.
Imputation Methods for Missing Items
Imputation of missing individual item scores will apply to MADRS and is described in 
Section 5.2.1. For all other scales where multiple items are summed to create a total, if any item 
of the scale is missing on one visit, the total score for that scale at that visit will be left blank.
5.1.4.
Change from Baseline
For all efficacy variables, changes from baseline will be determined over time for both the 
double-blind and the follow-up phases, using double-blind baseline.
5.2.
Primary Efficacy Endpoint
5.2.1.
Definition
The primary efficacy endpoint is the change in MADRS total score from Baseline (Day 1, 
predose) to 24 hours post first dose in the double-blind phase. The baseline assessment and 
assessments during the follow-up phase use a 7-day recall period, the Day 1 and Day 25 4-hours
post dose assessment uses a 4-hour recall period, the Day 2 24-hour post dose assessment uses a 
24-hour recall period, and the other assessments in the double-blind phase use a since last 
assessment recall period. 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). For the MADRS performed 
at 4 hours post dose on Day 1 and 25, the MADRS scores for the sleep item recorded predose on 
the same day will be carried forward. 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. If 2 or more items are missing, no imputation will be 
performed and the total score will be left missing. Otherwise, the total score will be calculated as 
the sum of the items present multiplied by the ratio of the maximum possible number of items 
(i.e., 10) to the number of items present.
5.2.2.
Primary Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is 
defined by the following 4 components:
Population: subjects with MDD who are at imminent risk of suicide, as defined through 
appropriate inclusion/exclusion criteria to reflect the targeted patient population;
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Variable: change from baseline to 24 hours post first dose (Day 2) in MADRS total score 
(see Section 5.2.1);
Intervention Effect: the effect of the initially randomized treatment that would have been 
observed had all subjects remained on their treatment until Day 2 of the double-blind phase;
Summary Measure: the difference in variable least square means. 
The primary analysis will be based on the full efficacy analysis set and the MADRS total scores 
collected at Day 2.
5.2.3.
Analysis Methods
The primary efficacy endpoint, change from Baseline (Day 1, predose) to 24 hours post first dose
(Day 2) in MADRS total score, will be analyzed using an analysis of covariance (ANCOVA) 
model, with factors for treatment (placebo or esketamine 84 mg), analysis center, standard of 
care antidepressant treatment as randomized (antidepressant monotherapy or antidepressant plus 
augmentation therapy), and baseline MADRS total score as a continuous covariate. Since 
subjects are hospitalized at the time of the primary endpoint, it is anticipated that missing data 
will be infrequent. However, if a subject has a MADRS total score at a time earlier than 24 hours 
post first dose but does not have the 24-hour value, the earlier value will be used for the primary 
efficacy analysis (ie, LOCF). The treatment effects will be estimated using least square means. A 
point estimate and 95% confidence interval for the treatment difference, along with the 
associated p-value will be provided. In addition, descriptive statistics (N, mean, SD, median, 
minimum and maximum) of the primary efficacy variable will be provided by analysis center.
The cumulative distribution function for any percent improvement from baseline to 24 hours in 
MADRS total score will be graphically presented. 
Descriptive statistics (N, mean, SD, median, minimum and maximum) for the MADRS total 
score and the change from baseline will be provided for both the observed case and LOCF data 
during the double-blind and follow-up phases. The ANCOVA model, as described above, will 
also be used to analyze all other post baseline time points for both observed case and LOCF data. 
Point estimates and 95% confidence intervals for the treatment differences will be provided. An 
additional analysis at Day 25 including remote contact data for subjects who discontinue during 
the double-blind phase using this ANCOVA model will be performed.
Both observed case data and LOCF means (standard error [SE]), mean changes (SE) from 
baseline, and least square mean changes (SE) from baseline will be presented graphically for 
the double-blind and follow-up phases.
Model Assumptions
The normality and equal variance assumptions underlying the primary ANCOVA model will be 
assessed graphically for the MADRS total score at 24 hours post first dose. Residuals from the 
primary model will be plotted against the predicted values and a QQ plot of the residuals versus 
the expected quantiles of the standard normal distribution will be presented. If either the equal 
variance or the normality assumption appears to be grossly violated, other methods including an 
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ANCOVA on ranks model or an appropriate transformation of the primary endpoint might be 
considered.
MMRM
To assess the sensitivity of the results of the ANCOVA analysis at End Point (DB) and End 
Point (F/U), a mixed-effects model using repeated measures (MMRM) based on observed case 
data will be performed comparing treatments for the change from Baseline (Day 1, predose) to 
each assessment in the double-blind and follow-up phases, including Day 25 (DB) and Day 90 
(F/U), in MADRS total score. The model will include baseline MADRS total score as a 
continuous covariate, and day, treatment, analysis center, standard of care antidepressant 
treatment as randomized (antidepressant monotherapy or antidepressant plus augmentation 
therapy), and day-by-treatment interaction as fixed effects, and a random subject effect. The 
within-subject variance between visits will be estimated via an unstructured variance-covariance 
matrix. In case of convergence problems, alternative variance-covariance structures will be tried 
in the following order, with the first structure that converges being used in the analysis: 
heterogeneous Toeplitz, standard Toeplitz, and AR(1) with separate subject random effect. 
Comparison of esketamine versus placebo will be performed using the appropriate contrast. 
Point estimates and 95% confidence intervals for the treatment differences will be provided for 
each timepoint.
Baseline Observation Carried Forward Imputation (BOCF)
To assess the sensitivity of the results of the ANCOVA (LOCF) model for the primary efficacy 
endpoint, a BOCF imputation will be applied. The change from Baseline (Day 1, predose) to 24 
hours post first dose (Day 2) in MADRS total score, will be analyzed using an ANCOVA
(BOCF) model, with factors for treatment (placebo or esketamine 84 mg), analysis center, 
standard of care antidepressant treatment as randomized (antidepressant monotherapy or 
antidepressant plus augmentation therapy), and baseline MADRS total score as a continuous 
covariate. The treatment effects will be estimated using least square means. A point estimate and 
95% confidence interval for the treatment difference. 
Sensitivity Analysis for Missing Data
If the overall missingness of the primary endpoint at 24 hours is above 5%, then additional 
sensitivity analyses that rely on Missing Not at Random assumptions will be performed to assess 
the robustness of the primary analysis and MMRM results. These analyses include a jump to 
reference multiple imputation as well as a delta adjustment multiple imputation analysis 
(including the establishment of the tipping point), which assumes a worsening of the MADRS 
scores after treatment discontinuation. 
Subgroup Analyses
Forest plots will be provided displaying analysis results for each subgroup listed in Section 2.6. 
The point estimate of the treatment difference and its 95% confidence interval for each subgroup 
will be based on an ANCOVA analysis for the primary endpoint using the appropriate contrast. 
The model will include factors for treatment, analysis center, standard of care antidepressant 
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treatment as randomized (antidepressant monotherapy or antidepressant plus augmentation 
therapy), subgroup and treatment-by-subgroup, and baseline MADRS total score as a covariate. 
The terms in the models will be adjusted for the subgroup of baseline MADRS total score 
(≤/> median). Baseline MADRS total score (as a continuous covariate) will not be included in 
the model when the dichotomized baseline MADRS total score is included in the model.
Individual Item Analyses
At each time point during the double-blind and follow-up phases, a frequency distribution of the 
MADRS individual item scores will be provided. Descriptive statistics (N, median, minimum 
and maximum) for these scores and the changes from baseline will be provided. The treatment 
difference will be estimated for each item using the Hodges-Lehmann estimate, which is the 
median of all possible paired differences for the change from baseline for individual item. 
Hodges-Lehmann estimates and the corresponding 95% CI for the treatment differences will be 
provided for each timepoint.
5.3.
Key Secondary Endpoint
5.3.1.
Definition
One module of the SIBAT includes the Clinical Global Impression – Severity of Suicidality –
Revised (CGI-SS-R). The key secondary endpoint is the change in CGI-SS-R from Baseline 
(Day 1, predose) to 24 hours post first dose in the double-blind phase. The CGI-SS-R 
summarizes the clinician’s overall impression of severity of suicidality. The CGI-SS-R rating 
will be based on the totality of information available to the clinician, including information from 
the SIBAT. This rating operates like numerous other CGI-severity scales that have been used in 
other psychiatric studies. These instruments have shown clinical validity and sensitivity to 
change. 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 patients).
5.3.2.
Analysis Methods
The analysis of the key secondary efficacy endpoint, change from baseline for CGI-SS-R at 
24 hours post first dose (Day 2), will be performed for LOCF data using an ANCOVA model on 
the ranks of change with factors for treatment, analysis center, standard of care antidepressant 
treatment as randomized (ie, antidepressant monotherapy or an antidepressant plus augmentation 
therapy) and baseline CGI-SS-R (unranked) as a covariate. The associated p-value will be 
provided. The treatment difference will be estimated using the Hodges-Lehmann estimate, which 
is the median of all possible paired differences for the change from baseline for CGI-SS-R at 
24 hours. The Hodges-Lehmann estimate and the corresponding 95% CI for the treatment 
difference will be provided. The treatment difference will also be estimated using least square 
means based on an ANCOVA model on the actual change with factors for treatment, analysis 
center, standard of care antidepressant treatment as randomized (ie, antidepressant monotherapy 
or an antidepressant plus augmentation therapy) and baseline CGI-SS-R (unranked) as a 
covariate. A point estimate and 95% confidence interval for the treatment difference will be 
provided. The cumulative distribution function for any improvement and percent improvement 
from baseline to 24 hours in CGI-SS-R will be graphically presented.
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The multiplicity, with regard to testing multiple endpoints (the primary and the key secondary),
will be controlled by a fixed sequence testing procedure, ie, the key secondary hypothesis will be 
tested only after the null hypothesis for the primary endpoint is rejected.
At each time point during the double-blind and follow-up phases, a frequency distribution of the 
CGI-SS-R score and changes from baseline will be provided for both the observed case and 
LOCF data. In addition, descriptive statistics (N, median, minimum, and maximum) for these 
scores and the changes from baseline will be provided for both the observed case and LOCF 
data. Hodges-Lehmann estimates and the corresponding 95% CI for the treatment differences 
will be provided for each timepoint. ANCOVA model on the change from baseline for both 
LOCF and observed case data will be performed for each time point as an additional exploratory 
analysis.
Both observed case data and LOCF frequency distributions will be presented graphically using 
stacked bar charts for baseline, 4 hours post first dose, 24 hours post first dose, and Day 25.
Item Response Modeling
Item response modeling will be used to estimate treatment difference using an odds ratio 
 
 
 ( ≤
Φ −  See Attachment 5. The analysis of CGI-SS-R will be performed based on the change 
from baseline for CGI-SS-R at 4 hours and 24 hours post first dose. 
 
 
 
 
 
 
 
This 
model, 
 will be 
estimated jointly by Bayesian modelling with Gibbs sampling method8 to take into account the 
uncertainty of estimation in each separate model9. Non-informative priors are used for 
parameters. R (version 3.3) will be used for this analysis with JAGS (version 4.2) via R-package 
R2jags. The posterior median estimate and 95% credible interval of the odds ratio will be 
reported.
Subgroup Analyses
Forest plots will be provided displaying analysis results for each subgroup listed in Section 2.6. 
The median estimate of the treatment difference in terms of odds ratio and its 95% credible 
interval for each subgroup will be based on item response modelling for the key secondary 
endpoint using the appropriate contrast. The model will include factors for treatment, analysis 
center, standard of care antidepressant treatment as randomized (antidepressant monotherapy or 
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antidepressant plus augmentation therapy), subgroup and treatment-by-subgroup, and baseline 
latent CGI-SS-R score as a covariate.
BOCF Imputation
To assess the sensitivity of the results of models for the key secondary endpoint (change from 
baseline for CGI-SS-R at 24 hours post first dose), a BOCF imputation will be applied. The 
treatment difference will be estimated using the Hodges-Lehmann estimate with BOCF data. The 
Hodges-Lehmann estimate and the corresponding 95% CI for the treatment difference will be 
provided. The treatment difference will also be estimated by least square means based on an 
ANCOVA (BOCF) model on the actual change with factors for treatment, analysis center, 
standard of care antidepressant treatment as randomized (ie, antidepressant monotherapy or an 
antidepressant plus augmentation therapy) and baseline CGI-SS-R (unranked) as a covariate. A 
point estimate and 95% confidence interval for the treatment difference will be provided. In 
addition, item response modeling will be used on BOCF data to estimate treatment difference. 
Posterior median treatment effect estimate and 95% credible interval of the odds ratio will be 
provided. 
Mediation Analysis
Mediation analysis will be performed to examine the mediating role of depressive symptoms 
assessed by change from baseline in MADRS total score on change from baseline in CGI-SS-R 
provided that both endpoints demonstrate a statistically significant difference between 
esketamine and placebo. In the mediation analysis framework, natural direct effect can be 
conceived of as independent treatment effect on the outcome (i.e., change in CGI-SS-R) that is 
above and beyond its effect on the mediator (i.e., change in MADRS total score); controlled 
direct effect can be conceived of as the independent treatment effect on the outcome controlling 
the mediator at a fixed level; and natural indirect effect can be conceived of as a treatment effect 
on the outcome that is mediated by its effect on the mediator.
Two analyses are suggested to assess the extent to which change in CGI-SS-R may be mediated 
by or independent of change in MADRS total score based on observed data for Day 2. The 
analyses will consider change in CGI-SS-R as an ordinal variable and change in MADRS total 
score as a continuous variable.

Parametric Counterfactual Approach: this approach introduced by VanderWeele et.al2
provides closed-form analytic expressions for controlled direct effect (CDE) on the odds 
ratio scale, for category ,
() = ( ≤|)
( > |) / (∗ ≤|)
(∗ > |)
where  is given level of mediator ,  and ∗are two levels of treatment group ,  is a 
set of covariates,  is the outcome when  = ,  = . The controlled direct effect can be 
expressed as the exponential of a linear combination of the coefficients based on a 
proportional odds model of the outcome.
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The analysis will be based on the proportional odds model of change in CGI-SS-R from 
baseline with factors for treatment, analysis center, standard of care antidepressant treatment 
as randomized (antidepressant monotherapy or antidepressant plus augmentation therapy), 
change from baseline in MADRS total score and baseline CGI-SS-R as a covariate. Estimate 
of the controlled direct effect will be obtained by plugging in the estimated coefficient 
values and the mean level of change in MADRS total score into the analytic expressions. 
Under the proportional odds model, the controlled direct effect will be constant across 
different levels of change in CGI-SS-R.

Simulation-based Counterfactual Approach: this approach introduced by Imai et.al3 obtains 
natural direct effect (NDE) and natural indirect effect (NIE) on the difference scales using 
numerical simulations, for category ,
  = !"∗= # −∗!"∗= #
 $ = !" = # −!"∗= #
where !"∗is the outcome when  =  and  is set to ∗, the level it would have been 
under treatment group  = ∗.
The approach uses non-parametric bootstrapping to construct the point estimate for natural 
direct effect and natural indirect effect from the bootstrap sampling distribution. The p-value 
is based on a percentile bootstrap method. The original data will be stratified by analysis 
center, and for each analysis center a random sample equal in size to the original one will be 
drawn. The abovementioned proportional odds model for change in CGI-SS-R and an 
ANCOVA model for change in MADRS total score will be used for each bootstrapped 
sample. The ANCOVA model will include factors for treatment, analysis center, standard of 
care antidepressant treatment as randomized (antidepressant monotherapy or antidepressant 
plus augmentation therapy), and baseline CGI-SS-R score (unranked) as a covariate. 
Mediation analysis may also be performed to examine the mediating role of severity of 
suicidality assessed by change from baseline in CGI-SS-R on change from baseline in 
MADRS total score, provided both endpoints demonstrate a statistically significant 
difference between esketamine and placebo. The simulation-based counterfactual approach 
described above would be used to assess the extent to which change in MADRS total score 
may be mediated by or independent of change in CGI-SS-R based on observed data for 
Day 2. 
5.4.
Other Secondary and Exploratory Variables
5.4.1.
Remission of MDD
5.4.1.1.
Definition
A subject is defined to be in remission of MDD (yes=1 and no=0) at a given time point if the 
MADRS total score is ≤12. Subjects who do not meet such criterion or discontinue prior to the 
time point for any reason will not be considered to be in remission.
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5.4.1.2.
Analysis Methods
Frequency distributions of subjects meeting criteria for remission will be provided at each time 
point during the double-blind and follow-up phases. The estimates of the treatment difference in 
proportions and the 95% CIs will be reported at each time point.
5.4.2.
Responder
5.4.2.1.
Definition
The percentage change from baseline at Day X is calculated as 100*(MADRS total score at 
Day X – Baseline MADRS total score)/(Baseline MADRS total score). Negative percent changes 
in MADRS total score indicate improvement (e.g., percent change ≤-50% indicates improvement 
≥50%). 
A subject is defined a responder (yes=1 and no=0) at a given time point if the percent 
improvement in MADRS total score is ≥50%. Subjects who do not meet such criterion or 
discontinue prior to the time point for any reason will not be considered a responder.
5.4.2.2.
Analysis Methods
Frequency distributions of subjects who achieve a response will be provided at each time point 
during the double-blind and follow-up phases. The estimates of the treatment difference in 
proportions and the 95% CIs will be reported at each time point.
5.4.3.
Resolution of Suicidality
5.4.3.1.
Definition
A subject is defined to have achieved resolution of suicidality (yes=1 and no=0) at a given time 
point if the CGI-SS-R score is 0 (normal, not at all suicidal) or 1 (questionably suicidal). 
Subjects who do not meet such criterion or discontinue prior to the time point for any reason will 
not be considered to have resolution of suicidality.
5.4.3.2.
Analysis Methods
Frequency distributions of subjects meeting criteria for resolution of suicidality will be provided 
at each time point during the double-blind and follow-up phases. The estimates of the treatment 
differences in proportions and 95% CIs will be reported.
5.4.4.
CGI-SR-I
5.4.4.1.
Definition
One module of the SIBAT includes the Clinical Global Impression of Imminent Suicide Risk 
(CGI-SR-I). The CGI-SR-I is a scale summarizing the clinician’s best assessment of the 
likelihood that the subject will attempt suicide in the next 7 days. The CGI-SR-I rating is scored 
on a 7-point scale from 0 (no imminent suicide risk) to 6 (extreme imminent suicide risk).
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5.4.4.2.
Analysis Methods
At each time point during the double-blind and follow-up phases, a frequency distribution of the 
CGI-SR-I score and change from baseline will be provided for both the observed case and LOCF 
data. In addition, descriptive statistics (N, median, minimum, and maximum) for these scores and 
the changes from baseline will be provided for both the observed case and LOCF data. Hodges-
Lehmann estimates and the corresponding 95% CI for the treatment differences will be provided 
for each timepoint.
As described in Section 5.3.2 the posterior median estimate and 95% credible interval of odds 
ratio from item response modeling will be reported at 4 hours and 24 hours post first dose.
Both observed case data and LOCF frequency distributions will be presented graphically using 
stacked bar charts for baseline, 4 hours post first dose, 24 hours post first dose, and Day 25.
5.4.5.
BHS
5.4.5.1.
Definition
The BHS (Attachment 2) is a self-reported measure to assess one’s level of negative expectations 
or pessimism regarding the future. It consists of 20 true-false items that examine the 
respondent’s attitude over the past week by either endorsing a pessimistic statement or denying 
an optimistic statement; 9 are keyed false and 11 are keyed true. These items fall within 3 
domains: (1) feelings about the future; (2) loss of motivation; and (3) future expectations. For 
every statement, each response is assigned a score of 0 or 1. The total BHS score is a sum of item 
responses and can range from 0 to 20, with a higher score representing a higher level of 
hopelessness. Total scores that range from 0 to 3 are considered within the normal range, scores 
4 to 8 identify mild hopelessness, scores 9 to 14 identify moderate hopelessness, and scores 
greater than 14 identify severe hopelessness.
The BHS will be administered using a recall period of the last 7 days.
5.4.5.2.
Analysis Methods
Changes from baseline over time in BHS total score will be analyzed based on observed case
data using MMRM as described in Section 5.2.3. In addition, the same ANCOVA model 
described in Section 5.2.3 will be performed for both observed case and LOCF data. The 
estimates of treatment differences based on the least square means and 95% CIs will be provided
for each model.
Descriptive statistics (N, mean, SD, median, minimum and maximum) for the BHS total score 
and the change from baseline will be provided for both the observed case and LOCF data during 
the double-blind and follow-up phases.
Both observed case data and LOCF mean values and changes from baseline over time will be 
graphically presented for the double-blind and follow-up phases.
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5.4.6.
EuroQol Group; 5 Dimension; 5 Level (EQ-5D-5L)
5.4.6.1.
Definition
The EQ-5D-5L (EuroQol Group - 5 Dimension - 5 Level) is a standardized 2-part instrument for 
use as a measure of health outcome, primarily designed for self-completion by respondents. It 
essentially consists of the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ-
VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-
care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is 
divided into 5 levels of perceived problems (Level 1 indicating no problem, Level 2 indicating 
slight problems, Level 3 indicating moderate problems, Level 4 indicating severe problems, and 
Level 5 indicating extreme problems).
The subject selects an answer for each of the 5 dimensions considering the response that best 
matches his or her health “today.” The descriptive system can be represented as a health state. 
The EQ-VAS self-rating records the respondent’s own assessment of his or her overall health 
status at the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the 
best health you can imagine). 
The time taken to complete the questionnaire varies with age, health status, and setting but is 
likely to be around 1 minute.
Individual scores from the 5 dimensions will be used to obtain a weighted health status index as 
shown below: 
(i)
Scores from each dimension will be combined to obtain a 5L profile score or health 
state: eg, a score of 1 for each dimension will give a 5L profile score of 11111. 
Dimension scores will be combined in the following order: Mobility, Self-Care, 
Usual Activities, Pain/Discomfort, Anxiety/Depression
(ii)
The value set of the Health Status Index for various values of 5L profile scores is 
published for Canada in the following website: 
https://www.ncbi.nlm.nih.gov/pubmed/26492214
(iii)
The Canadian value set will be used to get the HSI values for all the countries 
participating in the study
In addition, a sum score will be derived as follows: The scores of the five dimensions (values 1-5) 
will be added (sums between 5 and 25). From this score, subtract 5 (range 0-20) and multiply by 
5 (range 0-100)
5.4.6.2.
Analysis Methods
Descriptive statistics of actual values and changes from baseline by treatment group will be 
provided for the dimension scores, weighted EQ-5D health status index, the EQ-VAS, and the 
sum score at each time point for the double-blind and follow-up phases.
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Individual dimension responses will be summarized at each visit using a frequency distribution 
by treatment group for the double-blind and follow-up phases. Graphical presentations will also 
be provided using bar charts for baseline, 24 hours post first dose, and Day 25.
5.4.7.
QLDS
5.4.7.1.
Definition
The QLDS is a disease specific patient-reported outcome designed to assess health related 
quality of life in patients with MDD, ie, it captures the impact of depression and its treatment 
from the patient’s perspective. 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 score range is from 0 (good quality of life) to 34 (very poor quality of life). It has 
been shown to have acceptable psychometric properties and sensitivity to change.
5.4.7.2.
Analysis Methods
Changes from baseline over time in QLDS score will be analyzed based on observed case data
using MMRM as described in Section 5.2.3. In addition, the same ANCOVA model described in 
Section 5.2.3 will be performed for both observed case and LOCF data. The estimates of 
treatment differences based on the least square means and 95% CIs will be provided for each 
model.
Descriptive statistics (N, mean, SD, median, minimum and maximum) for the QLDS score and 
the change from baseline will be provided for both the observed case and LOCF data during the 
double-blind and follow-up phases.
Both observed case data and LOCF mean values and change from baseline over time will be 
graphically presented for the double-blind and follow-up phases.
5.4.8.
TSQM-9
5.4.8.1.
Definition
The TSQM-9 is a 9-item generic patient reported outcome instrument to assess patients’ 
satisfaction with medication. It is derived from the longer TSQM Version 1.4 and covers 3 
domains of effectiveness, convenience and global satisfaction. The instrument is scored by 
domain with scores ranging from 0-100 where a lower score indicates lower satisfaction. The 
recall period is “the last 2-3 weeks”.
5.4.8.2.
Analysis Methods
Descriptive statistics (N, mean, SD, median, minimum and maximum) for the TSQM-9 domain 
scores will be provided during the double-blind and follow-up phases.
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5.4.9.
SIBAT – Module 2 (My Risk/Protective Factors), Module 3 (My Current 
Thinking), Module 5 (My Risk) Questions 1,2, 3, and 4, Module 7 
(Global Clinical Impression) FoST, CGI-SR-LT, and Module 8 (Clinical 
Judgment of Optimal Suicide Management)
5.4.9.1.
Definition
Module 2 (My Risk/Protective Factors), Module 3 (My Current Thinking), Questions 1,2,3 and 4
in Module 5 (My Risk), Module 7 (Global Clinical Impression) Assessment of Frequency of 
Suicidal Thinking (FoST), and CGI-SR-LT from the SIBAT will be used to assess patient and 
clinician reported suicidality. Module 2 (My Risk/Protective Factors) asks patients to describe 
how they have acted or felt in the past 7 days. Each of the first 21 items has 6 response options 
ranging from “Never” to “All the time”. A total score is calculated by adding the scores of the 
first 21 questions (Attachment 3). Module 3 consists of 48 patient-reported items about their 
current thinking and takes approximately 7 minutes to complete. Each item has 6 response 
options ranging from “Strongly disagree” to “Strongly agree”. A total score is calculated by 
adding the scores of all 48 items with higher values indicating higher symptomatology 
(Attachment 3). Question 1 from Module 5 asks patients to describe their desire to die in the past 
7 days. There are 5 response options ranging from “I have not wanted to die” to “I wanted to die 
all of the time”. Question 2 from Module 5 asks patients to describe their intent to end their life 
in the past 7 days. There are 5 response options ranging from “I have not wanted to end my life” 
to “I wanted to end my life all of the time”. Question 3 from Module 5 asks patients to describe 
their thinking about suicide right now. There are 5 response options ranging from “I have no 
suicidal thoughts” to “I have suicidal thoughts all of the time”. Question 4 from Module 5 asks 
patients to describe the likelihood that they attempt to end their life in the near future. There are 
5 response options ranging from “I will not end my life in the near future” to “I will end my life 
in the near future”. Module 7 FoST is a clinician-reported global impression with response 
options of “Never”, “Rarely”, “Sometimes”, “Often”, “Most of the time”, and “All of the time”.
The CGI-SR-LT is a scale summarizing the clinician’s best assessment of subjects’ long-term 
risk for suicide. The CGI-SR-LT rating is scored on a 7-point scale from 0 (no suicide risk in the 
long term) to 6 (extreme risk for suicide in the long term). Module 8 asks clinicians about their 
assessment of the best clinical management for the subject. The score range is from 1 (No special 
management needed) to 11 (Not ratable). 
5.4.9.2.
Analysis Methods
Frequency distributions for Questions 1, 2, 3 and 4 from Module 5 (My Risk), Module 7 (Global 
Clinical Impression) FoST, CGI-SR-LT and Module 8 (Clinical Judgment of Optimal Suicide 
Management) will be provided during the double-blind and follow-up phases. In addition, 
descriptive statistics for these scores, Module 3 (My Current Thinking) total score and Module 2 
(My Risk/Protective Factors) total score and the changes from baseline will be provided.
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6.
SAFETY
6.1.
Adverse Events
Adverse events (AEs) are coded using the MedDRA dictionary (version 19.1 or above). 
Treatment-emergent adverse events (TEAEs) that occurred in the double-blind phase will be 
summarized by system organ class, preferred term, and treatment group. Adverse events that 
occurred in the follow-up phase will be summarized separately. In addition, separate summaries 
will be provided for AEs that occurred after DB phase for subjects who discontinued from DB 
phase and AEs that occurred after follow-up phase for subjects who discontinued from follow-up 
phase. Data listings will be provided for AEs with onset date after the end of trial date. For each 
adverse event, the percentage of subjects who experience at least 1 occurrence of the given event 
will be summarized by treatment group.
Adverse events occurring in different phases of the study are defined as below:

Treatment-emergent adverse events during the double-blind phase are defined as AEs with 
an onset during the double-blind phase. In other words, treatment-emergent AE during the 
double-blind phase should satisfy the condition: Double-blind start date/time ≤ AE onset 
date/time ≤double-blind end date. If onset time is missing and AE onset date is the same as 
the double-blind start date, the AE is defined to be treatment emergent in the double-blind 
phase.

Adverse events during the follow-up phase are defined as AEs with an onset during the 
follow-up phase. AEs during the follow-up phase should satisfy the condition: follow-up 
phase start date ≤ AE onset date ≤ follow-up phase end date. 
A TEAE is an event that is new in onset or increased in severity following treatment initiation. 
An event that starts prior to and ends after the initiation of study medication will be considered 
treatment-emergent only if the severity increases after the start of medication. Adverse events 
will not be considered treatment-emergent if they occur or increase in severity during the follow-
up phase. 
In addition, AEs will be summarized by severity and relationship to study drug using the 
preferred term. For the summaries of AEs by severity/relationship to study drug, the observation 
with the most severe occurrence/closest relationship to study drug will be chosen if there is more 
than one incident of an adverse event reported during the analysis phase by the subject. The 
proportion of TEAEs occurring on dosing days and the proportion of TEAEs that occur on 
dosing days with same day resolution will be summarized. Duration and resolution time of 
severe TEAEs will also be summarized.
Serious AEs (SAEs) and AEs that lead to study discontinuation will be summarized separately 
by treatment group, system organ class, and preferred term. TEAEs leading to dose reduction or 
interruption due to intranasal study medication will also be summarized. Data listings will also 
be generated for deaths, other SAEs, and discontinuations due to AEs.
The TEAEs potentially related to suicidality (preferred terms:  Completed suicide, Depression 
suicidal, Intentional overdose, Intentional self-injury, Multiple drug overdose intentional, 
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Poisoning deliberate, Self injurious behavior, Self-injurious behaviour, Self-injurious ideation, 
Suicidal behaviour, Suicidal behavior, Suicidal ideation, Suicide attempt) will be summarized.
Adverse Events of Special Interest
Clinically relevant TEAEs of special interest will be examined separately grouped in the 
following categories: 

Suggestive of abuse
potential
(Aggression, Confusional state, Decreased activity, 
Dependence, Disorientation, Dissociation, Dissociative disorder, Dizziness, Drug abuse, 
Drug abuser, Drug dependence, Drug use disorder, Drug detoxification, Drug diversion, 
Drug rehabilitation, Drug tolerance, Drug tolerance increased, Drug withdrawal convulsions, 
Drug withdrawal headache, Drug withdrawal syndrome, Euphoric mood, Feeling abnormal, 
Feeling drunk, Feeling of relaxation, Hallucination, Hallucination, auditory, Hallucination, 
gustatory, Hallucination, olfactory, Hallucination, synaesthetic, Hallucination, tactile, 
Hallucination, visual, Hallucinations, mixed, Inappropriate affect, Mental impairment, 
Product tampering, Psychomotor hyperactivity, Psychotic disorder, Rebound effect, Somatic 
hallucination, Somnolence, Substance abuser, Substance dependence, Substance use, 
Substance use disorder, Substance-induced mood disorder, Substance-induced psychotic 
disorder, Thinking abnormal, Withdrawal arrhythmia, Withdrawal syndrome);

Increased blood pressure (Blood pressure increased, Blood pressure diastolic increased, 
Blood pressure systolic increased, Hypertensive crisis, Hypertensive emergency, 
Hypertension)

Increased heart rate (Heart rate increased, Tachycardia, Extrasystoles)

Transient dizziness/vertigo (Dizziness, Dizziness exertional, Dizziness postural, Dizziness 
procedural, Procedural dizziness, Vertigo, Vertigo labyrinthine, Vertigo positional, Vertigo 
CNS origin); 

Impaired cognition (Cognitive disorder);

Cystitis (Allergic cystitis, Chemical cystitis, Cystitis, Cystitis erosive, Cystitis 
haemorrhagic, Cystitis interstitial, Cystitis noninfective, Cystitis ulcerative, Cystitis-like 
symptom, Pollakiuria, Dysuria, Micturition, Urgency, Nocturia);

Anxiety (Agitation, Anticipatory anxiety, Anxiety, Anxiety disorder, Fear, Feeling jittery, 
Irritability, Nervousness, Panic attack, Tension);

Anticipated Dosing-related AEs (Anxiety, Anticipatory anxiety, Dissociation, Dizziness, 
Dizziness postural, Feeling abnormal, Feeling drunk, Nausea, Somnolence, Vertigo, 
Vomiting).
The number and percentage of subjects taking concomitant medication for dissociation events 
(preferred term of Dissociation) at any time during the double-blind phase will be provided. In 
addition, number of occurrences of TEAEs of suggestive of abuse potential will be summarized 
by intranasal dosing session.
In addition, a summary of treatment-emergent AEs of cardiac safety (preferred terms: cardiac 
flutter, electrocardiogram QT prolonged, palpitations, seizure, sudden cardiac death, sudden 
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death, syncope, torsade de pointes, ventricular arrhythmia, ventricular fibrillation, ventricular 
flutter, ventricular tachycardia) will be provided.
6.2.
Clinical Laboratory Tests
Descriptive statistics (N, mean, SD, median and range) for observed values and changes from 
baseline will be provided for clinical laboratory tests (hematology, chemistry and urinalysis) at 
each scheduled time point in the double-blind phase.
Clinical laboratory tests that meet the criteria for markedly abnormal will be listed by subject for 
the double-blind and follow-up phases. The incidence of treatment-emergent markedly abnormal 
laboratory values that occurred at any time during the double-blind phase will be presented. 
Clinical laboratory test values will be considered “treatment-emergent markedly abnormal” 
(TEMA) using the criteria defined by the Sponsor (Janssen Research & Development, LLC) 
listed in Attachment 1. The identification of TEMA laboratory values is based on the post-
baseline value being out of range while the baseline value is either missing or within the range 
given in Attachment 1. If post-baseline laboratory results are above the upper limit and the 
baseline value is below the lower limit, then the post-baseline abnormality will also be 
considered TEMA. The same applies to the post-baseline value being below the lower limit with 
the baseline value being above the upper limit.
The incidence of subjects with ALT or AST values >3*upper limit of normal (ULN) will be 
presented. Additionally, incidence of hepatic toxicity (Hy's Law4) defined as ALT or AST values 
>3*ULN AND total bilirubin values >2*ULN will be presented. Similar to the markedly 
abnormal analysis, only subjects with baseline ALT or AST values ≤3*ULN (AND baseline 
total bilirubin values ≤2*ULN for hepatic toxicity) (or if baseline value is missing) will be 
eligible for these analyses.
6.3.
Vital Signs, Weight, and BMI
Descriptive statistics for values and changes from baseline at each scheduled time-point during 
the double-blind and follow-up phases will be presented for blood pressure (systolic and 
diastolic), pulse (heart) rate, respiratory rate, oxygen saturation, weight, temperature, and BMI. 
In addition, descriptive statistics of pulse rate and blood pressure (systolic and diastolic) values, 
changes and percent changes from predose will be provided for each dosing day. Frequency 
distributions of maximum percent increase from predose and time of maximum percent increase 
will also be presented for blood pressure. Descriptive statistics of maximum increase and 
maximum percent increase from predose will be provided for blood pressure for each dosing 
day. Note that if the maximum value within a phase occurs at multiple time points, the earliest 
time point is selected. Furthermore, descriptive statistics for highest value and greatest change 
from predose over all visits will be presented for blood pressure (systolic and diastolic).
The proportion of subjects who have a treatment-emergent abnormality, as defined in Table 5
below, will be presented for the double-blind phase. The double-blind baseline will be used to 
determine abnormal values. A listing of subjects meeting any of the criteria will also be provided 
for the double-blind phase.
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Table 5:
Treatment-Emergent Abnormality Categories for Vital Signs
Post-baseline value outside of normal limit if:
Vital Parameter
Abnormally low
Abnormally high
Pulse (bpm)
A decrease from baseline of ≥15 to a 
value ≤50
An increase from baseline of ≥15 to a 
value ≥100
Systolic BP (mmHg)
A decrease from baseline of ≥20 to a 
value ≤90
An increase from baseline of ≥20 to a 
value ≥180
Diastolic BP (mmHg)
A decrease from baseline of ≥15 to a 
value ≤50
An increase from baseline of ≥15 to a 
value ≥105
BP = blood pressure
The proportion of subjects who experienced treatment-emergent markedly elevated blood 
pressure (systolic BP≥180 or diastolic BP≥110) at any time during the double-blind phase will be 
summarized by treatment group and hypertension status. In addition, the proportion of visits with 
highest blood pressure measured at 1.5 hours after dosing and systolic BP increase≥10 from 
predose or diastolic BP increase from predose≥5 will be summarized by treatment group.
Mean (+/-SE) values for systolic BP, diastolic BP and heart rate will be summarized and 
presented graphically over the double-blind phase by treatment group and hypertension status. In 
addition, for subjects with hypertension who receive antihypertensive medication, the same 
tables and graphs will be summarized by medication type (beta-blockers, multiple agents (beta 
blockers + others), all other agents and none). Furthermore, the highest value and greatest change 
for systolic BP and diastolic BP after dosing across all visits will be presented graphically by 
treatment group.
A listing of subjects with oxygen saturation less than 93% will be provided.
6.4.
Nasal Examination
Targeted nasal examinations (including the upper respiratory tract/throat) will be conducted by a 
qualified healthcare practitioner. The objective of the examination at Screening is to rule out any 
subjects with anatomical or medical conditions that may impede drug delivery or absorption. 
Subsequent examination will consist of a visual inspection of the nostrils, nasal mucosa, and 
throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption and epistaxis and 
graded as follows: absent, mild, moderate, or severe. 
Abnormalities observed during the targeted nasal examinations at screening and post-baseline
will be summarized and listed by treatment group.
6.5.
Electrocardiogram
The ECG variables that will be analyzed include heart rate (HR), respiratory rate (RR), pulse rate 
(PR) interval, QRS interval, QT interval and corrected QT (QTc) intervals. The QTc intervals
will include the QTcB (Bazett) and QTcF (Fridericia).
The maximum post-baseline value during the double-blind phase will be computed for each ECG 
parameter using data from both scheduled and unscheduled visits.
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The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. Summary tables for values and changes from baseline will be presented at 
each time point during the double-blind phase.
The frequency of treatment-emergent abnormalities will be tabulated and presented for the 
double-blind phase. The identification of treatment-emergent abnormal ECG values is based on 
the post-baseline value (a value occurring after the first study drug administration) being out of 
range while the baseline value is either missing or within the limits given in Table 6. If post-
baseline ECG results are above the upper limits (abnormally high) and the baseline value is 
below the lower limits (abnormally low), then the post-baseline abnormality will also be 
considered treatment-emergent. The same applies to the post-baseline value being below the 
lower limits (abnormally low) with the baseline value being above the upper limits (abnormally 
high). Abnormal ranges for the HR, PR, QRS and QT intervals are given in Table 6.
Table 6:
Limits for HR, PR, QRS and QT Interval Abnormality
ECG parameter
Abnormally Low
Abnormally High
HR (bpm)
≤50
≥100
PR interval (msec)
--
≥210
QRS interval (msec)
≤50
≥120
QT interval (msec)
≤200
≥500
Based on the maximum QTc value for each subject during the double-blind phase (separate for 
each QTc correction) the incidence of abnormal QTc values and changes from baseline will be 
summarized by treatment group. Criteria for abnormal corrected QT intervals and changes from 
baseline are given in Table 7 and are derived from the ICH E14 Guidance1 (the same criteria 
apply to all QT corrections).
Table 7:
Criteria for Abnormal QTc Values and Changes From Baseline
Parameter
Classification
Criteria
Clinically Significant QTc Value
No
≤500
Yes
>500
QTc change from baseline
No concern
≤30
Concern
>30 - 60
Clear concern
>60
QTc value
Normal
≤450
>450 – 480
>450 - ≤480
>480 – 500
>480 - ≤500
>500
>500
These criteria are based on ICH E14 Guideline
The proportion of subjects with treatment emergent abnormalities will be presented for the 
double-blind phase. Listings of subjects with abnormalities will be provided for the double-blind 
and follow-up phases.
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6.6.
Other Safety Parameters
6.6.1.
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S)
The MOAA/S will be 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 [No response to painful stimulus; corresponds to ASA continuum for general 
anesthesia] to 5 [Readily responds to name spoken in normal tone (awake); corresponds to ASA 
continuum for minimal sedation].
On each intranasal dosing day, the MOAA/S will be performed every 15 minutes from predose 
to 1.5 hours postdose.
If the score is ≤3 at any time during the 90 minute postdose interval, the MOAA/S will be 
performed every 5 minutes until a score of 4 is reached (at which point a frequency of every 
15 minutes can be resumed until t = 90 minutes postdose). 
If a subject does not have a score of at least 5 at t = 90 minutes postdose, the subject should 
continue to be monitored. For subjects with a score of 4, the assessment should be repeated every 
15 minutes. And for subjects with a score of ≤3, the assessment should be repeated every 
5 minutes until the score returns to 5 or the subject is referred for appropriate medical care, if 
clinically indicated.
Descriptive statistics of the MOAA/S score and changes from pre-dose will be summarized at 
each scheduled time point. In addition, the proportion of subjects experiencing sedation (score 
less than or equal to 3) will be presented by treatment group during the double-blind phase. In 
addition, the proportion of subjects with MOAA/S score less than or equal to 4 and less than or 
equal to 2 will be presented separately by treatment group during the double-blind phase.
Mean MOAA/S scores will be presented graphically for each dosing day.
6.6.2.
Clinician Administered Dissociative States Scale (CADSS)
The Clinician Administered Dissociative States Scale (CADSS) is an instrument for the 
measurement of present-state dissociative symptoms and will be administered to assess 
treatment-emergent dissociative symptoms. On each dosing day, the CADSS will be performed 
predose, and at 40 minutes and 1.5 hours postdose. The CADSS comprises 23 subjective items 
and participant’s responses are coded on a 5-point scale (0 = “Not at all”, 1 = “Mild”, 2 = 
“Moderate”, 3 = ‘Severe” and 4 = “Extreme”). If any CADSS items are scored zero at 
40 minutes, these items will not need to be repeated at 1.5 hours postdose. These zero scores at 
40 minutes will be carried forward to 1.5 hours. The CADSS is divided into 3 components using 
the following scoring method:
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Component
Questions
Range
Depersonalization
Sum of 3, 4, 5, 6, 7, 20, 23
0-28
Derealization
Sum of 1, 2, 8, 9, 10, 11, 12, 13, 16, 17, 18, 19, 21
0-52
Amnesia
Sum of 14, 15, 22
0-12
Total Score
Sum of 1 through 23
0-92
For the total score and each component, a higher score represents a more severe condition.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of the total scores and 
component scores at each time point and visit, along with change from the pre-dose time point 
within each visit, will be presented. Descriptive statistics of highest value and greatest change for 
the CADSS total score after dosing across all visits will also be presented.
In addition, the proportion of subjects with an increase in CADSS total score from the pre-dose 
value at any visit during the double-blind phase will be presented by treatment group. A 
frequency distribution of subjects with an increase in CADSS total score >4 at any visit during 
the double-blind phase will be presented by treatment group.
Mean changes in CADSS total score from pre-dose value will be presented graphically for each 
dosing day. Boxplots of CADSS total score over time will be also be provided. In addition, the 
highest value and greatest change for the CADSS total score after dosing across all visits will be 
presented graphically by treatment group.
6.6.3.
Columbia Classification Algorithm for Suicide Assessment (C-CASA)
Responses from the SIBAT will be mapped to corresponding categories of the C-CASA 
(Columbia Classification Algorithm for Suicide Assessment) 2012 Plus.5,6 If a subject maps to 
multiple categories at the same visit, then the most severe category will be considered as their C-
CASA category for that visit. Attachment 4 contains the mapping algorithm. The first post 
baseline mapping will occur at Day 8 since that is the first post baseline visit with responses to 
each of the modules used in the mapping. Using the C-CASA 2012 Plus, potentially suicide-
related events will be classified using the following 18 categories:
Suicidal Ideation (SI-1 to SI-X)
SI-1: Passive Suicidal ideation
SI-2: Active Suicidal Ideation: Non-specific (no method, intent or plan)
SI-3: Active Suicidal Ideation: method, but no intent or plan
SI-4: Active Suicidal Ideation: method and intent, but no plan
SI-5: Active Suicidal Ideation: method, intent and plan
SI-X: Active Suicidal Ideation: other
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Suicidal Behavior (SB-1 to SB-5)
SB-1: Completed Suicide
SB-2: Suicide Attempt
SB-3: Interrupted Suicide Attempt
SB-4: Aborted Suicide Attempt
SB-5: Preparatory acts towards imminent suicidal behavior
Self-Injurious Behavior (SIB-1 to SIB-2)
SIB-1: Self-Injurious Behavior Without Suicidal Intent
SIB-2: Self-Injurious Behavior, Intent unknown
No Suicidal Ideation or Behavior / Not Enough Information / Other (13-17)
13: Not enough information (fatal)
14: Not enough information (non-fatal)
15: Other (accidental, psychiatric medical), no deliberate self-harm
16: No suicidal ideation or behavior
17: Not mapped to categories above
A frequency distribution of the 18 categories at each scheduled time point by treatment will be 
provided. In addition, the proportion of subjects classified in a more severe C-CASA category
compared the baseline category at any visit during the double-blind and follow-up phases will be 
presented by treatment group.
The most severe category for each subject will also be summarized into one of four broad 
categories: No suicidal ideation or behavior/Not enough information/Other, Self-Injurious 
behavior, Suicidal ideation, and Suicidal behavior. A frequency distribution of the most severe 
category during the double-blind and follow-up phases will be summarized by treatment group. 
Shifts from the baseline visit to the most severe category during the double-blind and follow-up 
phases will be summarized by treatment group.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
Details of the pharmacokinetic and pharmacodynamic analysis are provided in a separate 
document.
8.
BIOMARKER/PHARMACOGENOMIC ANALYSES
Details of biomarker and pharmacogenomic analyses are provided in a separate document.
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9.
HEALTH ECONOMICS
9.1.
Healthcare Resource Use Questionnaire (HRUQ)
Medical resource utilization data, associated with medical encounters, will be collected using the 
Healthcare Resource Use Questionnaire (HRUQ) on an ongoing basis whenever an encounter 
occurs. The HRUQ includes information regarding utilization of healthcare services (including 
the timing and type of serves), enabling changes in level and quantity of services to be 
considered as a variable in economic models.
Frequency distributions and descriptive statistics (N, mean, SD, median, minimum and 
maximum) for the HRUQ, including 30-day and 60-day readmission, and emergency room visits
related to MDD and suicidality, will be provided during the double-blind and follow-up phases.
A summary of the duration of the initial hospitalization will also be provided.
10.
RELATIONSHIP BETWEEN CGI-SS-R AND OTHER RELEVANT CLINICAL 
ENDPOINTS
The relationship between changes in CGI-SS-R scores and changes in relevant endpoints will be 
evaluated to demonstrate sensitivity to changes in severity of suicidality as assessed by the CGI-
SS-R. The SIBAT CGI-SS-R was designed to comprehensively evaluate the severity of 
suicidality by taking into account a broad range of suicide ideation and behavior. The CGI-SS-R 
was designed to detect changes in suicidality over short periods of time (i.e., hours). The CGI-
SS-R has face validity; the category ratings are directly interpretable as different levels of 
severity of suicidality. The correlation between changes in CGI-SS-R scores and changes in the 
MADRS total, MADRS suicidal ideation item, and the SIBAT Module 7 (Global Clinical 
Impression) FoST will be presented.
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REFERENCES
1.
International Conference on Harmonization (ICH) Tripartite Guideline E14. London: s.n., 2005. pp. The 
clinical evaluation of QT/QTc interval prolongation and proarrhythmic for non-antiarrhythmic drugs.
2.
VanderWeele, T.J., Zhang, Y., Lim, P. (2016). Mediation analysis with an ordinal outcome. Epidemiology, 
27(5):651-5.
3.
Imai K, Keele L, Tingley D (2010). A general approach to causal mediation analysis. Psychological Methods, 
Vol. 15, No. 4, pp. 309–334
4.
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation 
and Research (CDER), Center for Biologics Evaluation and Research (CBER). [2009] Guidance for industry 
drug induced liver injury: premarketing clinical evaluation. Available: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf.
5.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide 
Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal risk analysis of 
antidepressants. Am J Psychiatry. 2007;164:1035-1043.
6.
United States Food and Drug Administration, United States Department of Health and Human Services. 
Guidance for Industry: Suicidality: Prospective Assessment of Occurrence in Clinical Trials, Draft Guidance. 
August 2012. Revision 1. Available: http://www.fda.gov/downloads/Drugs/Guidances/UCM225130.pdf
7.
Fox, Jean-Paul. Bayesian item response modeling: Theory and applications. Springer Science & Business 
Media, 2010.
8.
Plummer, Martyn. "JAGS: A program for analysis of Bayesian graphical models using Gibbs sampling." 
Proceedings of the 3rd international workshop on distributed statistical computing. Vol. 124. 2003. 
9.
Wong, Wan Ling, et al. "Accounting for Standard Errors of Vision-Specific Latent Trait in Regression Models 
Accounting for SEs in Regression Models." Investigative ophthalmology & visual science 55.9 
(2014):5848-5854.
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ATTACHMENTS
Attachment 1: Criteria of Markedly Abnormal Laboratory Values
Markedly Abnormal Limits
Laboratory Parameter
Low
High
Alanine aminotransferase (ALT) (SGPT) [U/L]
N/A
200
Alanine aminotransferase (ALT) (SGPT) [U/L]
N/A
>3X ULN
Albumin [g/L]
24
60
Alkaline phosphatase [U/L]
N/A
250
Aspartate aminotransferase (AST) (SGOT) [U/L]
N/A
250
Aspartate aminotransferase (AST) (SGOT) [U/L]
>3X ULN
Basophils [%]
N/A
6
Bicarbonate [mmol/L]
15.1
34.9
Bilirubin, total [mol/L]
N/A
51.3
Blood urea nitrogen [mmol/L]
N/A
17.9
Calcium [mmol/L]
1.5
3
Chloride [mmol/L]
94
112
Creatine kinase (U/L)
N/A
990
Creatinine [mol/L]
N/A
265.2
Eosinophils [%]
N/A
10
Erythrocytes (RBC) [x1012/L] -- female
3.0
5.5
                                                   -- male
3.0
6.4
Gamma glutamyl transferase [U/L]
N/A
300
Glucose [mmol/L]
2.2
16.7
Hemoglobin [g/L]
80
190
Hematocrit [fraction] -- female
0.28
0.50
                                   -- male
0.24
0.55
Lactate Dehydrogenase [U/L]
N/A
500
Leukocytes(WBC) [x109/L]
2.5
15.0
Lymphocytes [%]
10
60
Monocytes [%]
N/A
20
Neutrophils, segmented [%]
30
90
Phosphate [mmol/L]
0.7
2.6
Platelet count [x109/L]
100
600
Potassium [mmol/L]
3.0
5.8
Protein, total [g/L]
50
N/A 
Sodium [mmol/L]
125
155
Urate [mol/L]
89.2
594.8
Urine pH
N/A
8.0
Hy’s Law criteria:
    Alanine aminotransferase (ALT) (SGPT) [U/L] or Aspartate     
aminotransferase (AST) (SGOT) [U/L]
>3X ULN
AND
Bilirubin, total [mol/L]
>2X ULN
Note: The same limits apply to both males and females unless gender is indicated; 
N/A = Not applicable.
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Attachment 2: Beck Hopelessness Scale Scoring
Add the number of responses appearing in the green cells. This is the total score.
1.
I look forward with hope and enthusiasm
T
F
2.
I might as well give up because there is nothing I can do about making things 
better for myself
T
F
3.
When things are going badly, I am helped by knowing that they cannot stay that 
way forever
T
F
4.
I can’t imagine what my life would be like in ten years
T
F
5.
I have enough time to accomplish the things I want to do
T
F
6.
In the future, I expect to succeed in what concerns me most
T
F
7.
My future seems dark to me
T
F
8.
I happen to be particularly lucky, and I expect to get more of the good things in 
life than the average person
T
F
9.
I just can’t get the breaks, and there’s no reason I will in the future
T
F
10.
My past experiences have prepared me well for the future
T
F
11.
All I can see ahead of me is unpleasantness rather than pleasantness
T
F
12.
I don’t expect to get what I really want
T
F
13.
When I look ahead to the future, I expect that I will be happier than I am now
T
F
14.
Things just won’t work out the way I want them to
T
F
15.
I have great faith in the future
T
F
16.
I never get what I want, so it is foolish to want anything
T
F
17.
It’s very unlikely that I will get any real satisfaction in the future
T
F
18.
The future seems vague and uncertain to me
T
F
19.
I can look forward to more good times than bad times
T
F
20.
There’s no use in really trying to get anything I want because I probably won’t 
get it.
T
F
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Attachment 3: SIBAT Module 2 and Module 3 Scoring
SIBAT Module 2: Each of the first 21 items of SIBAT Module 2 has 5 response options: 
“Never”, “Rarely”, “Sometimes”, “Often”, “Most of the time” and “All the time”, with the 
corresponding scores listed below. The total score is calculated by adding the scores of the first 
21 items.
Over the past 7 days…
Scoring Algorithm
1
...I have felt hopeful.
5
4
3
2
1
0
2
...I have felt agitated.
0
1
2
3
4
5
3
...I have felt happy. 
5
4
3
2
1
0
4
…my life has felt empty.
0
1
2
3
4
5
5
...I have felt valued by others.
5
4
3
2
1
0
6
...my emotions have been stable.
5
4
3
2
1
0
7
...I have wanted to end my life.
5
4
3
2
1
0
8
...I have felt hopeless.
0
1
2
3
4
5
9
...I have felt calm.
5
4
3
2
1
0
10
...I have felt depressed. 
0
1
2
3
4
5
11
…my life has felt fulfilled.
5
4
3
2
1
0
12
...I have felt worthless.
0
1
2
3
4
5
13
...I have gotten angry easily.
0
1
2
3
4
5
14
...my sleep has been good.
5
4
3
2
1
0
15
...I have had sudden, unexpected urges to take 
my life.
0
1
2
3
4
5
16
...I have felt anxious.
0
1
2
3
4
5
17
...my relationships with others have been good.
5
4
3
2
1
0
18
...I have felt isolated from others.
0
1
2
3
4
5
19
…I have thought about killing myself.
0
1
2
3
4
5
20
…I have wanted to hurt other people.
0
1
2
3
4
5
21
...I have heard a voice telling me to kill myself.
0
1
2
3
4
5
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SIBAT Module 3: Each of the 48 items of SIBAT Module 3 has 6 response options: “Strongly 
Disagree”, “Disagree”, “Slightly Disagree”, “Slightly Agree”, “Agree”, “Strongly Agree”, with 
the corresponding scores listed below. The total score is calculated by adding the scores of the 
48 items. 
1
I am glad to be alive.
5
4
3
2
1
0
2
I feel worthless.
0
1
2
3
4
5
3
It is difficult to control my urges to end my life.
0
1
2
3
4
5
4
I feel powerless to improve my situation.
0
1
2
3
4
5
5
My spiritual/religious beliefs prevent me from 
ending my life.
5
4
3
2
1
0
6
I wish to die in my sleep in the near future.
0
1
2
3
4
5
7
My concern for others prevents me from ending 
my life.
5
4
3
2
1
0
8
If I developed a life-threatening illness, I would 
make every effort to overcome it.
5
4
3
2
1
0
9
Nothing in life gives me pleasure.
0
1
2
3
4
5
10
I have been shamed and should die.
0
1
2
3
4
5
11
I feel so depressed that I would be better off 
dead.
0
1
2
3
4
5
12
I think I will end my life within the next year.
0
1
2
3
4
5
13
I feel lonely.
0
1
2
3
4
5
14
My emotional distress is so severe that I want to 
end my life.
0
1
2
3
4
5
15
I feel so stressed that it would be better if I were 
dead.
0
1
2
3
4
5
16
People or forces in the world want me to be 
dead.
0
1
2
3
4
5
17
I feel guilty about things I have done.
0
1
2
3
4
5
18
Others would be better off if I were dead.
0
1
2
3
4
5
19
There is no future for me.
0
1
2
3
4
5
20
I worry that there will be no one to help care for 
me.
0
1
2
3
4
5
21
I fantasize about ending my life.
0
1
2
3
4
5
22
I have life goals that are important to me.
5
4
3
2
1
0
23
I wish I were dead.
0
1
2
3
4
5
24
I feel trapped in my current unhappy situation.
0
1
2
3
4
5
25
I am a good person.
5
4
3
2
1
0
26
My life is hopeless and ending my life is the only 
way out.
0
1
2
3
4
5
27
There is a greater purpose for my life.
5
4
3
2
1
0
28
My thoughts are mixed up and I am confused.
0
1
2
3
4
5
29
I want to make my life a better one.
5
4
3
2
1
0
30
I feel neglected.
0
1
2
3
4
5
31
Death is the only solution to my problems.
0
1
2
3
4
5
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32
Some people in my life give me happiness.
5
4
3
2
1
0
33
I am fully prepared to end my life.
0
1
2
3
4
5
34
Helping others gives my life purpose.
5
4
3
2
1
0
35
Nobody will care if I am dead.
0
1
2
3
4
5
36
I want to stay alive.
5
4
3
2
1
0
37
My physical pain is so severe that I want to end 
my life.
0
1
2
3
4
5
38
My emotional (mental) pain is so severe that I 
want to end my life.
0
1
2
3
4
5
39
I want to spend more time alone.
0
1
2
3
4
5
40
I feel anxious much of the time.
0
1
2
3
4
5
41
I feel agitated much of the time.
0
1
2
3
4
5
42
I feel frightened much of the time.
0
1
2
3
4
5
43
I am talented and skilled.
5
4
3
2
1
0
44
I feel in control of my life.
5
4
3
2
1
0
45
I am a burden to others.
0
1
2
3
4
5
46
I am scared of dying.
5
4
3
2
1
0
47
I have troubling thoughts that I cannot control.
0
1
2
3
4
5
48
I am having a crisis in my life.
0
1
2
3
4
5
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Attachment 4: SIBAT Mapping to the C-CASA 2012 Plus
C-CSSRS / 
Expanded C-
CASA Code 
Number
2012 C-CASA Plus Category
1
SI-1
Passive Suicidal ideation
2
SI-2
Active Suicidal Ideation: Non-specific (no method, intent or plan)
3
SI-3
Active Suicidal Ideation: method, but no intent or plan
4
SI-4
Active Suicidal Ideation: method and intent, but no plan
5
SI-5
Active Suicidal Ideation: method, intent and plan
X
SI-X
Active Suicidal Ideation: other
6
SB-1
Completed Suicide
7
SB-2
Suicide Attempt
8
SB-3
Interrupted Suicide Attempt
9
SB-4
Aborted Suicide Attempt
10
SB-5
Preparatory acts towards imminent suicidal behavior
11
SIB-1
Self-Injurious Behavior Without Suicidal Intent
12
SIB-2
Self-Injurious Behavior, Intent unknown
13
Other
Not enough information (fatal)
14
Other
Not enough information (non-fatal)
15
Other
Other (accidental, psychiatric medical), no deliberate self-harm
16 
Other
No suicidal ideation or behavior
17
Other
Not mapped
Baseline
C-CSSRS / 
Expanded 
C-CASA 
Code 
Number
2012 Expanded 
C-CASA 
Category
How SIBAT maps to 2012 C-CASA Plus Categories
Lifetime (BASELINE)
1
SI-1
Passive Suicidal 
ideation
Inclusion: About Me: #17 = Yes
                   Or
                    My Current Thinking:  #6, or 10, or 11, or 15, or 18, or 23, or 31 = 
                    Slightly Agree/Agree/Strongly Agree
                   Or
                   My Risk:  #1 = 1/2/3/4
                    Or 
Exclusion: About Me: #18 = Yes
                    Or 
                    My Risk/Protective Factors: #7, 15, or 19 = rarely, sometimes, often,    
                    most of the time, all the time
                   Or
                   My Current Thinking #3, 12, 14, 21, 26, 33, 37 or 38 = 
                   Slightly Agree/Agree/Strongly Agree 
                   Or 
                   My Risk: #2 or 3 = 1 /2 /3 /4              
                   Or
                   My Risk: #4 = 2 /3 /4
                   Or
                   My Risk: #5 = 3 / 4 
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C-CSSRS / 
Expanded 
C-CASA 
Code 
Number
2012 Expanded 
C-CASA 
Category
How SIBAT maps to 2012 C-CASA Plus Categories
Lifetime (BASELINE)
2
SI-2
Active Suicidal 
Ideation: Non-
specific (no 
method, intent or 
plan)
Inclusion: About Me:  #18b = Yes
                   Or
                   My Risk/Protective Factors: #7, 15, or 19 = rarely, sometimes, often, 
                    most of the time, all the time
                    Or
                    My Current Thinking:  #3, 12, 14, 21, 26, 33, 37, or 38
                    (Slightly Agree/Agree/Strongly Agree) 
                    Or
                   My Risk: #2 or 3 = 1 /2 /3 /4              
                  
                   Or
                   My Risk: #5 = 3 / 4 
Exclusion: About Me: #18c or 18d or 18g or 18h or 18j or 18k = Yes 
                  Or
                  My Risk: #4 = 2 /3 /4
3
SI-3
Active Suicidal 
Ideation: method, 
but no intent or 
plan
Inclusion: About Me:  #18 and 18d = Yes
Exclusion: About Me: #18c, or 18g or 18h or 18j or 18k = Yes
                   Or
                   My Risk: #4 = 2 /3 /4
4
SI-4
Active Suicidal 
Ideation: method 
and intent, but no 
plan
Inclusion: About Me:  #18 and 18c = Yes or My Risk: #4 = 2 /3 /4
                   AND 
                   About Me 18d = Yes
Exclusion: About Me: #18g or 18h or 18j or 18k = Yes 
5
SI-5
Active Suicidal 
Ideation: method, 
intent and plan
Inclusion: About Me:  #18 and 18c = Yes or My Risk: #4 = 2 /3 /4
                   AND 
                   About Me 18d=Yes
                  AND
                   About Me (18g or 18h or 18j or 18k) = Yes
Exclusion: None
X
SI-X
Active Suicidal 
Ideation:  Other
Inclusion: About Me: #18b = Yes
                   Or
                   My Risk/Protective Factors: #7, Or 15, Or 19 = rarely, sometimes, often, 
                   most of the time, all the time
                   Or
                   My Current Thinking:  #3, OR 12, OR 14, OR 21, OR 26, OR 33, OR 37, OR 
                   38 (Slightly Agree/Agree/Strongly Agree) 
                  Or
                  My Risk: #2 = 1/2/3/4
                  Or 
                  My Risk: #3 = 1 /2 /3 /4              
                  Or
                  My Risk: #4 = 2 /3 /4
                  Or
                  My Risk: #5 = 3 / 4
                  Or
                  About Me: #18c or 18d or 18g or 18h or 18j or 18k = Yes  
Exclusion: Map to any of the following categories: SI-2, OR SI-3, OR SI-4, OR SI-5
6
SB-1
Completed 
Suicide
Inclusion: Not Applicable
7
SB-2
Suicide Attempt
Inclusion: About Me:  #18L = Yes
Exclusion: None
8
SB-3
Interrupted 
Suicide Attempt
Inclusion: About Me:  #18v= Yes
Exclusion: None
9
SB-4
Aborted Suicide 
Attempt
Inclusion: About Me:  #18s = Yes
Exclusion: None
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C-CSSRS / 
Expanded 
C-CASA 
Code 
Number
2012 Expanded 
C-CASA 
Category
How SIBAT maps to 2012 C-CASA Plus Categories
Lifetime (BASELINE)
10
SB-5
Preparatory acts 
towards imminent 
suicidal behavior
Inclusion: About Me:  #18i or 18j= Yes
Exclusion: None
11
SIB-1
Self-Injurious 
Behavior Without 
Suicidal Intent
Inclusion: About Me:  #19 = Slightly Agree/Agree/Strongly Agree 
Exclusion: None
12
SIB-2
Self-Injurious 
Behavior, Intent 
unknown
Inclusion: About Me:  #19 ‘not sure’
Exclusion: None
13
Other
Not enough 
information (fatal)
Inclusion:  Not Applicable
Exclusion: None
14
Other
Not enough 
information (non-
fatal)
Inclusion:  Not Applicable
Exclusion: None
15
Other
Other (accidental, 
psychiatric 
medical), no 
deliberate self-
harm
Inclusion: About Me: (#14 or 15 = Yes) AND (#18L = No AND #19 = Never)
Exclusion:  None
16 
Other
No suicidal 
ideation or 
behavior
Inclusion: My Current Thinking: # 12 and 23 = Disagree/Strong Disagree
Exclusions:  About Me: #17 or #18 = Yes 
                   Or
                   My Risk/Protective Factors: #7, 15, and 19 = rarely, sometimes, often, 
                   most of the time, all the time
                   Or
                   My Current Thinking #3 or 6 or 10 or 11 or 12 or 14 or 15 or 18 or 21 or 
                   23, or 26, or 31, or 33 or 37 or 38 = Slightly Agree/Agree/Strongly Agree
                   Or
                   My Risk:  #1 or 2 or 3 = 1 /2 /3 /4              
                   Or
                   My Risk: #4 = 2 /3 /4
                   Or
                   My Risk:  #5 = 3 / 4 
17
Other
Not Mappable
Y: If mapping to C-CASA Code Number 1 and 2 and 3 and 4 and 5 and 6 and 7 and 8 
and 9 and 10 and 11 and 12 and 13 and 14 and 15 and 16 and X = No or missing, then 
YES
N: If not YES, then NO
Initial Most Severe category: 
     SI:     5 > 4 > X > 3 > 2 > 1
       SB:   6 > 7 > 8 > 9 > 10
       SIB:  12 > 11
  
Overall severity determination:  6 > 7 > 8 > 9 > 10 > 5 > 4 > X > 3 > 2 > 1 > 12 > 11 > 13 > 14 > 16 > 15 > 17
If both inclusion and exclusion criteria are met, the exclusion criterion takes precedence over the inclusion criterion and the mapping 
condition is NOT met.
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Post-Baseline
C-CSSRS / 
Expanded 
C-CASA 
Code 
Number
2012 Expanded C-
CASA Category
How SIBAT maps to 2012 C-CASA Plus Categories
Post Baseline
1
SI-1
Passive Suicidal 
ideation
Inclusion: My Current Thinking:  #6, or 10, or 11, or 15, or 18, or 23, or 31 = 
                   Slightly Agree/Agree/Strongly Agree
                   Or
                   My Risk:  #1 = 1/2/3/4
Exclusion: My Risk/Protective Factors: #7, 15, or19 = rarely, sometimes, often, 
                   most of the time, all the time
                   Or
                   My Current Thinking #3, 12, 14, 21, 26, 33, 37 or 38 = 
                   Slightly Agree/Agree/Strongly Agree 
                    Or 
                    My Actions: #10 = Yes
                    Or
                    My Risk: #2 or 3 = 1 /2 /3 /4              
                    Or
                    My Risk: #4 = 2 /3 /4
                    Or
                    My Risk: #5 = 3 / 4 
2
SI-2
Active Suicidal 
Ideation: Non-
specific (no 
method, intent or 
plan)
Inclusion: My Risk/Protective Factors: #7, 15, or 19 = rarely, sometimes, often,       
                  most of the time, all the time
                  Or
                  My Current Thinking:  #3, 12, 14, 21, 26, 33, 37, or 38 = 
                  Slightly Agree/Agree/Strongly Agree 
                  Or 
                 My Actions: #10 a = Yes
                 Or
                 My Risk: #2 or 3 = 1 /2 /3 /4              
                 Or
                 My Risk: #5 = 3 / 4 
          
Exclusion: My Actions: #10b or 10c or 10d or 10g = Yes, or #10e is any answer 
                 other than ‘NO’
                 Or
                 My Risk: #4 = 2 /3 /4
3
SI-3
Active Suicidal 
Ideation: method, 
but no intent or 
plan
Inclusion: My Actions:  #10c = Yes
Exclusion: My Actions: #10b or 10d or 10g = Yes, or #10e is any answer other than 
                 ‘NO’
                 Or
                 My Risk: #4 = 2 /3 /4
4
SI-4
Active Suicidal 
Ideation: method 
and intent, but no 
plan
Inclusion: My Actions: (# 10b or 10g = Yes) or My Risk: #4 = 2 /3 /4
                  AND
                  My Actions 10c = Yes
Exclusion: My Actions: #10d = Yes, or #10e is any answer other than ‘NO’
5
SI-5
Active Suicidal 
Ideation: method, 
intent and plan
Inclusion: My Actions: (# 10b or 10g = Yes) or My Risk: #4 = 2 /3 /4
                  AND 
                  My Actions 10c = Yes 
                  AND 
                   My Actions (#10d = Yes or #10e is any answer other than ‘NO’)
Exclusion: None
NCT03097133


JNJ54135419  (esketamine)
Statistical Analysis Plan 54135419SUI3002
57
Approved, Date: 3 May 2019
C-CSSRS / 
Expanded 
C-CASA 
Code 
Number
2012 Expanded C-
CASA Category
How SIBAT maps to 2012 C-CASA Plus Categories
Post Baseline
X
SI-X 
Active Suicidal 
Ideation: other
Inclusion: My Risk/Protective Factors: #7, or 15, or 19 = rarely, sometimes, often, 
                  most of the time, all the time
                  Or
                  My Current Thinking:  #3, OR 12, OR 14, OR 21, OR 26, OR 33, OR 37, or 
                  38 (Slightly Agree/Agree/Strongly Agree) 
                  Or 
                  My Actions:  #10 a = Yes
                  Or
                  My Risk: #2 or 3 = 1 /2 /3 /4              
                  Or
                  My Risk: #4 = 2 /3 /4
                  Or
                  My Risk: #5 = 3 / 4
                  Or
                  My Actions: #10b or 10c or 10d or 10g = Yes, or #10e is any answer other 
                  than ‘NO’
                
Exclusion:  Map to any of the following categories: SI-2, OR SI-3, OR SI-4, OR SI-5
6
SB-1
Completed Suicide
Inclusion: Introduction: Response 1a1
Exclusion: None
7
SB-2
Suicide Attempt
Inclusion: Introduction: Response 1a4
                   Or
                   My Actions:  #3 or 5 = Yes
Exclusion: None
8
SB-3
Interrupted Suicide 
Attempt
Inclusion: My Actions:  #8 = Yes
Exclusion: None
9
SB-4
Aborted Suicide 
Attempt
Inclusion: My Actions:  #7= Yes
Exclusion: None
10
SB-5
Preparatory acts 
towards imminent 
suicidal behavior
Inclusion: My Actions: # 10f or 10g = Yes
Exclusion: None
11
SIB-1
Self-Injurious 
Behavior Without 
Suicidal Intent
Inclusion: My Actions:  # 2 = Yes AND #3 = No
                   Or
                   My Actions:  # 4 = Yes AND #3 = No
                    Or
                   My Actions:  #9= Yes               
Exclusion: None
12
SIB-2
Self-Injurious 
Behavior, Intent 
unknown
Inclusion: My Actions: (Either #2 or 4 = Yes) AND #3 = Uncertain)
                   Or
                   My Actions:  #9 = Uncertain
Exclusion: None
13
Other
Not enough 
information (fatal)
Inclusion:  Introduction: Response 1a2 or 1a3
Exclusion: None
14
Other
Not enough 
information (non-
fatal)
Inclusion:  Introduction: Response 1a6 
Exclusion: None
15
Other
Other (accidental, 
psychiatric 
medical), no 
deliberate self-
harm
Inclusion:  My Actions: #1 = No
                    Or            
                    My Actions: #1 = Yes AND (My Actions #2 and 3 = No) 
                    Or 
                    Introduction: Response 1a5
Exclusion: None
NCT03097133


JNJ54135419  (esketamine)
Statistical Analysis Plan 54135419SUI3002
58
Approved, Date: 3 May 2019
C-CSSRS / 
Expanded 
C-CASA 
Code 
Number
2012 Expanded C-
CASA Category
How SIBAT maps to 2012 C-CASA Plus Categories
Post Baseline
16 
Other
No suicidal 
ideation or 
behavior
Inclusion: My Current Thinking: #12 and 23 = Disagree/Strong Disagree
Exclusion: My Risk/Protective Factors: #7, 15, or 19 = rarely, sometimes, often, 
                   most of the time, all the time
                   Or
                   My Current Thinking #3 or 6 or 10 or 11 or 12 or 14 or 15 or 18 or 21 or 
                   23, or 26, or 31, or 33 or 37 or 38 = Slightly Agree/Agree/Strongly Agree
                   Or
                   My Actions: #3 or 5 or 7 or 8 or 10 = Yes
                   Or
                   My Risk:  #1 or 2 or 3 = 1 /2 /3 /4              
                   Or
                   My Risk: #4 = 2 /3 /4
                   Or
                   My Risk:  #5 = 3 / 4 
17
Other
Not mapped
Y: If mapping to C-CASA Code Number 1 and 2 and 3 and 4 and 5 and 6 and 7 and 8 
and 9 and 10 and 11 and 12 and 13 and 14 and 15 and 16 and X = No or missing, then 
YES
N: If not YES, then NO
Initial Most Severe category: 
     SI:     5 > 4 > X > 3 > 2 > 1
       SB:   6 > 7 > 8 > 9 > 10
       SIB:  12 > 11
  
Overall severity determination:  6 > 7 > 8 > 9 > 10 > 5 > 4 > X > 3 > 2 > 1 > 12 > 11 > 13 > 14 > 16 > 15 > 17
If both inclusion and exclusion criteria are met, the exclusion criterion takes precedence over the inclusion criterion and the mapping 
condition is NOT met.
NCT03097133