Clinical trial NCT03185819
Conditions: Depressive Disorder, Major
Sponsor: Janssen Research & Development, LLC
Start date: 2017-10-05; Completion date: 2023-03-31
Enrollment: 147 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy of a single (first) dose of 3 fixed doses of intranasal esketamine {28 milligram (mg), 56 mg, and 84 mg} compared with psychoactive placebo (oral midazolam) in rapidly reducing the symptoms of major depressive disorder (MDD) including suicidal ideation in participants 12 to less than 18 years of age who are assessed to be at imminent risk for suicide.

Detailed description:
This study will enroll participants with major depressive disorder (MDD) presenting with suicidal ideation who are assessed to be at imminent risk for suicide. The study will be conducted in 4 phases: a screening evaluation performed within 48 hours prior to Day 1 intranasal dose; a 25-day double-blind treatment phase (Days 1-25); an 8-week initial post-treatment phase (Days 25-81); and a subsequent phase to complete a full 6-month post-treatment follow-up (Days 81-200). Efficacy, safety, pharmacokinetic, biomarker, and pharmacogenomic evaluations will be performed in the study at defined schedule. The duration of the participant's participation will be approximately 29 weeks. 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 midazolam solution 0.125 milligram per kilogram (mg/kg) orally 2 times per week for 4 weeks and 3 intranasal doses of matched placebo to esketamine. arm 2: Participants will receive intranasal esketamine 84 mg as 3 intranasal doses of esketamine in each nostril (each dose contains 14 mg of esketamine) along with oral placebo 2 times per week for 4 weeks. arm 3: Participants will receive intranasal esketamine 56 mg as 2 intranasal doses of esketamine in each nostril (each dose contains 14 mg of esketamine) along with oral placebo 2 times per week for 4 weeks. arm 4: Participants will receive intranasal esketamine 28 mg as 1 intranasal doses of esketamine in each nostril (each dose contains 14 mg of esketamine) along with oral placebo 2 times per week for 4 weeks.
Interventions: intervention 1: Intranasal Placebo intervention 2: Midazolam Placebo Solution intervention 3: Midazolam intervention 4: Esketamine intervention 5: Esketamine intervention 6: Esketamine
Intervention descriptions: intervention 1: Participants will receive placebo as intranasal dose to match intranasal esketamine. intervention 2: Participants will receive placebo as oral dose to match midazolam drug. intervention 3: Participants will receive midazolam solution 0.125 mg/kg as oral dose to match placebo. intervention 4: Participants will receive esketamine at a dose of 28 mg as intranasal solution. intervention 5: Participants will receive esketamine at a dose of 56 mg as intranasal solution. intervention 6: Participants will receive esketamine at a dose of 84 mg as intranasal solution.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 22 November 2020
Janssen Research & Development *
Clinical Protocol
A Double-blind, Randomized, Psychoactive Placebo-controlled, Study to Evaluate the 
Efficacy and Safety of 3 Fixed Doses (28 mg, 56 mg and 84 mg) 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 Pediatric Subjects Assessed to 
be at Imminent Risk for Suicide
Protocol ESKETINSUI2002; Phase 2b
AMENDMENT 4
JNJ-54135419  (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:         2016-004422-42
Status:
Approved
Date:
22 November 2020
Prepared by:
Janssen Research & Development  
EDMS number:
EDMS-ERI-132382053, 5.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient will 
maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 22 November 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 37
TIME AND EVENTS SCHEDULE – DOUBLE-BLIND TREATMENT PHASE .......................................... 49
TIME AND EVENTS SCHEDULE – POST-TREATMENT FOLLOW-UP PHASE..................................... 52
SIBAT TIME AND EVENTS SCHEDULE – DOUBLE-BLIND TREATMENT PHASE .............................. 55
SIBAT TIME AND EVENTS SCHEDULE – POST-TREATMENT FOLLOW-UP PHASE......................... 55
ABBREVIATIONS ...................................................................................................................................... 56
1.
INTRODUCTION................................................................................................................................ 58
1.1.
Background .................................................................................................................................... 59
1.1.1.
Nonclinical Studies ..................................................................................................................... 59
1.1.2.
Clinical Studies ........................................................................................................................... 60
1.1.2.1.
Completed and Ongoing Clinical Studies with Intranasal Esketamine.................................... 60
1.1.2.2.
Human Pharmacokinetics and Product Metabolism................................................................ 61
1.1.2.3.
Efficacy .................................................................................................................................... 62
1.1.2.4.
Safety and Tolerability............................................................................................................. 63
1.2.
Psychoactive Placebo Control ....................................................................................................... 66
1.3.
Overall Rationale for the Study...................................................................................................... 67
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 67
2.1.
Objectives and Endpoints .............................................................................................................. 67
2.1.1.
Objectives ................................................................................................................................... 67
2.1.2.
Endpoints.................................................................................................................................... 69
2.2.
Hypothesis ..................................................................................................................................... 70
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 70
3.1.
Overview of Study Design.............................................................................................................. 70
3.2.
Study Design Rationale.................................................................................................................. 72
3.2.1.
Study Population......................................................................................................................... 72
3.2.2.
Treatment and Study Duration ................................................................................................... 73
3.2.3.
Control, Randomization and Blinding ......................................................................................... 73
3.2.4.
Esketamine Dose........................................................................................................................ 74
3.2.5.
Psychoactive Placebo................................................................................................................. 75
3.2.6.
Efficacy Measures ...................................................................................................................... 75
3.2.7.
Safety Evaluations...................................................................................................................... 78
3.2.8.
Pharmacokinetic Assessments................................................................................................... 79
3.2.9.
Biomarker and Pharmacogenomic (DNA and RNA) Evaluations............................................... 79
3.2.9.1.
Biomarker ................................................................................................................................ 79
3.2.9.2.
Pharmacogenomic/Epigenetic (DNA and RNA)...................................................................... 79
4.
SUBJECT POPULATION.................................................................................................................. 79
4.1.
Inclusion Criteria ............................................................................................................................ 80
4.2.
Exclusion Criteria ........................................................................................................................... 83
4.3.
Prohibitions and Restrictions ......................................................................................................... 86
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JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 22 November 2020
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 86
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 88
6.1.
Oral Study Drug ............................................................................................................................. 89
6.2.
Intranasal Study Drug .................................................................................................................... 89
6.3.
Guidance on Blood Pressure Monitoring on Study Medication Dosing Days................................ 90
7.
TREATMENT COMPLIANCE............................................................................................................ 91
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 91
9.
STUDY EVALUATIONS .................................................................................................................... 91
9.1.
Study Procedures........................................................................................................................... 91
9.1.1.
Overview..................................................................................................................................... 91
9.1.2.
Screening Phase ........................................................................................................................ 93
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 93
9.1.4.
Post-Treatment Follow-up Phases ............................................................................................. 96
9.1.5.
Early Withdrawal......................................................................................................................... 96
9.2.
Efficacy Evaluations....................................................................................................................... 97
9.2.1.
Children’s Depression Rating Scale, Revised (CDRS-R) .......................................................... 97
9.2.2.
Suicide Ideation and Behavior Assessment Tool (SIBAT) ......................................................... 97
9.2.3.
Montgomery-Asberg Depression Rating Scale .......................................................................... 98
9.2.4.
Children’s Depression Inventory 2: Self-Report (Short) ............................................................. 98
9.3.
Pharmacokinetics........................................................................................................................... 99
9.3.1.
Evaluations ................................................................................................................................. 99
9.3.2.
Analytical Procedures................................................................................................................. 99
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 99
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations........................................................................ 100
9.5.
Biomarker and Pharmacogenomic (DNA and RNA) Evaluations ................................................ 100
9.6.
Safety Evaluations ....................................................................................................................... 101
9.7.
Other Evaluations......................................................................................................................... 107
9.8.
Sample Collection and Handling.................................................................................................. 107
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ......................................................................................................................... 108
10.1.
Completion ................................................................................................................................... 108
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study ................................................. 108
10.3.
Withdrawal from the Use of Research Samples .......................................................................... 109
11.
STATISTICAL METHODS............................................................................................................... 110
11.1.
Subject Information ...................................................................................................................... 110
11.2.
Sample Size Determination ......................................................................................................... 110
11.3.
Efficacy Analyses ......................................................................................................................... 110
11.4.
Pharmacokinetic Analyses........................................................................................................... 112
11.5.
Biomarker and Pharmacogenomic Analyses............................................................................... 112
11.6.
Safety Analyses ........................................................................................................................... 113
11.7.
Independent Data Monitoring Committee .................................................................................... 115
12.
ADVERSE EVENT REPORTING .................................................................................................... 115
12.1.
Definitions .................................................................................................................................... 115
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 115
12.1.2.
Attribution Definitions................................................................................................................ 117
12.1.3.
Severity Criteria ........................................................................................................................ 117
12.2.
Special Reporting Situations........................................................................................................ 118
12.3.
Procedures................................................................................................................................... 118
12.3.1.
All Adverse Events.................................................................................................................... 118
12.3.2.
Serious Adverse Events ........................................................................................................... 119
12.3.3.
Pregnancy................................................................................................................................. 120
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 22 November 2020
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 120
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 121
13.1.
Procedures................................................................................................................................... 121
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 121
14.
STUDY DRUG INFORMATION....................................................................................................... 121
14.1.
Physical Description of Study Drug(s) ......................................................................................... 121
14.2.
Packaging .................................................................................................................................... 122
14.3.
Labeling........................................................................................................................................ 122
14.4.
Preparation, Handling, and Storage............................................................................................. 123
14.5.
Drug Accountability ...................................................................................................................... 123
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 123
16.
ETHICAL ASPECTS ....................................................................................................................... 124
16.1.
Study-Specific Design Considerations......................................................................................... 124
16.2.
Regulatory Ethics Compliance..................................................................................................... 127
16.2.1.
Investigator Responsibilities ..................................................................................................... 127
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 129
16.2.3.
Informed Consent/Pediatric Assent Form................................................................................. 130
16.2.4.
Privacy of Personal Data .......................................................................................................... 131
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 132
16.2.6.
Country Selection ..................................................................................................................... 132
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 132
17.1.
Protocol Amendments.................................................................................................................. 132
17.2.
Regulatory Documentation .......................................................................................................... 133
17.2.1.
Regulatory Approval/Notification .............................................................................................. 133
17.2.2.
Required Prestudy Documentation........................................................................................... 133
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 134
17.4.
Source Documentation................................................................................................................. 134
17.5.
Case Report Form Completion .................................................................................................... 135
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 136
17.7.
Record Retention ......................................................................................................................... 136
17.8.
Monitoring .................................................................................................................................... 137
17.9.
Study Completion/Termination..................................................................................................... 137
17.9.1.
Study Completion/End of Study................................................................................................ 137
17.9.2.
Study Termination..................................................................................................................... 138
17.10.
On-Site Audits .............................................................................................................................. 138
17.11.
Use of Information and Publication.............................................................................................. 138
REFERENCES.......................................................................................................................................... 140
INVESTIGATOR AGREEMENT ............................................................................................................... 155
LIST OF ATTACHMENTS
Attachment 1:
Prohibited/Permitted Concomitant Medications ....................................................... 146
Attachment 2:
Growth Charts: Stature-for-Age Percentiles for Use in Blood Pressure 
Assessments ............................................................................................................ 149
Attachment 3:
95th Percentile Blood Pressure Levels For Sex by Age and Height......................... 151
Attachment 4:
Postdose Blood Pressure: Withdrawal Criteria Levels for Sex by Age and 
Height ....................................................................................................................... 153
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 22 November 2020
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Dose administration of Intranasal Esketamine 28, 56, 84 mg or Placebo................................ 90
Table 2:
Approximate Volume of Blood to be Collected from Each Subject .......................................... 92
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 72
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 22 November 2020
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
30 January 2017
Amendment 1
28 April 2017
Amendment 2
14 June 2017
Amendment 3
20 November 2018
Amendment 4
01 December 2020
Amendments below are listed beginning with the most recent amendment.
Amendment 4 (01 December 2020)
The overall reason for the amendment: The overall reason for the amendment is to update the text related to 
statistical methods on sample size determination and multiple testing procedure. The multiple testing procedure 
has been modified to improve power while controlling the overall Type I error rate when comparing the 
individual doses with psychoactive placebo.
Applicable Section(s)
Description of Change(s)
Rationale: Text for sample size determination and multiple testing procedure was updated to improve power 
while controlling the overall Type 1 error rate when comparing the individual doses with psychoactive placebo.
Synopsis, Sample 
Size Determination;
Section 11.2. Sample 
Size Determination
Text was revised as follows:
The sample size for this study was calculated assuming an effect size of 0.65 between any 
dose of esketamine and psychoactive placebo for the change from baseline at 24 hours 
postdose for the CDRS-R total score and a 1 2-sided significance level of 0.025 0.05. A 
total of 145 subjects will be randomized in this study. Using a 1:1:1:2 randomization ratio 
(esketamine 28 mg: esketamine 56 mg: esketamine 84 mg: psychoactive placebo), 
approximately 58 subjects will need to be randomized to psychoactive placebo and 29 
subjects will need to be randomized to each esketamine treatment group to achieve 80% 
power for the comparison of each esketamine dose 94% power for the comparison 
of the pooled doses of esketamine 56 mg and esketamine 84 mg versus psychoactive 
placebo and 92% power for at least one of the 2 esketamine higher doses (56-mg and 
84-mg)  versus psychoactive placebo. The effect size of 0.65 is based on results from 
study ESKETINSUI2001 (mean difference between treatment groups of -7.2 and a pooled 
SD of 11.02) for MADRS total score.
Rationale: A pooled sequential multiple testing strategy will be implemented to control Type 1 error.
Synopsis, Primary 
Efficacy Analysis;
Section 11.3. Efficacy 
Analysis
Text was revised as follows:
As the primary analysis, each dose will be compared to psychoactive placebo using the 
appropriate contrast at a 1 sided significance level of 0.025. A fixed sequence test 
procedure will be applied where the 84 mg dose will be tested first and the 56 mg dose 
will be tested only if the 84 mg dose is shown to be significant.
A pooled sequential multiple testing procedure will be implemented to control for 
Type 1 error.  The esketamine 56-mg and 84-mg treatment groups will be pooled and 
compared with psychoactive placebo at a 2-sided significance level of 0.05. If this 
comparison achieves statistical significance in favor of esketamine, the 56-mg dose 
and the 84-mg dose will each be simultaneously tested versus psychoactive placebo 
at the 2-sided significance level of 0.05 based on the closed testing procedure. The 
28-mg dose will be tested only if both the individual doses of 56 mg and 84 mg are 
shown to be significant.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Rationale: An additional database lock (DBL) and analysis of efficacy and safety will be performed when the last 
subject completes the double-blind Day 25 visit. This analysis will enable selection of a dose for the planned Phase 
3 trial, facilitating Phase 3 trial design and preparation as early as possible. Database locks will also be performed 
at Days 81 and 200 (study completion)
Synopsis,
Other Objectives
Section 2.1.1. 
Objective
Other Objective
Text was revised as follows:

To evaluate the safety and tolerability of intranasal esketamine at specified times 
through the initial 25 day double-blind treatment period (Day 25), the 8-week 
post-treatment follow-up (Day 81) and 6-month post-treatment follow-up, with 
special attention given to the following assessments:

Effects on suicidal ideation and behavior using the SIBAT

Effects on cognitive function as measured by the Cogstate computerized 
cognitive battery
Section 5. 
TREATMENT 
ALLOCATION AND 
BLINDING
Blinding
In general, randomization codes will be disclosed fully only if the study is completed and 
the clinical database is closed. However, an analysis is planned after the last subject 
completes the Day 25 81 visit. Randomization codes will be disclosed to the sponsor in 
order to plan for Phase 3 studies.
Section 11. 
STATISTICAL 
METHODS
An analysis of efficacy and safety will be performed after the last subject completes the
8 week Post Treatment Follow up phase (Day 81) 25-day Double-blind Treatment 
Period (Day 25). This analysis will enable selection of a dose for the planned Phase 3 
trial, facilitating Phase 3 trial design and preparation. Database locks will also be 
performed after the last subject completes the Day 81 Visit and Day 200 Visit, 
respectively.
Amendment 3 (20 November 2018)
Overall reasons for the amendment: The protocol was modified to 1) streamline the assessment schedule 
(number, type and timing of study visits and visit windows) to reduce burden for subjects who discontinue the 
study; 2) update Attachment 1  (Prohibited and Permitted Concomitant Medications) with new guidelines; 3) add 
blood pressure withdrawal criteria and clarify blood pressure exclusion criteria and guidance; 4) include changes 
to biomarker and pharmacogenomic assessments; and 5) update consent/assent language to reflect the pediatric 
study population requirements. 
Applicable Section(s)
Description of Change(s)
Rationale: Blood Pressure (BP) exclusionary criterion was updated to include information for both Screening 
(Day -1) and Day 1.  Attachment 2 “Weight Chart” was replaced by a “Stature Chart” as the “Weight Chart” was 
erroneously included and stature is needed to determine the appropriate criteria for individual subject BP 
thresholds. Titles for Attachments 2 and 3 were revised accordingly, and Attachment 4 was added to include 
guidance for postdose BP withdrawal values. Language was updated for clarity.
Synopsis Key Exclusion 
Criteria
Exclusion criterion was modified as follows:
On Day -1 (screening) or Day 1 of the double-blind phase prior to 
randomization, a supine or semi-supine SBP and/or DBP ≥ the 95th percentile 
for sex, age and height is exclusionary. Subjects who fall below the 5th or above 
the 95th percentile for their age, sex, and height should be evaluated using the 
parameters for the 5th or 95th percentile. Note that subjects whose SBP and/or 
DBP values are ≥ the 95th percentile for sex, age and height may be reevaluated 
with a repeated measure once after 5 minutes of rest to assess eligibility.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Section 4.2. Exclusion Criteria
Exclusion criterion 7 was revised as follows:
Criterion modified per Amendment 3
7.2.
On Day -1 (screening) or Day 1 of the double-blind phase prior to 
randomization, a supine or semi-supine SBP and/or DBP ≥ the 95th percentile 
for sex, age and height is exclusionary. Subjects who fall below the 5th or above 
the 95th percentile for their age, sex, and height should be evaluated using the 
parameters for the 5th or 95th percentile. Note that subjects whose SBP and/or 
DBP values are ≥ the 95th percentile for sex, age and height may be reevaluated 
with a repeated measure once after 5 minutes of rest to assess eligibility.
Section 6.3. Guidance on 
Blood Pressure Monitoring on 
Study Medication Dosing
Days
Text was revised to reflect the new titles of Attachments 2 and 3, and to add 
information for a new attachment (Attachment 4):
Attachment 2 (Growth Charts: Stature-for-Age Percentiles for Use in Blood 
Pressure Assessments) and Attachment 3 (95th Percentile Blood Pressure Levels 
For Sex by Age and Height) will be used to determine the 95th percentile for 
both the systolic (SBP) and diastolic blood pressures (DBP) by sex, age and 
height percentile (refer to Attachment 3 for instructions).
On any dosing day, if either the postdose SBP or DBP levels are equal to or 
greater than the sex, age and height values in Attachment 4 (Postdose Blood 
Pressure: Withdrawal Criteria Levels for Sex by Age and Height), the blood 
pressure should be repeated after the subject rests for at least 5 minutes (ie, 
sitting or supine). If the values are still equal to or greater than the sex, age and 
height values in Attachment 4, the subject should be withdrawn from the study
and appropriate follow-up clinical care should be initiated.
Rationale: Withdrawal criteria were updated to include 1) additional therapies that are excluded during the study, 
and 2) to include the withdrawal of subjects whose postdose withdrawal values for systolic and/or diastolic blood 
pressure exceeds individual thresholds that are equal to or above the 99th percentile for age, height and sex plus 
1.28 SD over the mean. These values are now added in Attachment 4. 
Section 10.2. Discontinuation 
of Study
Treatment/Withdrawal from 
the Study
The following withdrawal criteria were added:

Requires treatment with ECT, TMS, ketamine or esketamine

Subjects whose postdose SBP or DBP measures are equal to or greater than 
the sex, age and height values in Attachment 4 (after a repeated 
measurement).
Rationale: Text related to early withdrawal and discontinuation during the Double-Blind and Post-Treatment 
Follow-Up phase was updated in Section 9.1.5. and deleted from Section 10.2. to avoid redundancy.
Changes were made to reduce burden while still thoroughly assessing safety parameters for subjects who 
discontinue the study.
Section 9.1.5. Early 
Withdrawal
The text was revised as follows:
Subjects who discontinue Double-Blind Study treatment for reasons other than 
withdrawal of consent/assent, lost to follow-up or death will have the DB EW 
visit conducted at the time of discontinuation. In addition, if the DB EW visit 
occurs on Day 1 to Day 21, a remote contact visit (eg, by telephone) will be 
conducted 5 days (+/-2 days) after the last dose of study medication. If remote 
contact D+5 occurs within 2 days of the early withdrawal visit, use the +2 day 
window to conduct the remote contact D+5 visit. A remote contact visit will 
also be conducted on Day 25 to assess PWC-20, CDRS-R and MADRS, and for 
collection of concomitant therapies and AEs. If the DB EW visit occurs on or 
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
after Day 22 (assuming dose administered), D25 RC visit is not required, 
however, RC D+5 (5 days after last dose) should be performed.
Subjects who discontinue from the Post-Treatment Follow-Up phase for reasons 
other than withdrawal of consent/assent, lost to follow-up or death will have the 
Post-Treatment Early Withdrawal visit conducted at the time of discontinuation. 
In addition, if the PT EW visit occurs prior to completion of the Day 81 visit, a 
remote contact (eg, by telephone) will be performed on Day 81 for PWC-20, 
CDRS-R and MADRS, and for collection of concomitant therapies and AEs. If 
the PT EW visit occurs within ±5 days window of Day 81 (Visit 18), then early 
withdrawal visit will be adequate, and the Day 81 RC visit is not required. If 
subjects discontinue anytime between Day 25 postdose and Day 28 RC of the 
PT phase, the PT EW visit is not required; however, Day 28 RC should be 
performed.
Section 10.2. Discontinuation 
of Study 
Treatment/Withdrawal from 
the Study
The following text was deleted, and instructions added to refer to Section 9.1.5.:
Subjects who discontinue study treatment prior to completion of the Double-
Blind Treatment phase (Day 25 visit), will have an Early Withdrawal visit 
conducted at the time of treatment discontinuation. Subjects who discontinue 
double-blind study treatment for reasons other than withdrawal of consent, lost 
to follow-up or death will be contacted remotely 3 and 10 days after the last 
dose of intranasal study medication to assess adverse events, any withdrawal 
symptoms utilizing PWC 20, and rebound with assessment of CDRS-R and 
MADRS. Additionally, these subjects will return for the Day 25 and Day 81 
visit assessments. If subjects refuse to return for in-person assessment on Day 
25 and 81, remote contact (eg, by telephone) on Days 25 and 81 for CDRS-R 
and MADRS assessments and adverse event collection is acceptable. 
If the Early Withdrawal visit occurs within a window of ±1 days of the Day 25 
visit of the Double-Blind Treatment phase, or within a window of ±5 days of 
the Day 81 visit of the follow-up phase, the Day 25 or Day 81 visits, 
respectively, are not required.
Subjects who discontinue from the Post-Treatment Follow-Up phase prior to 
completion of the Day 81 visit will have the Post-Treatment Early Withdrawal 
visit conducted at the time of discontinuation. Subjects who discontinue for 
reasons other than withdrawal of consent, lost to follow-up or death will return 
for the Day 81 visit. For subjects who refuse to return for in-person assessment, 
remote contact (eg, by telephone) on Day 81 for CDRS-R and MADRS 
assessments and adverse event collection is acceptable. Subjects who 
discontinue from the Post-Treatment Follow-Up Phase after completion of the 
Day 81 visit will have the Post-Treatment Early Withdrawal visit conducted at 
the time of discontinuation.
Rationale: The CGI-SR-I was added to correct the inadvertent omission from the protocol as an objective and 
endpoint.
Synopsis, Other Objectives,
Endpoints; Overview of Study 
Design
CGI-SR-I was added to “Other Objectives” and “Endpoints”:

To evaluate the efficacy of single and repeated doses of intranasal 
esketamine compared with psychoactive placebo in reducing symptoms of 
suicidal ideation, as assessed by the Clinical Global Impression – Imminent 
Suicide Risk (CGI-SR-I) from the Suicide Ideation and Behavior 
Assessment Tool (SIBAT) at 4 hours and 24 hours post first dose and 
through the end of the Double-Blind Treatment phase (Day 25).
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
10
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)

CGI-SR-I from SIBAT
o
Changes from baseline, post single and repeated doses, at 4 hours 
and 24 hours post first dose, through the end of the Double-Blind 
Treatment phase (Day 25).
CGI-SR-I was added as “other efficacy evaluation”:

The primary efficacy evaluation is the CDRS-R; other efficacy evaluations 
are SIBAT/CGI-SS-R and CGI-SR-I, MADRS, CDI 2:SR(S).
Section 2.1.1. Objectives 
CGI-SR-I was added to “Other Objectives”

To evaluate the efficacy of single and repeated doses of intranasal 
esketamine compared with psychoactive placebo in reducing symptoms of 
suicidal ideation, as assessed by the Clinical Global Impression – Imminent 
Suicide Risk (CGI-SR-I) from the Suicide Ideation and Behavior 
Assessment Tool (SIBAT) at 4 hours and 24 hours post first dose and 
through the end of the Double-Blind Treatment phase (Day 25).
Section 2.1.2. Endpoints
CGI-SR-I was added to “Other Efficacy Endpoints”

CGI-SR-I from SIBAT
o
Changes from baseline, post single and repeated doses, at 4 hours 
and 24 hours post first dose, through the end of the Double-Blind 
Treatment phase (Day 25).
Section 3.1. Overview of 
Study Design
Section 3.2.6. Efficacy 
Measures
CGI-SR-I was added as “other efficacy evaluation”:

The primary efficacy evaluation is the CDRS-R; other efficacy evaluations 
are SIBAT/CGI-SS-R and CGI-SR-I, MADRS, CDI 2:SR(S).
Added description for “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). 
The CGI-SR-I will be used to evaluate other objectives by 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
Synopsis, Other Efficacy 
Analyses; Section 11.3. 
Efficacy Analyses
CGI-SR-I was added to the text for “Other Efficacy Analyses”:
The ranks of changes from baseline over time for both CGI-SS-R and CGI-SR-I 
will be analyzed using an ANCOVA model using last observation carried 
forward data with factors for treatment and center and baseline CGI-SS-R and 
CGI-SR-I (unranked) as a covariate. Treatment differences 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 and CGI-SR-I.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
11
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Rationale: Clarifications were made to indicate that biological data will be used to predict inter-individual 
variability in esketamine treatment response. Additionally, text was modified to make it clear that the Day 4 
biomarker collection should occur at the same time as the PK collection during the 1.5 to 2.5 hour postdose 
window, thus reducing the number of separate venipunctures. Finally, text has been added to clarify the timing 
and duration of “fasting” prior to a blood sample collection, and to also make it clear that if fasting is not feasible,
subjects should try to eat a low-fat diet for at least 8 hours prior to the sample collection. Added “RNA” to the 
title of Section 9.5. Biomarker and Pharmacogenomic (DNA and RNA) Evaluations.
Synopsis, Endpoints;
Section 2.1.2. Endpoints
Modified the text to include “biological predictors”:

Biomarkers

Characteristics of esketamine mechanism of action or biological 
predictors of inter-individual variability 
Time and Events Schedule, 
Double-Blind Treatment 
Phase, footnote “ii”
Added the following to the T&E table:
On Day 4, biomarker sampling to be performed during the 1.5 to 2.5 hour PK 
window.
Footnote “ii” was clarified as follows:
ii.  These samples will be collected along with the 1.5 to 2.5 hour PK collection.
Section 9.5. Biomarker and 
Pharmacogenomic (DNA and 
RNA) Evaluations
The text was modified as follows:
If possible, blood samples should be collected under fasting conditions 
(minimum 8 hours prior to biomarker sample collection, water is permitted). 
When fasting is not feasible, subjects should follow a low fat diet for at least 8 
hours prior to sample collection, if possible. Subjects should refrain from 
exercise/strenuous physical activity and the use of non-steroidal anti-
inflammatory drugs (NSAIDs) for 24 hours prior to blood collection. Not 
following these recommendations will not constitute a protocol violation.
Rationale: There is a large body of evidence that depression and antidepressant treatment response are both 
related to changes in gene transcription.  Thus, RNA collection was added to the study protocol to allow for 
explorations of these relationships.  As a result, changes were made to the text to add collection of samples for 
RNA analyses, and to make clear that these samples will be collected predose.  Additionally, text was added to 
make clear that the RNA will be used for analyses of gene transcription both in the present study, and in 
combination with RNA samples from other studies, to investigate the biological bases of inter-individual 
variability in depression phenotypes. 
Synopsis,
Overview of Study Design
and Biomarker and 
Pharmacogenomic (DNA and 
RNA) Evaluations
The text was modified to include RNA:
Blood samples for DNA and RNA analyses will be collected from subjects who 
consent/assent separately to this component of the study (where local 
regulations permit). Subject participation in DNA and RNA research is 
optional.
Time and Events Schedule,
Double-Blind Treatment 
Phase [Pharmacogenomic
(DNA & RNA) – Optional]
Clarified in footnote “t” that blood sample collection for the pharmacogenomic 
blood sample collection at Day 25 will occur predose:
t. Performed predose
Section 3.2.9. Biomarker and 
Pharmacogenomic (DNA and 
RNA) Evaluations, Section 
3.2.9.2. Pharmacogenomic/
Epigenetic (DNA and RNA)
Added text for collection of samples for RNA analyses:
The goal of the pharmacogenomic component is to collect DNA and RNA 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 
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
12
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
and suicidality in patients with MDD assessed to be at imminent risk for 
suicide. 
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.
Section 9.5. Biomarker and 
Pharmacogenomic (DNA and 
RNA) Evaluations, 
Pharmacogenomics, 
Epigenetics, and Gene 
Transcription Evaluations
Added text for collection of samples for RNA analyses and to clarify that RNA 
will be used for analyses of gene transcription:
Subject participation in pharmacogenomics/epigenetic/gene transcription 
evaluations is optional. Whole blood samples for DNA and RNA analyses will 
be collected from all subjects who provide consent/assent for pharmacogenomic 
research at the time points indicated in the Time and Events Schedule.
DNA and RNA samples will be analyzed for the assessment of genetic variation 
and transcription of 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 and RNA 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 markers throughout the genome (as 
appropriate) in relation to esketamine or MDD clinical endpoints.
All genetic data obtained during this study may be included in ongoing cross-
study analyses to investigate the relationship between depression severity and 
phenotypes and biomarkers.
Synopsis, Statistical Methods, 
Biomarker and 
Pharmacogenomic Analyses; 
Section 11.5. Biomarker and 
Pharmacogenomic Analyses
Added text for collection of samples for RNA analyses and to clarify that RNA 
will be used for analyses of gene transcription:
Pharmacogenomic analyses (DNA and RNA) may include candidate gene 
analyses, genome-wide association analyses, and gene transcription analyses in 
relation to treatment response, non-response, and MDD. Additional exploratory 
analyses may be performed.
Rationale: Text was added to allow for collection of menstrual cycle information.  Menstrual cycle phase can 
affect values for many biomarkers related to stress, metabolism, and inflammation. A line was added to the T&E 
table for clarity.
Time and Events Schedule, 
Double-Blind Treatment 
Phase (Biomarkers)
In the Time and Events Schedule – Double Blind Treatment Phase, Menstrual 
Cycle Tracking was added as a line in the T&E table to be conducted when 
biomarker samples are taken.
Section 9.5. Biomarker and 
Pharmacogenomic (DNA and 
RNA) Evaluations
Text was added to indicate that menstrual cycle tracking was added to the Time 
and Events Schedule as a study procedure:
Per the Time and Events Schedule, information on menstrual cycle (date of first 
day of last period, average length of cycle) will be recorded at each visit when 
blood samples for biomarker analysis are collected.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
13
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Rationale: Under “Clinical Laboratory Tests”, criteria were modified to allow standard of care local laboratory 
test results to be used for eligibility if performed up to 72 hours prior to signing of ICF (formerly 24 hours) to 
reduce the need for an additional blood draw if the timeframe exceeds 24 hours. The timing for collection of the 
screening central laboratory samples was clarified.
Statement on the UDS test was updated to add qualifier on how UDS should be performed. Text was updated to 
clarify timing of assessments for Cogstate® computerized cognitive battery, pulse oximetry and MOAA/S.
Section 9.6.  Safety 
Evaluations,
Clinical Laboratory Tests
Deleted “random” from urine sample for urinalysis:
Blood samples for serum chemistry and hematology and a urine sample for 
urinalysis will be collected. 
Modified criteria for standard of care local laboratory test results:
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 72 hours prior to the screening visit (ie, 
signing of the ICF), results for those laboratory tests required per protocol at 
screening can be used for determination of subject eligibility. 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.
Added text to clarify that central laboratory samples must be collected at Day -1 
(screening), following ICF process:
At Day -1 (screening), following ICF process, central laboratory samples must 
also be collected.
Under the Urinalysis bullet point, clarified that urinalysis is performed at the 
central laboratory using a dipstick and added “specific gravity” to list. Central 
laboratory wording added to sediment testing.

Urinalysis 
Dipstick performed at central laboratory
-specific gravity
Sediment (if central laboratory dipstick 
result is abnormal)
Section 9.6. Safety 
Evaluations, Clinical 
Laboratory Tests;
Section 5. Treatment 
Allocation and Blinding
Added qualifier on how urine drug screen (UDS) should be performed:
To maintain the integrity of the study blind, a urine drug screen (UDS) should 
not be performed during the DB period unless medically necessary. If deemed 
medically necessary, the medical monitor should be contacted and UDS should 
be performed predose on dosing days.
Section 9.6. Safety 
Evaluations, Cogstate 
computerized cognitive 
battery
Clarified timing of assessments:
The Cogstate computerized cognitive battery is a validated set of assessments 
which will be performed to assess verbal learning and memory and evaluate 
cognitive function. There are 4 in-study assessment times for these: between 
Day 4 and Day 8 (prior to discharge; predose if performed on dosing day), Day 
25 predose, DB EW, Day 81, Day 200, PT EW.
Section 9.6. Safety 
Evaluations, Vital Signs 
(Temperature, Pulse/Heart 
Rate, Respiratory Rate, Blood 
Pressure)
Clarified timing of assessments:
Blood pressure, heart rate, and respiratory rate performed at predose (should be 
performed between t = -15 min and t = 0) and at t = 40 mins, 1 hr, and 1.5 hrs 
postdose; temperature at predose only.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
14
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Section 9.6. Safety 
Evaluations, Pulse Oximetry
Clarified timing and documentation of assessment:
On each dosing day, the device will be attached to the finger, toe, or ear, and 
SpO2 should be monitored and documented once predose between t = -15 min 
and t =0 (first spray) and then every 15 minutes postdose for approximately 1.5 
hours.
Section 9.6. Safety 
Evaluations, Modified 
Observer's Assessment of 
Alertness/Sedation 
(MOAA/S)
Clarified timing of assessment:
On each intranasal dosing day, the MOAA/S should be performed once predose 
between t = -15 min and t = 0 (first spray), and every 15 min for approximately 
1.5 hrs postdose (or longer, if necessary).
Section 9.6. Safety 
Evaluations, Brief Psychiatric 
Rating Scale, Positive 
Symptom Subscale (BPRS+)
Clarified timing of assessments:
On each dosing day, BPRS+ to be performed predose and at 40 minutes and 1.5 
hours postdose.
Section 16.2.1. Investigator 
Responsibilities, Safety during 
Study
Clarified timing of assessments:
Based on previous studies, it is known that certain adverse drug reactions occur 
postdose, peak around 40 minutes, and then dissipate, usually within 4 hours. 
The study includes careful monitoring following study drug dosing. Vital signs 
are performed at predose (should be performed between t = -15 minutes and t = 
0) and at 40 minutes, 1 hour, and 1.5 hours postdose. Oxygenation should be 
monitored predose (performed between t = -15 minutes and t = 0), and every 
15 minutes thereafter through to approximately 1.5 hours postdose, or longer, if 
necessary. Additionally, other known side effects of esketamine (eg, 
dissociation, sedation, conceptual disorientation, hallucinogenic behavior, and 
abnormal thought content) are monitored closely during this time using specific 
assessment tools like CADSS, MOAA/S, and BPRS+. On each dosing day, 
CADSS and BPRS+ should be performed predose and at 40 minutes and 1.5 
hours postdose; MOAA/S should be performed predose (between t = -15 
minutes and t = 0) and every 15 minutes thereafter through to approximately 1.5 
hours postdose, or longer, if necessary.
Rationale: Text was clarified with respect to the timing for repeat B3 and B10 administration.
Section 9.7. Other 
Evaluations, Questions B3 and 
B10 from the MINI-KID
If screening is longer than 24 hours prior to randomization, the B3 and B10 
MINI-KID assessment must be repeated to confirm eligibility.
Rationale: Footnotes were reordered for clarity. Extraneous text was removed from footnotes. Visits and visit 
windows for subjects who discontinue treatment have been updated. Standard of care psychological therapy line 
in the Post-Treatment Follow-Up T&E was added. UDS removed from Day 25 and footnote added to clarify how 
UDS testing should be performed. Weight measurement was added to Day 25 as it was previously omitted in 
error. Changes were made to the timing of collection of DNA and biomarkers to reduce subject burden. DNA 
collection was added to Day -1 to allow for the acquisition of epigenetic (methylation) markers prior to the first 
dose of esketamine. These epigenetic markers can then be compared to levels of gene methylation observed after 
treatment (Day 25). Menstrual cycle tracking added as a line under Biomarkers in the Double-Blind Treatment 
T&E table. Errors in the SIBAT T&E were corrected, some footnotes were deleted. Footnote “b” was added
modify instructions for SIBAT assessments if hospital discharge occurs on a visit day.
Time and Events Schedule,
Double-Blind Treatment and 
Post-Treatment Follow-Up 
Phase, SIBAT Time and 
Footnote “a” added:
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
15
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Events Schedule, Double-
Blind Treatment and Post-
Treatment Follow-Up Phase
a. Day -1 and Day 1 visits may occur on the same day. If done on same day, 
vital signs to determine eligibility must be performed both as part of the 
screening visit and as part of the Day 1 visit (predose).
Modified footnotes “e”, “f” and “g” pertaining to discontinuation and early 
withdrawal from the Double-Blind Treatment phase:
e. Subjects who discontinue from the DB phase for reasons other than lost to 
follow up, death, or withdrawal of consent/assent will have the DB EW visit 
conducted at the time of discontinuation. In addition, if the DB EW visit occurs 
on Day 1 to Day 21, subjects will have remote contact visit (eg, by telephone) 
on Day 25 to assess PWC-20, CDRS-R and MADRS, and for collection of 
concomitant therapies and AEs (Refer to Sections 9.1.5. and 10.2).
f. If the DB EW visit occurs on or after Day 22 (assuming dose administered), 
D25 RC visit is not required, however, RC D+5 (5 days after last dose) should 
be performed. If subjects discontinue anytime between Day 25 postdose and 
Day 28 RC of the PT phase, the PT EW visit is not required; however, Day 28 
RC should be performed.
g. For subjects who discontinue DB treatment for reasons other than lost to 
follow up, death, or withdrawal of consent/assent, a remote contact visit will be 
conducted 5 days (+/-2 days) after the last dose of study medication. If RC D+5 
occurs within 2 days of the EW visit, use the +2 day window to conduct the RC 
D+5 visit. 
Modified footnotes “mm”, “nn” and “oo” pertaining to discontinuation and 
early withdrawal from the Post-Treatment Follow-Up phase:
mm. Subjects who discontinue from the PT phase for reasons other than lost to 
follow up, death, or withdrawal of consent/assent will have the PT EW visit 
conducted at the time of discontinuation. If the PT EW visit occurs prior to 
completion of the Day 81 visit, a remote contact will be performed on Day 81 
for PWC-20, CDRS-R and MADRS, and for collection of concomitant 
therapies and AEs. (refer to Sections 9.1.5 and 10.2).
nn. If the PT EW visit occurs within ±5 days window of Day 81 (Visit 18) of 
the PT phase, then EW visit will be adequate, and the Day 81 RC visit is not 
required.
oo. Subjects who discontinue from the PT Follow-up Phase for reasons other 
than lost to follow up, death, or withdrawal of consent/assent after completion 
of the Day 81 visit will have the PT EW visit conducted at the time of 
discontinuation (refer to Section 10.2).
Footnote “o” for urine pregnancy test was modified to remove “drug screen”:
o. In addition to the scheduled time points, additional pregnancy tests can be 
performed during the study at the investigator’s discretion (refer to Section 5).
UDS on Day 25 was removed in order to preserve the integrity of the study 
blind. Footnote “p” was added to clarify how UDS testing should be performed:
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
16
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
p. Due to the need to preserve the integrity of the study blind, a urine drug 
screen (UDS) should not be performed during the DB period unless medically 
necessary. If deemed medically necessary, the medical monitor should be 
contacted and UDS should be performed predose on dosing days.
Weight measurement was added to Day 25.
Modified footnotes “u”, “x” and “z” to clarify timing of assessments:
u. Blood pressure, heart rate, and respiratory rate performed at predose (should
be performed between t = -15 min and t = 0) and at t = 40 mins, 1 hr, and 1.5 
hrs postdose; temperature at predose only (tympanic recommended).
x. On each dosing day, continuous arterial oxygen saturation monitoring by 
pulse oximetry (SpO2) should be monitored and documented once predose 
between t = -15 min and t = 0 (first spray), and then every 15 mins postdose for 
approximately 1.5 hrs (see Section 9.6). 
z. On each dosing day, MOAA/S should be performed once predose between t 
= -15 min and t = 0 (first spray), and every 15 min for approximately 1.5 hrs 
postdose (longer, if necessary; refer to Section 9.6). 
In the Double-Blind Treatment Phase, Menstrual Cycle Tracking was added as 
a line in the T&E table to be conducted when biomarker samples are taken.
Administrative and Standard of care psychological therapy rows were included 
in the Post-Treatment Follow-Up phase of the Time and Events Schedule.
The following changes were made to the timing of sample collection:

Day 1 draws for biomarkers moved to Day -1

DNA and RNA sampling added to Day -1

RNA sampling added to Day 25/DB EW

On Day 4, biomarker sampling to be performed during the 1.5 to 2.5 
hour PK window

On Day 25, clinical labs moved from postdose to predose; DNA, RNA 
and biomarkers collected at the same time.
Updated the SIBAT Time and Events Schedule (Double- Blind Treatment 
Phase and Post-Treatment Follow-Up Phase) to be consistent with the main 
Time and Events Schedule (Double-Blind Treatment Phase and Post-Treatment 
Follow-Up Phase). Footnote “b” is new:
b. 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.
Section 3.2.2. Treatment and 
Study Duration
Text was aligned with changes to the visit schedule per Section 9.1.4. Post-
Treatment Follow-Up Phases:
Visits will continue to occur twice a week for the first 2 weeks (Days 28, 32, 
35, 39), after which visits will occur weekly (Days 46 and 53), then every 2 
weeks (Days 67 and 81). The Day 28 and 35 visits are remote contact visits. 
After the Day 81 visit, subjects will enter the extended Post-Treatment Follow-
Up phase (Days 81-200), during which they will have monthly visits to assess 
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
17
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
safety. Investigators may add follow-up visits as dictated by the subject’s 
clinical condition and the investigator’s clinical judgment.
Section 9.1.4 Post-Treatment 
Follow-Up Phases
Text was aligned with the Time and Events schedule:
The Day 28 and 35 visits are remote contact visits to assess the PWC-20, CDRS-
R and MADRS, and collect concomitant therapies and AEs.
Rationale: PCP was added to the below sections to correct omissions. Mentions of esketamine were removed and 
sites will be directed to capture this information under ketamine.
Synopsis, Objectives; Section 
2.1.1. Objectives
Text modified as follows:

To evaluate the potential for ketamine or PCP abuse during the follow-up as 
measured by the Timeline Follow-Back (TLFB).
Synopsis, Endpoints; Section 
2.1.2. Endpoints
Text modified as follows:

Safety endpoints will be evaluated throughout the study, as follows: 

TLFB methodology to evaluate use of ketamine or PCP.
Section 9.6. Safety 
Evaluations, Timeline Follow-
Back (TLFB)
Text modified as follows:
The TLFB will be used to assess the potential for ketamine and PCP abuse 
during the follow-up phase. The Timeline Follow-Back (TLFB), a clinical and 
research tool used to obtain a variety of quantitative estimates of alcohol and 
drug use, will be used to evaluate the potential for ketamine or PCP abuse 
during the follow-up.
Rationale: Updated the informed consent/pediatric assent language to accurately reflect the pediatric study 
population requirements.
Section 4.1. Inclusion Criteria; 
Section 9.1.2. Screening 
Phase; Section 10.3. 
Withdrawal from the Use of 
Research Samples; Section 
16.1. Study-Specific Design 
Considerations; Section 
16.2.1. Investigator 
Responsibilities; Section 
16.2.3. Informed 
Consent/Pediatric Assent 
Form; Section 16.2.4. Privacy 
of Personal Data; Section 
16.2.5. Long-Term Retention 
of Samples for Additional 
Future Research
Added “subject(s) and/or parent(s)/LAR(s)” and “pediatric assent/informed 
consent” wherever applicable.
Section 16.2.3. Informed Consent/Pediatric Assent Form: Entire section was 
modified.
Rationale: Text was added to selectively permit subjects to be rescreened.
Section 4. Subject Population
Text was modified as follows:
Requests to rescreen an individual subject must be evaluated and approved by 
the sponsor representative or medical monitor on a case-by-case basis.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
18
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Rationale:  To clarify standard of care psychotherapy guidance, text was included to provide guidance on 
acceptable types of psychotherapies, and to state that the frequency of psychotherapy visits should be determined 
based on clinical need at the discretion of the treatment team.
Section 6. Dosage and 
Administration; Section 9.1.3. 
Double-Blind Treatment 
Phase
Text was modified as follows:
Treatment with a psychological intervention is also required, at least through 
the initial 8-week Post-Treatment Follow-Up phase (Day 81). The specific 
antidepressant and type of psychological intervention selected for a given 
subject will be based on the treating physician(s) clinical judgment, knowledge 
of the subject’s prior treatment history, and practice guidelines. Acceptable 
types of psychological interventions include individual cognitive behavioral 
therapy (CBT), interpersonal therapy, family therapy, and psychodynamic 
psychotherapy. Other evidence -based psychotherapies may be allowed after 
consultation with the medical monitor.  The frequency of psychotherapy visits 
should be determined based on clinical need, at the discretion of the treatment 
team.
Rationale: Text was modified to clarify the number of nights associated with the 5 days of recommended 
inpatient hospitalization, and to specify order of SIBAT administration.
Section 9.1.3. Double-Blind 
Treatment Phase
Text was modified as follows:
Subjects will remain in the inpatient psychiatry unit or other permitted setting 
for a recommended duration of 5 days (4 nights) from randomization, with 
shorter or longer hospitalizations permitted if clinically warranted per local 
standard of care.
Specified the order of SIBAT as follows:

SIBAT 

Patient Portion

Clinician Portion
Rationale: Text was revised to clarify that the TLFB includes a paper calendar.
Section 17.4. Source 
Documentation
Test was revised as follows:
Subject- and investigator-completed scales and assessments designated by the 
sponsor will be considered source data. The CDRS-R, MADRS, SIBAT, CDI 
2:SR(S), MOAA/S, YMRS, PWC-20, BPRS+, MINI-KID, Cogstate
computerized cognitive battery, TLFB (including paper calendar), nasal 
symptom questionnaire, and CADSS will be considered source data.
Rationale: Redundant text was deleted.
Section 3.2.7. Safety 
Evaluations
The following text was deleted:
A list of prohibited therapies is provided in Attachment 1 for general guidance 
for the investigator; however, this list is not all-inclusive.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
19
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Rationale: Text related to prohibitions and restrictions was clarified.
Section 4.3. Prohibitions and 
Restrictions; Section 8. 
Prestudy and Concomitant 
Therapy
The text was modified as follows:
Subjects may not receive electroconvulsive therapy (ECT), trans-cranial 
magnetic stimulation (TMS), ketamine or other antidepressant therapies (aside 
from those allowed) during the study.
A list of concomitant therapies that are prohibited, permitted, and permitted 
with restrictions is provided in Attachment 1 for general guidance for the 
investigator; however, this list is not all-inclusive.
Rationale: Table 2 and accompanying text were updated to clarify timing of sample collection and blood 
volumes collected from each subject during each study phase. Added DNA sampling at Day -1 and added RNA 
sampling to Day -1 and Day 25/DB EW.
Section 9. Study Evaluations
The text was modified as follows:
The Time and Events Schedule summarizes the frequency and timing of 
efficacy, PK, biomarker, pharmacogenomic (DNA and RNA), and safety 
measurements applicable to this study.
The maximum total blood volume to be collected from each subject will be 
approximately 56.5 mL for subjects who are participating in 
pharmacogenomics/epigenetic evaluations (see Table 2); total blood volume 
will be less for subjects who are not participating in these evaluations, as 
presented in Table 2.
Table 2 footnotes “b” and “d” were modified as follows:
b. At screening, 2 samples will be collected for analysis – 1 sample each for the 
SoC local laboratory (to have results prior to Day 1 dose) and the central 
laboratory (see Section 9.6 for further details). Volume is approximate for local 
laboratories. 
d. Pharmacogenomic (DNA and RNA) blood sample(s) will be collected only 
from subjects who have consented to provide an optional sample for genetic 
research.
Rationale: Attachment 1 was modified to clarify the list of prohibited/permitted concomitant medications and the 
guidelines for concomitant medication use. 
Attachment 1:
Prohibited/Permitted 
Concomitant Medications 
Table of Prohibited/Permitted Concomitant Medications was edited to include 
new guidelines for washout timing, updated information on medications that are 
prohibited, permitted and permitted with restrictions and clarify the reasons in 
the comments column for some therapies that are permitted with restrictions.
Information was reordered for clarity (therapies presented in alphabetical order
by drug class) and additional medications were added.
Rationale: “Weight Chart” was replaced by a “Stature Chart” as the “Weight Chart” was erroneously included 
and stature is needed to determine individual blood pressure thresholds.
Attachment 2: Growth Charts: 
Stature-for-Age Percentiles 
for Use in Blood Pressure 
Assessments
Added the following tables:
Growth Charts: Stature-for-Age Percentiles for Use in Blood Pressure 
Assessments (Boys and Girls, 2 to 20 years)
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JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
20
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Rationale: Attachment (95th percentile blood pressure levels) was revised to be used with growth charts to 
determine appropriate criteria for exclusion.
Attachment 3: 95th Percentile 
Blood Pressure Levels For 
Sex by Age and Height
Revised the following tables (for boys and girls):
95th Percentile Blood Pressure Levels for Sex by Age and Height
Rationale: New attachment (postdose blood pressure withdrawal criteria) was added to be used to determine 
individual postdose blood pressure thresholds.
Attachment 4: Postdose Blood 
Pressure: Withdrawal Criteria 
Levels for Sex by Age and 
Height
Added the following tables (for boys and girls):
Postdose Blood Pressure: Withdrawal Criteria Levels for Sex by Age and 
Height. 
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made
Amendment 2 (14 June 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 protocol was modified to 1) permit the initiation of standard of care 
antidepressant during the 1st 7 days  of double-blind treatment, to reflect local standard of care in regions where it 
is not routine to initiate two medications simultaneously; 2) remove cognitive assessment at baseline and replace 
the RAVLT with the International Shopping List Test (ISLT); 3) expand description of safety evaluations; and 4) 
clarify within the Time & Events schedule the different recall periods for efficacy assessments used at certain study 
visits
Applicable Section(s)
Description of Change(s)
Rationale: Modification that subjects will receive standard of care antidepressant medication that may be 
initiated or optimized during the first 7 days of the double-blind phase if starting two medications simultaneously 
is not consistent with local clinical practice.
Time & Events Schedule, 
Double-Blind Treatment 
Phase, footnote (kk)
Revision indicating that antidepressant treatment may be initiated or optimized 
within the first 7 days of the Double-Blind Treatment Phase if starting two 
medications simultaneously is not consistent with local clinical practice.
T&E Schedule: Standard of Care Antidepressant Assignment: Predose: footnote 
(kk) added.
3.1. Overview of Study 
Design, 
Figure 1, legend, footnote (a)
The text was revised as follows (bold text added; strikeout text deleted):
Standard of care Antidepressant treatment medication will should be initiated or 
optimized on Day 1. However initiating standard of care antidepressant 
medication up to 7 days after the first dose of study medication (Day 1) is 
permitted if starting two medications simultaneously is not consistent with 
local clinical practice.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
21
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
6. Dosage and 
Administration;
9.1.3. Double-Blind 
Treatment Phase
Antidepressant therapy should be chosen and started on or before Study
medication should be initiated or optimized on Day 1. However initiating 
standard of care antidepressant medication up to 7 days after the first dose 
of study medication (Day 1) is permitted if starting two medications 
simultaneously is not consistent with local clinical practice.
16.1 Study-Specific Design
Precautions to Ensure Subject Safety in the Study
The study will be conducted in the context of standard clinical care, including 
hospitalization the initiation or optimization of antidepressant and psychological 
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 should will receive standard of 
care antidepressant medication beginning on initiated or optimized on Day 1. 
However, initiating standard of care antidepressant medication up to 7 days 
after the first dose of study medication (Day 1) is permitted if starting two 
medications simultaneously is not consistent with local clinical practice.
Rationale: Clarification that subjects must agree to take one of the prescribed antidepressant therapies at least 
during the double-blind treatment phase (Day 25).
Synopsis, Subject 
Population;
4.1. Inclusion Criteria
Inclusion Criterion No. 7 was revised as follows (bold text added; strikeout text 
deleted):
As part of the newly initiated or optimized standard of care treatment, subject 
must agree to take one of the prescribed non-investigational antidepressant 
medications (fluoxetine, escitalopram, sertraline) for at least the duration of
during the double-blind treatment phase (Day 25).
Rationale: Modification to reflect that the Cogstate safety assessment will not be performed at screening as 
subjects in acute crisis may not be able to be accurately assessed. 
Time & Events Schedule,
Double-Blind Treatment 
Phase
The following Safety Assessment will not be performed at screening:
Cogstate test battery cognitive assessment
Rationale: Modification to reflect that instead of the Rey Auditory Verbal Learning Test (RAVLT) the ISLT will 
used to evaluate verbal learning and memory to accommodate all languages in countries where the study is being 
conducted.
Synopsis, Objectives, Endpoints, 
Hypothesis;
Synopsis, Safety Evaluations;
Synopsis, Statistical Methods, 
Safety Analyses;
Time & Events Schedule, 
Double Blind Treatment Phase, 
Post-Treatment Follow-up 
Phase,
footnote (bb);
2.1.1. Objectives;
2.1.2. Endpoints;
3.1. Overview of Study Design;
3.2.7. Safety Evaluations;
9.6. Safety Evaluations;
11.6. Safety Analyses;
17.4. Source Documentation
The Rey Auditory Verbal Learning Test (RAVLT), designed to assess verbal 
learning and memory, will not be used to evaluate cognitive function as part 
of the safety and tolerability assessment for this study

Text referring to the Rey Auditory Verbal Learning Test (RAVLT) 
has been deleted and has been replaced with text referring to the ISLT 
where appropriate.
The “Cogstate test battery cognitive assessment” has been changed to:

“Cogstate computerized cognition battery”.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
22
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
9.6. Safety Evaluations
The following additional information is provided on safety evaluations: 
Young Mania Rating Scale (YMRS) 
YMRS will be administered to assess treatment-emergent occurrence and 
severity of manic episodes. The YMRS is an eleven-item multiple choice 
questionnaire which is used to measure the severity of manic episodes in children 
and young adults. It is based on the patient’s subjective report of his or her 
clinical condition over the previous hours. Additional information is based upon 
clinical observations made during the clinical interview. The scale is completed 
by a clinician or other trained rater and takes 15-30 minutes to complete. The 
symptom items were selected based upon published descriptions of the core 
symptoms of mania; the YMRS is a reliable, valid and sensitive rating scale to 
measure the severity of mania.122
Physician Withdrawal Checklist (PWC-20)
The PWC-20 will be administered by the clinician to assess potential withdrawal 
symptoms following cessation of intranasal esketamine treatment. The PWC-20 
is a 20-item simple and accurate method to assess potential development of 
discontinuation symptoms after stopping of study medication. The PWC-20 is a 
reliable and sensitive instrument for the assessment of anxiolytic discontinuation 
symptoms.106 Discontinuation symptoms occur early and disappear rather 
swiftly, depending upon speed of taper, daily medication dose, and drug 
elimination half-life.106
Cogstate computerized cognitive battery  
The Cogstate computerized cognitive battery, is a validated set of assessments 
which will be performed to assess verbal learning and memory and evaluate 
cognitive function. 12, 28, 64 There are 4 in-study assessment times for these: 
between Day 4 and Day 8 (prior to discharge; pre-dose if performed on dosing 
day), Day 25 pre-dose or early withdrawal from double-blind phase, Day 81, 
Day 200 or early withdrawal assessment for the post-treatment follow-up phase.
The battery will provide assessment of multiple cognitive domains, including 
attention, visual and verbal learning and memory, and executive function. The 
tests use culture neutral stimuli, enabling use in multilingual/multicultural 
settings. The computerized battery includes:

Simple and choice reaction time tests; scored for speed of response: 
o
Detection (DET; Psychomotor Function)
o
Identification (IDN; Attention)

Visual episodic memory; visual recall test 
o
One Card Learning (OCL; Visual Learning)

Working memory (n back task); scored for speed of correct response 
o
One Back (ONB; Working Memory)

Verbal learning and memory assessment
o
International Shopping List Task (ISLT)

Executive function; maze/sequencing test, scored for total number of errors:
o
The Groton Maze Learning Test (GML; Executive Function)
All measures in the cognitive battery have been validated against traditional 
neuropsychological tests and are sensitive to the effects of various drugs on 
cognitive performance, including alcohol and benzodiazepines. The subject 
completed computerized cognitive test battery has been used for cognitive 
assessment in several child and adolescent research trials including attention 
deficit hyperactivity disorder,7 and demonstrates good reliability and validity in 
child and adolescent populations.6 The ISLT has also been used in adolescent 
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
trials, demonstrating sensitivity, reliability and validity. The subject completed 
cognitive battery requires approximately 25 minutes; the clinician administered 
ISLT requires approximately 15 minutes in total.
9.6. Safety Evaluations
All assessments are completed by the subject except the verbal learning and 
memory assessment, the International Shopping List Task (ISLT), that will be 
administered by the clinician. The ISLT is a 12-word three-trial verbal list-
learning test. The word lists used in the ISLT consist of foodstuffs common to 
the culture or language group. The verbal presentation of the word list and the 
recording of responses are completed by the rater and controlled by a laptop 
computer or tablet. For each 12-word list that is used, the software selects at 
random the order in which words are presented to subjects. After the third trial is 
completed, the subject will also complete a series of other tasks for 15-20 
minutes, before being asked to recall the 12 words from the ISLT again – this is 
called a Delayed Recall trial. The subject will also be shown a list of words and 
asked to recognize previously presented words, a Word Recognition trial.
Timeline Follow-Back (TLFB)
TLFB will be used to assess the potential for ketamine, esketamine, and PCP 
abuse during the follow-up phase. The Timeline Follow Back (TLFB),35 a 
clinical and research tool used to obtain a variety of quantitative estimates of 
alcohol and drug use, will be used to evaluate the potential for ketamine or 
esketamine or PCP abuse during the follow-up. The Timeline Follow-Back 
method has been used in studies to quantify ketamine use in adults, as well as to 
evaluate substance use in various adolescent populations.62
11.6. Safety Analyses
The text was revised as follows (bold text added; strikeout text deleted):
Cogstate Computerized Cognitive Battery RAVLT and Cogstate test 
battery
Cognitive function data from the RAVLT Cogstate computerized cognitive 
battery and Cogstate test battery cognitive screening assessment will be 
summarized descriptively at each designated scheduled visit by treatment group.
TimeLine Follow-Back (TLFB)
The TLFB, a clinical and research tool used to obtain a variety of quantitative 
estimates of ketamine and PCP abuse, will be summarized descriptively at each 
scheduled visit by treatment group.
Rationale: Clarification that in addition to nasal examination, a nasal symptom questionnaire will be performed 
to monitor for any signs of adverse effects on the nasal mucosa, as part of the safety evaluations.
Synopsis, Overview of Study 
Design;
Synopsis, Safety 
Evaluations;
3.1. Overview of Study 
Design;
3.2.7. Safety Evaluations;
Safety Evaluations revised to include nasal symptom questionnaire 
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JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Rationale: Clarification that the Children’s Depression Inventory 2, Self-Report (Short Form) (CDI 2:SR[S]) is a 
12-item patient rated self-assessment of depressive symptoms in youth. A 24-hour recall period will be used on 
Day 2; a 2-week recall period will be used at all other assessments.
3.2.6. Efficacy Measures
The text was revised as follows (bold text added; strikeout text deleted)
Children’s Depression Inventory 2, Self-Report (Short Form) (CDI 2:SR[S])
The CDI 2:SR(S) assessment is a multi rater patient rated assessment of 
depressive symptoms in youth aged 7 to 17 years and an efficient screening 
measure that contains 12 items and takes 5 to 10 minutes to administer.
9.2.3. Children’s Depression 
Inventory 2, Self-Report 
Study
Descriptive text regarding the multi-rater CDI 2 has been deleted since it is not 
applicable to this study. 
The CDI 2: SR(S) is based on the Children’s Depression Inventory 2 (CDI 2) 
and Children’s Depression Inventory 2 Self-Report (CDI 2:SR). The CDI 2 is a 
comprehensive multirater assessment of depressive symptoms in youth aged 7 to 
17 years. When used with other sources of verified information, the CDI 2 can 
aid in the early identification of depressive symptoms, the diagnosis of 
depression and related disorders, and the monitoring of treatment effectiveness. 
The CDI 2 quantifies depressive symptomatology using reports from 
children/adolescents (full length and short), teachers, and parents (or alternative 
caregivers).
9.2.3. Children’s Depression 
Inventory 2, Self-Report 
Study
Correction to description of CDI 2: SR assessment:
The CDI 2:SR is a 1228-item self-reported assessment.
Time & Events Schedule
Footnote (u) CDI 2:SR(S) – Subject-completed assessment. A 24-hour recall 
period applies on Day 12; a 2-week recall period applies at all other assessments.
Rationale: Clarification of the recall periods in this study used for assessment of the Efficacy Evaluations: 
CDRS-R and MADRS
9.2.1. Children’s Depression 
Rating Scale Revised 
(CDRS-R)
Efficacy Evaluations: CDRS-R and MADRS: clarification of the recall periods in 
this study
The text was revised as follows (bold text added; strikeout text deleted)
9.2.1. Children’s Depression Rating Scale, Revised (CDRS-R)
The typical recall period for the CDRS-R is 7 days. In this study, the CDRS-R 
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. The 4 recall 
periods: a 7-day recall on Day 1 (predose); a 4-hour recall at the 4-hour 
postdose assessment on Days 1 and 25; a 24-hour recall at the post-dose 
assessment on Day 2; and a “since last assessment” recall predose on Day 4 
through Day 25 dosing days. “Since last assessment” recall will also be used 
in Post-Treatment Follow-up assessments on Days 28, 32, 35 and 39. A7-day 
recall will be used for Post-Treatment Follow-up assessments on Days 
46-200. The sleep item score is not assessed at the 4-hour postdose time 
point on Day 1 and Day 25. For the CDRS-R performed at 4 hours postdose on 
Days 1 and 25, the CDRS-RS scores for the sleep item recorded predose on the 
same day will be carried forward to calculate the total score.
9.2.2. Montgomery-Asberg 
Depression Rating Scale
9.2.2. Montgomery-Asberg Depression Rating Scale
The typical recall period for the MADRS is 7 days. In this study, the MADRS 
will be administered using 4 recall periods: a 7-day recall on Day 1 
(predose); a 4-hour recall at the 4 hour postdose assessment on Days 1 and 
25; a 24-hour recall at the post-dose assessment on Day 2; and a “since last 
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
25
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
assessment” recall predose on Day 4 through Day 25 dosing days. “Since last 
assessment” recall will also be used in Post-Treatment Follow-up 
assessments on Days 28, 32, 35 and 39. A 7-day recall will be used for Post-
Treatment Follow-up assessments on Days 46 -200. The sleep item score is 
not assessed at the 4-hour postdose time point on Day 1 and Day 25. 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, Tthe MADRS scores for the sleep item 
recorded predose on the same day will be carried forward to calculate the total 
score.
9.1.3. Double-Blind 
Treatment Phase
MADRS and CDRS-R will be performed at both predose and 4-hour 
postdose assessments on Day 25 (visit 10) of the double-blind treatment 
phase.
Rationale: Clarification of the recall periods for the MADRS and CDRS-R efficacy assessments during the 
Double-Blind Treatment Phase and the Post-Treatment Follow-up Phase
Time & Events Schedule
The CDRS-R and MADRS assessments were expanded to indicate each of the 
four recall periods in order to clarify for the site.
The following changes were made to the Time & Events Schedule:
Double-Blind Treatment Phase: Efficacy Assessments
Children’s Depression Rating Scale Revised (CDRS-R)o and Montgomery-
Asberg Depression Rating Scale (MADRS)z: assessments on Days 1 (predose 
and 4 hours), 2, 4, 8, 11, 15, 18, 22, 25, D/C and DB EW were modified.
The following changes were made: 
-
Children’s Depression Rating Scale Revised (CDRS-R)o (recall: 7 days): 
assessment predose on Day 1;
-
Montgomery-Asberg Depression Rating Scale (MADRS)z (recall: 7 days): 
assessment predose on Day 1; 
-
CDRS-R (recall: 4-hours postdose): Day 1, 4-hours (visit 2) and Day 25 
(visit 10);
-
MADRS (recall: 4 hours postdose): Day 1, 4-hours (visit 2) and Day 25 
(visit 10);
-
CDRS-R (recall: 24 hours postdose): Day 2;
-
MADRS (recall: 24 hours postdose): Day 2;
-
CDRS-R (recall: since last assessment predose): Day 4 through to Day 
25, D/C and DB EW;
-
MADRS (recall: since last assessment predose): Day 4 through to Day 25, 
D/C and DB EW
Post-Treatment Follow-up Phase: Efficacy Assessments
Children’s Depression Rating Scale Revised (CDRS-R)o and Montgomery-
Asberg Depression Rating Scale (MADRS)z: assessments on Days 32, 39, 46, 
53, 67, 81, every 4 weeks up to and including Day 200, and PT EW were
modified
The following changes were made:
-
Children’s Depression Rating Scale Revised (CDRS-R): (recall: 7 days)o: 
Day 46, 53, 67, 81, every 4 weeks up to including Day 200, and PT EW
-
Montgomery-Asberg Depression Rating Scale (MADRS) (recall: 7 
days)z: Day 46, 53, 67, 81, every 4 weeks up to including Day 200, and 
PT EW
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
26
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
-
CDRS-R (recall: since last assessment): Days 28 RC, 32, 35 RC, 39
-
MADRS (recall: since last assessment): Days 28 RC, 32, 35 RC, 39
Time & Events Schedule, 
Double-Blind and Post-
Treatment Follow-up Phase, 
Footnotes
The following changes were made to the Time & Events Schedule Footnotes 
(text added in bold; strikethough text deleted):
-
Day 22 and Day 25 of the Double-Blind Treatment Phase: footnote (a) 
“visit can be performed ±3 days” changed to footnote (b) “visit can be 
performed ±1 day”
-
Footnote (a) Intranasal treatment sessions should not be given on 
consecutive days.
-
The statement above in footnote (a) is made in Section 6. Dosage and 
Administration
-
Footnote (d) Subjects who discontinue study treatment prior to 
completion of the double-blind treatment phase (Day 25 visit), will have 
an EW visit conducted at the time of treatment discontinuation. Subjects 
who discontinue double-blind study treatment for reasons other than 
withdrawal of consent, lost to follow-up or death will be contacted 
remotely (eg, by telephone) 3 and 10 days after the last dose of intranasal 
study medication to assess adverse events, and any withdrawal symptoms 
utilizing PWC 20. Additionally, these subjects will return for the Day 25 
and Day 81 visit assessments. If subjects refuse to return for in-person 
assessment on Day 25 and 81, remote contact (eg, by telephone) on Days 
25 and 81 for CDRS-R and MADRS assessments and adverse event 
collection is acceptable.  
-
Footnote (o) CDRS-R – Clinician-administered assessment. A predose 
total score of ≥58 is required for subject eligibility. There are 4 recall 
periods: a 7-day recall period applies predose on Day 1 (predose); a 4-
hour recall at the 4-hour postdose assessment on Day 1 and Day 25; 
and a 24-hour recall at the 4 hour postdose assessment on and Day 2; 
assessments respectively. A and a “since last assessment” recall period 
applies predose on Day 4 through Day 25 dosing days. “Since last 
assessment” recall will also be used in Post-Treatment Follow-up all 
other CDRS R assessments performed on Days 28, 32, 35, and 39. A 
7-day recall will be used for Post-Treatment Follow-up assessments 
on Days 46-200. at an interval <7 days. For all assessments performed at 
intervals ≥7 days, the 7 day recall version of the CDRS R will be used 
(eg, Post Treatment Follow up visits 12 and 14 22). At the Day 1, 4 hour 
postdose time point and on Day 25, the sleep item score is not assessed.
-
Footnote (z) MADRS - Clinician-administered assessment. There are 4 
recall periods: aA 7-day recall period applies on Day 1 (predose); a 4-
hour recall at the 4-hour postdose assessment on Day 1 and Day 25; a 
24-hour recall at the post-dose assessment on Day 2; and a “since last 
assessment” recall period applies predose on Day 4 through Day 25 
dosing days. “Since last assessment” recall will also be used in Post-
Treatment Follow-up assessments on Days 28, 32, 35 and 39. A 7-day 
recall will be used for Post-Treatment Follow-up assessments on Days 
46-200.at all other assessments. At the Day 1, 4 hour time point and on 
Day 25, the sleep item score is not assessed.
Time & Events Schedule, 
Double-Blind Treatment 
Phase
The following footnote was added:
Footnote (nn): MADRS and CDRS-R will be performed at both predose and 4-
hour postdose assessments on Day 25 (visit 10) of the double-blind treatment 
phase
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JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
27
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
SIBAT Time & Events 
Schedule
Day 22 and Day 25 of the Double-Blind Treatment Phase: footnote (a) “visit can 
be performed ±3 days” changed to footnote (b) “visit can be performed ±1 day”
Rationale: Time and Events Schedule was modified to include a Remote Contact (RC) visit during the 
Double-Blind Phase for CDRS-R, MADRS, PWC-20 and adverse event collection, in subjects who discontinue 
from double-blind treatment for reasons other than lost to follow-up, death, or withdrawal of consent.
Time & Events Schedule, 
Double-Blind Treatment 
Phase;
The following changes were made to the Time and Events Schedule – Double-
Blind Treatment Phase:
Column added to the Double-Blind Treatment Phase for Remote Contact (DB 
RC) for the following assessments:
-
CDRS-R (recall: since last assessment) 
-
MADRS (recall: since last assessment)
-
Physician Withdrawal Checklist (PWC-20)
-
Adverse event collection. 
The following footnote was added:
Footnote (oo): For subjects who discontinue from double-blind treatment for
reasons other than lost to follow up, death, or withdrawal of consent, Remote 
Contact (RC) will be implemented 3 and 10 days after the last dose of intranasal 
study medication to assess adverse events, withdrawal symptoms using PWC 20 
and rebound using CDRS-R and MADRS assessments. If the EW visit is > 3 
days from last dose, the 3 day RC will not be done.
Rationale: Study Evaluations, Table 2 and accompanying text updated to include blood volumes collected from 
each subject during the Post-Treatment Follow-up Phase, to correct for total blood volume collected during the 
Double-Blind Treatment Phase, and to delete statement that site participation in biomarker evaluations is 
optional.
9.1.1. Study Evaluations, 
Overview
Table 2: Approximate Volume of Blood to be Collected from Each Subject
The following changes were made:
Correction of Approximate total blood volume for DB treatment phase with 
biomarker and pharmacogenomics/epigenetic samples: from 26.3 to 32.3 mL
Inclusion of blood volumes for Post-Treatment Follow-up Phase
-
Central Serum Chemistry (Day 81, Day 200/EW): Total blood vol. 2.2 
mL 
-
Central Hematology (Day 81, Day 200/EW): Total blood vol. 2.4 mL
-
Approximate total blood volume for Post-Treatment Follow-up Phase: 4.6 
mL
Correction of Approximate total blood volume for study to include both Double-
Blind and Post-Treatment Follow-up Phase:
-
Including biomarker and pharmacogenomic samples: from 44.9 to 49.5
mL
-
Without pharmacogenomic samples: 47.5 mL
Editorial changes
Changes to legend to include PT, post-treatment
Changes to footnotes (bold text added, strikeout text deleted):
-
Footnote (c) Biomarker samples are as scheduled in the Time and 
Events ScheduleOptional site participation (based on operational 
capabilities).
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JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
28
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
-
Footnote (d) Pharmacogenomic bBlood sample(s) will be collected only 
from subjects who have consented to provide an optional sample for 
genetic research.
9.5. Biomarker and 
Pharmacogenomic (DNA) 
Evaluations
Biomarker Evaluations
The following text was deleted for consistency with Table 2, footnote (c) above:
“Site participation in biomarker evaluations is optional based on operational 
capabilities; subjects at participating sites are required to participate.”
Rationale: Correction of error. Revised text states that subject will have completed study if assessments up to 
and including Week 29 are completed.
10.1 Completion
The following text was revised (bold text added; strikeout text deleted):
A subject will be considered to have completed the study if he or she has 
completed assessments up to and including Week 2529.
Rationale: Clarification that the Post-Treatment Early Withdrawal visit will be conducted at the time of 
discontinuation for subjects who discontinue from the Post-Treatment Follow-up Phase
10.2 Discontinuation of 
Study Treatment/Withdrawal 
from the study
Withdrawal from the Study During the Post-Treatment Follow-up Phase
The following text was added (bold text):
Subjects who discontinue from the Post-Treatment Follow-up Phase after 
completion of the Day 81 visit will have the Post-Treatment Early 
Withdrawal visit conducted at the time of discontinuation. In addition, the 
investigator must ensure the subject is appropriately transitioned and/or followed 
for any additional care required when a subject discontinues participation in 
the study for any reason.
Rationale: Clarification as to which safety and efficacy assessments will be performed for subjects who 
discontinue treatment prior to completion of the Double-Blind treatment phase.
9.1.5. Early Withdrawal;
10.2 Discontinuation of 
Study Treatment/Withdrawal 
from the study
Discontinuation from study treatment prior to completion of the Double-Blind 
treatment phase.
The text was revised as follows (bold text added):
Subjects who discontinue study treatment prior to completion of the double-blind 
treatment phase (Day 25 visit), will have an EW visit conducted at the time of 
treatment discontinuation. Subjects who discontinue double-blind study 
treatment for reasons other than withdrawal of consent, lost to follow-up or death 
will be contacted remotely (eg, by telephone) 3 and 10 days after the last dose of 
intranasal study medication to assess adverse events, and any withdrawal 
symptoms utilizing PWC 20, and rebound with assessment of CDRS-R and 
MADRS. Additionally, these subjects will return for the Day 25 and Day 81 visit 
assessments. If For subjects who refuse to return for in-person assessment on 
Day 25 and 81, remote contact (eg, by telephone) on Days 25 and 81 for CDRS-
R and MADRS assessments and adverse event collection is acceptable.
The investigator must ensure the subject is appropriately transitioned 
and/or followed for any additional care required when a subject 
discontinues participation in the study for any reason.
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JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
29
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Rationale: Clarification as to which efficacy assessments will be performed for subjects who discontinue 
treatment prior to completion of the Post-Treatment Follow-up phase.
9.1.5. Early Withdrawal;
10.2 Discontinuation of 
Study Treatment/Withdrawal 
from the study
9.1.5. Early Withdrawal
Discontinuation from study treatment prior to completion of the Post-Treatment 
Follow-up phase.
The text was revised as follows (bold text added):
For subjects who refuse to return for in-person assessment, remote contact (eg, 
by telephone) on Day 81 for CDRS-R and MADRS assessments and adverse 
event collection is acceptable.
For information obtained via remote contact, written documentation of the 
communication must be available for review in the source documents. During 
remote contact visits with the subject by site personnel, adverse event 
information will be obtained, and CDRS-R and MADRS assessments will be 
performed by appropriately qualified staff. In addition, the investigator must 
ensure the subject is appropriately transitioned/followed for any additional care 
required.
Rationale: Clarification of timing of the Early Withdrawal visit and assessments in relation to the Day 25 and 
Day 81 visits.
Time & Events Schedule, 
Double-Blind Treatment 
Phase,
footnote (ll)
The following text was added:
If the Early Withdrawal visit occurs within a window of ±1 day of Day 25 (visit 
10) of the double-blind treatment phase, then the Early Withdrawal visit will be 
adequate and the Day 25 visit is not required. However, the subject must still 
complete the Day 81 clinic visit.
Time & Events Schedule, 
Post-Treatment Follow-up 
Phase, footnote (mm)
If the Early Withdrawal visit occurs within a window of ±5 days of Day 81 (visit 
18) of the follow-up phase, then the Early Withdrawal visit will be adequate and 
the Day 81 visit is not required.
9.1.5. Early Withdrawal;
10.2. Discontinuation of 
Study Treatment/Withdrawal 
from the Study
If the Early Withdrawal visit occurs within a window of ±1 days of the Day 25 
visit of the double-blind treatment phase, or within a window of ±5 days of the 
Day 81 visit of the follow-up phase, then the Day 25 or Day 81 visits, 
respectively, are not required.
Time & Events Schedule, 
footnote (d);
SIBAT Time & Events 
Schedule, footnote (f)
9.1.5 Early Withdrawal;
10.2. Discontinuation of 
Study Treatment/Withdrawal 
from the Study
The text was revised as follows (bold text added):
Additionally, these subjects will return for the Day 25 and Day 81 visit 
assessments.
9.1.5. Early Withdrawal
The following text was added:
Subjects who discontinue from the Post-Treatment Follow-Up phase after 
completion of the Day 81 visit will have the Post-Treatment Early Withdrawal 
visit conducted at the time of discontinuation only.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
30
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Rationale: Correction of investigational drug treatment dose in Table 1
6.2 Intranasal Study Drug, 
Table 1
The following changes were made to the heading in Table 1 (bold text added; 
strikeout text deleted):
Dose administration of Intranasal Esketamine 28, 54, 56, 84 mg or Placebo
Rationale: Changes to permit use of Isotretinoin, only in consultation with the medical monitor
Attachment 1
Prohibited Concomitant medications with Intranasal Study Medication 
(esketamine or placebo)
The following addition was made to the table:
Isotretinoin may only be used in consultation with the medical monitor 
Restrictions: no episodic use, only continuous use.
Rationale: Clarification of text regarding Justification for use of Psychoactive Placebo, and aspects of the 
Investigators responsibilities for Safety, including monitoring potential adverse drug reactions. 
16.1. Study-Specific Design 
Considerations
The following text was deleted (bold text added; strikeout text deleted):
Justification for Using Psychoactive Placebo
Subjects and their consenting parent or legal guardian will be informed of the 
equal chance of receiving esketamine or psychoactive placebo.
16.2.1. Investigator 
Responsibilities
Safety during study
Blood volumes used for testing in pediatric populations are monitored closely 
and Aall phlebotomy volumes for this study have been minimized to adhere to 
the Committee for Human Medicinal Products (CHMP) and Paediatric 
Committee (PDCO) guideline recommendations. To increase subject comfort, an 
indwelling catheter has been recommended.
Based on previous studies, it is known that certain adverse drug reactions occur 
postdose, peak around 40 minutes, and then dissipate, usually within 4 hours. 
The study includes careful monitoring following study drug dosing, every 4 
hours performed at predose and at 40 minutes, 1 hour, and 1.5 hours 
postdose, with special attention to blood pressure, heart rate and oxygenation, 
with the latter vital signs monitored 15 minutes predose, immediately after 
the first spray (t = 0), and every 15 minutes thereafter through to 
approximately 1.5 hours postdose, or longer, if necessary. Additionally, other 
known after effects of esketamine (eg, dissociation, sedation, conceptual 
disorientation, hallucinogenic behavior, and abnormal thought content) are 
monitored closely during this time using specific assessment tools like CADSS, 
MOAA/S, and BPRS. On each dosing day, CADSS and BPRS+ will be 
performed predose and at 40 minutes and 1.5 hours postdose, whereas 
MOAA/S will be performed every 15 minutes, from 15 minutes predose to 
1.5 hours postdose, or longer, if necessary.
Rationale: Text updated to include complete list of assessments to be considered source data
17.4. Source Documentation
The text was revised as follows (bold text added; strikeout text deleted):
Subject- and investigator-completed scales and assessments designated by the 
sponsor will be considered source data. The CDRS-R, MADRS, SIBAT, CDI 2 
SR(S), MOAA/S, YMRS, PWC-20, RAVLT, BPRS+, MINI-KID, Cogstate
computerized cognitive battery Cogstate test battery, TLFB, nasal symptom 
questionnaire and CADSS will be considered source data
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
31
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of subject and site staff entry of assessments and patient reported outcomes.
9.1.3. Double-Blind 
Treatment Phase
The text was revised as follows (bold text added):
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 if electronic entry is not functioning.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made
Amendment 1 (28 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 revise the protocol to 
address feedback from Health Authorities, improve clarity, enhance safety, and align the protocol with currently 
ongoing studies in a related population.
Applicable Section(s)
Description of Change(s)
Rationale: Revisions were made to minimize risk to subjects.
Treatment Time and 
Events Schedule; 
3.2.7, Safety 
Evaluations; 
9.1.5, Early 
Withdrawal; 
10.2, Discontinuation 
of Study Treatment
Text was revised to indicate that monitoring visits will occur 3 and 10 days post 
treatment to assess adverse events and withdrawal symptoms.
4.1. Inclusion Criteria
Inclusion criterion #14 was revised to include that contraceptive methods should be 
discussed in detail with the subject by the investigator, and that subjects must be willing 
and able to participate in all study activities.
10.2. Discontinuation 
of Study Treatment
Worsening of underlying condition and a change from voluntary to involuntary 
hospitalization were added as reasons for discontinuing treatment.
Rationale: Exclusion criteria were revised to more precisely define the study population.
Synopsis, Key 
Exclusion Criteria; 
4.2, Exclusion 
Criteria
Exclusion Criterion #4 was revised to clarify that substance and alcohol use disorders 
must meet DSM-5 severity criteria of moderate to severe in order to be considered 
exclusionary; and that a lifetime history of ketamine, phencyclidine (PCP), lysergic acid 
diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-
related use disorder is exclusionary.
Exclusion Criterion #6 was revised to include examples of clinically significant cardiac 
and endocrine conditions.
Exclusion Criterion #7 was revised to indicate the following:
-
elevated blood pressure in children is based on a single measurement, rather than an 
average of 3 or more measurements; 
-
on Day 1, prior to randomization, a supine or semi-supine SBP and/or DBP ≥ the 
95th percentile for sex, age and height is exclusionary; 
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
32
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
-
an abnormal blood pressure measurement at screening may be repeated once after 5 
minutes of relaxation for subject eligibility; 
-
subjects with conditions in which blood pressure elevation could pose a serious risk 
are excluded. 
Synopsis, Key 
Exclusion Criteria; 
4.2, Exclusion 
Criteria 
Exclusion Criterion #8 was revised to include methamphetamines, 3,4-methylenedioxy 
methamphetamine (MDMA) and heroin as drugs that result in exclusion from the study 
at screening, and that subjects who have a positive urine test result for cannabinoids may 
be eligible to participate in the study, provided they do not meet DSM-5 severity criteria 
for a moderate to severe substance abuse disorder.
3.2.1. Overview of 
Study Design
Text was revised to align with revisions related to exclusion criteria #4, 6, 7 and 8.
6.2.1. Guidance on 
Blood Pressure 
Monitoring
Guidance on blood pressure monitoring was revised to align with revisions related to 
Exclusion Criterion #7.
Rationale: Text was revised to correct and expand the description of procedures for pulse oximetry and Modified 
Observer’s Assessment of Alertness/Sedation data.
9.6. Safety 
Evaluations, Pulse 
Oximetry; Safety 
Evaluations, 
Modified Observer’s 
Assessment of 
Alertness and 
Sedation (MOAA/S)
The text describing collection of data for pulse oximetry, and MOAA/S was revised as 
follows, respectively, and text was added to inform site personnel as to how to proceed 
in the event a subject’s oxygen saturation level falls below 93% (bold text added and 
strike out 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 postdoseafter 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.). 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. If oxygen 
saturation levels are <95% predose, dosing should be postponed, and the subject 
should be evaluated by an appropriate practitioner to determine suitability to 
continue in the study.
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.)
Rationale: The text was updated to clarify that the duration of hospitalization may be shorter or longer than the 
recommended period, based on the clinical needs of a given subject and local practice; and that discharge before
5 days or after 10 days must be discussed with the sponsor.
3.1. Overview of 
Study Design, 
Figure 1.
Figure 1 revised to indicate that visits on Days 28 and 35 will occur by remote contact.
Footnote “c” was revised to indicate that continued hospitalization longer than 10 days 
must be discussed with the sponsor’s medical monitor on a weekly basis.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
33
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
9.1.3. Double-blind 
Treatment Phase
Text was revised as follows (bold text added):
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 decision to discharge a subject from the hospital should be 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.
Time and Events 
Schedule – Post-
Treatment Follow-Up 
Phase; SIBAT Time 
and Events Schedule 
– Post-Treatment 
Follow-Up Phase; 
Text in the footnotes was revised for consistency with the changes described above in 
Sections 3.1 and 9.1.3.
Rationale: The description of the urine drug test was revised to reflect the full range of drugs evaluated in the 
urine drug screen.
9.6. Safety 
Evaluations, Clinical 
Laboratory Tests
The list of drugs screened in the urine drug test was replaced with the following list of 
drugs: amphetamine, barbiturates, benzodiazepines, cocaine, marijuana (THC), 
methadone, methamphetamine, methylenedioxymethamphetamine (MDMA), opiates, 
phencyclidine (PCP), and tricyclic antidepressants.
Rationale: Text was revised to improve clarity.
Treatment Time and 
Events Schedule 
Footnotes “o” and “u” were revised to better describe the recall periods used for CDRS-
R and CDI 2:SR, respectively, at each time point they are administered.
Treatment and 
SIBAT Time and 
Events Schedules; 
3.2.7. Safety
Evaluations
All references to “remote contact” and “telephone contact” were revised to “remote 
contact (eg, by telephone).”
Synopsis, Overview 
of Study Design; 
Time and Events 
Schedule – Double-
blind Treatment 
Phase; 
3.1. Overview of 
Study Design; 
9.1.2. Screening 
Phase;
9.1.3 Double-Blind 
Treatment Phase
As applicable for each section, the following changes were made:
-
The location “inpatient psychiatric unit” was revised to “inpatient psychiatric unit or 
other permitted setting”.
-
The number of anticipated sites (45) was added.
-
A statement was added to clarify that the duration of hospitalization may vary per 
local standard of care.
Section 1.1.2.3. 
Efficacy
Text was revised to more clearly present efficacy results from Study 
ESKETINTRD2003.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
9.1.3. Double-blind 
Treatment Phase
9.1.4. Post-treatment 
Follow-up Phases
9.1.5. Early 
Withdrawal
10.2. Discontinuation 
of Study Treatment
The following text concerning procedures following the death of a subject was added to 
Section 9.1:
If a subject dies, the date and cause of death will be collected and documented on the 
eCRF.
Also, procedural instructions related to early withdrawal were moved within Section 9.1 
to Section 9.1.5 and revised to reflect additional remote contact in the first 2 weeks post 
treatment for the assessment of adverse events and withdrawal symptoms.
9.6. Safety 
Evaluations, Targeted 
Nasal Examination 
and Nasal Symptom 
Questionnaire
Text describing the Nasal Examination and Nasal Symptom Questionnaire was revised 
as follows (bold text added and strikeout text deleted):
Subsequent examinations 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 the presence and severity of symptoms will be graded as 
follows: none, mild, moderate, or severe. 
In addition, subjects a clinician or designated study staff will be asked to complete a 
nasal symptom questionnaire.
Rationale: Text was revised to accommodate differences in antidepressant prescribing practices.
6. Dosage and 
Administration; 
9.1.3. Double-blind 
Treatment Phase
Clarified that unless clinical judgment dictates otherwise, it is recommended that 
subjects who have not previously been treated with an antidepressant receive standard of 
care antidepressant treatment with fluoxetine.
Rationale: Text was revised to include evaluation of the post-treatment occurrence of PCP use.
9.6. Safety 
Evaluations, Timeline 
Follow-back
PCP was added as a drug to be assessed by the Timeline Follow-back assessment for 
abuse potential.
Rationale: Text was revised to allow for collection and analysis of final laboratory values from subjects who 
withdraw from the study before the Day 81 visit.
Treatment Time and 
Events Schedule –
Post-treatment 
Follow-up Phase
9.6. Safety 
Evaluations, Timeline 
Follow-back
Schedule revised to indicate the collection of laboratory analytes at the post-treatment 
early withdrawal visit, including a footnote to indicate this collection only applies if the 
patient withdraws before the Day 81 visit.
Rationale: The recommended sequence in which patient-reported outcomes are performed was revised to include 
the Children’s Depression Inventory 2: Self-Report (short version) (CDI 2-SR(S)).
9.1.3. Double-blind 
Treatment Phase
The text describing the recommended sequence for performing patient-reported 
outcomes was revised as follows (bold text added):
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 and CDRS-R 

CDI 2-SR(S)
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
35
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
Rationale: Text was added to support statistical methodology.
Synopsis, Sample 
Size Determination; 
11.2. Sample Size 
Determination
To support the assumed effect size of 0.65, the mean difference between treatment 
groups (-7.2) and pooled SD (11.02) observed in MADRS total score in Study 
ESKETINSUI2001 were added.
Synopsis, Primary 
Efficacy Analyses; 
Synopsis, Other 
Efficacy Analyses; 
11.3. Efficacy 
Analyses
Text was revised to indicate that point estimates and 95% confidence intervals for 
treatment differences will be provided with the primary and other efficacy analyses; that 
the Hodges-Lehmann estimate will be used to estimate treatment differences; and that 
descriptive statistics will be provided, as appropriate.  
Synopsis, 
Pharmacokinetics 
Analyses; 
11.4. 
Pharmacokinetic 
Analyses
Text was revised to indicate that standard errors and 95% confidence intervals will be 
provided as part of the pharmacokinetic analysis.  
Rationale: To avoid unnecessary restriction of study participation.
Attachment 1. 
Prohibited 
Concomitant 
Medications
Text was revised to define the parameters around the use of corticosteroid and opioid 
medications.
Rationale: To correct minor errors.
Synopsis
Literature references were deleted in the synopsis.
Synopsis, Safety 
Evaluations
Timeline Follow-Back (TLFB) was added to the list of safety evaluations.
1.1.2.2. Human 
Pharmacokinetics and 
Product Metabolism;
3.2.4. Esketamine 
Dose
Description of subjects in Study ESKETINTRD2003 was revised to state “adult 
subjects” instead of “subjects”.
4.1. Inclusion Criteria
The repeated text (“sexually active subjects”) was deleted in Inclusion Criterion #12 as 
shown below (strikeout text deleted):
During the double-blind treatment phase (from Day 1 through the day of the last dose of 
study drug) and for a minimum of 1 spermatogenesis cycle, defined as approximately 90 
days after receiving the last dose of study drug, sexual abstinence is strongly 
recommended; however, sexually active subjects heterosexually active male subjects
must:…
The last four inclusion criteria were renumbered as 13, 14, 15, and 16 (instead of 14, 15, 
16, and 17).
9.1.2. Screening 
Phase
Text was revised as follows (strikeout text deleted):
The clinician-administered assessments at screening can be performed in the order 
preferred by the clinical site.: MINI KID, Questions B3 and B10 from MINI KID 
(current status). If the screening phase is longer than 24 hours, Question B3 and B10 
from MINI-KID (current status) must be repeated to confirm eligibility.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
36
Status: Approved, Date: 22 November 2020
Applicable Section(s)
Description of Change(s)
12. Adverse Event 
Reporting, Solicited 
Adverse Events
Missing word added to the following sentence (bold text added): 
Solicited adverse events are predefined local and systemic events for which the subject 
is specifically questioned.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
37
Status: Approved, Date: 22 November 2020
SYNOPSIS
A Double-blind, Randomized, Psychoactive Placebo-controlled, Study to Evaluate the Efficacy and Safety 
of 3 Fixed Doses (28 mg, 56 mg and 84 mg) 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 Pediatric Subjects Assessed to be at Imminent Risk for Suicide
Esketamine is the S-enantiomer of ketamine, which has been widely used for the induction and maintenance 
of anesthesia since the 1970s. Because of its ability to block the N-methyl-D-aspartate (NMDA) glutamate 
receptor, ketamine has shown efficacy in the treatment of symptoms of major depressive disorder (MDD). 
This study is intended to evaluate the efficacy, safety and dose response of 3 doses of esketamine in subjects 
12 to <18 years of age with MDD who are assessed to be at imminent risk for suicide.
Major depressive disorder is one of the most prevalent mental health conditions and the psychiatric 
diagnosis most commonly associated with suicide. Epidemiology studies estimate that the 12-month 
prevalence of MDD is 2% in children and 4% to 8% in adolescents; that MDD is the main predictor of 
suicidal ideation among children and adolescents; and that 40% to 80% of adolescents meet the diagnostic 
criteria for depression at the time of suicide attempt. Similar to adults, there is a substantial link between 
clinical depression and suicide in adolescents with up to 60% of adolescent suicide victims having a 
depressive disorder at the time of death. Therefore, MDD with imminent risk for suicide is a serious, 
potentially lethal condition that requires immediate intervention.
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 for depressed adolescents at 
imminent risk for suicide is hospitalization and treatment with antidepressant medication, combined with 
psychotherapy.However, hospitalization is temporary and not completely effective, and the risk for suicide 
remains high in the weeks after discharge. For example, one study found that 13.9% of hospitalized 
adolescents (12-15 years of age) reattempted suicide within 3 months of discharge.
According to several treatment guidelines, 3 antidepressants are recommended as pharmacological 
treatment options in children and adolescents with MDD: fluoxetine (Prozac®), escitalopram (Lexapro®), 
and sertraline (Zoloft®). However, because standard of care antidepressants may take up to 4 to 6 weeks to 
exert their full effect, there is a significant unmet need for a drug therapy with a rapid onset of effect to 
decrease depressive symptomatology, including suicidal ideation.
Ketamine and esketamine (the S-enantiomer of ketamine) are approved and widely used in children and 
adults for the induction and maintenance of anesthesia via intramuscular (IM) or intravenous (IV) 
administration. The desired analgesic-anesthetic effects of esketamine are attributed to the blockade of 
ionotropic N-methyl-D-aspartate (NMDA) glutamate receptors. Affinity for the NMDA receptor is 
approximately 3- to 4-fold greater for esketamine than for its enantiomer, arketamine (R ketamine, the R-
enantiomer of ketamine).
Several pilot studies using IV ketamine in subjects with MDD or bipolar depression also suggested that 
ketamine may reduce suicidal ideation within hours of administration. In addition, 2 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).
The mechanism of action of esketamine is distinct from conventional antidepressant treatments, which 
target modulatory monoaminergic neurotransmitters (serotonin, norepinephrine, and/or dopamine), 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.
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
38
Status: Approved, Date: 22 November 2020
Administered intranasally, esketamine is rapidly and well-absorbed, and can offer patients better 
convenience. Janssen Research & Development is developing intranasal esketamine both for treatment-
resistant depression (TRD) and for the rapid reduction of the symptoms of MDD, including suicidal 
ideation, in adult patients who are assessed to be at imminent risk for suicide. As part of the pediatric 
development program, this study is evaluating the efficacy, safety and dose response of esketamine in 
subjects 12 to <18 years of age with MDD who are assessed to be at imminent risk for suicide.
For the most comprehensive nonclinical and clinical information regarding esketamine (JNJ-54135419), 
refer to the latest version of the Investigator's Brochure for esketamine, and associated addenda.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Primary Objective
The primary objective is to assess the efficacy of a single (first) dose of 3 fixed doses of intranasal 
esketamine (28 mg, 56 mg, and 84 mg) compared with psychoactive placebo (oral midazolam) in rapidly
reducing the symptoms of MDD, including suicidal ideation, in subjects 12 to <18 years of age who are 
assessed to be at imminent risk for suicide. Efficacy will be assessed by the change from baseline in 
Children’s Depression Rating Scale, Revised (CDRS-R) total score at 24 hours post first dose (Day 2).
Other Objectives
The other objectives are the following: 

To evaluate the dose response of intranasal esketamine compared with psychoactive placebo in 
reducing the symptoms of MDD, including suicidal ideation, as assessed by the change from baseline 
in CDRS-R total score at 24 hours post first dose (Day 2) and Day 25.

To evaluate the efficacy of single and repeated doses of intranasal esketamine compared with 
psychoactive placebo in reducing symptoms of suicidal ideation, as assessed by the Clinical Global 
Impression of Severity of Suicidality, revised version (CGI-SS-R) from the Suicide Ideation and 
Behavior Assessment Tool (SIBAT) 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 single and repeated doses of intranasal esketamine compared with 
psychoactive placebo in reducing symptoms of MDD as assessed by the following:

CDRS-R total score at 4 hours post first dose, through the end of the Double-Blind Treatment 
phase (Day 25), and during the 6-month Post-Treatment Follow-Up phase.

Montgomery-Asberg Depression Rating Scale (MADRS) total score at 4 hours and 24 hours post 
first dose, through the end of the Double-Blind Treatment phase (Day 25), and during the 6-month 
Post-Treatment Follow-Up phase.

Children’s Depression Inventory 2: Self-Report (short version) (CDI 2:SR[S])TM score at 24 hours 
post first dose and through the end of the Double-Blind Treatment phase (Day 25).

To evaluate the efficacy of single and repeated doses of intranasal esketamine compared with 
psychoactive placebo in reducing symptoms of suicidal ideation, as assessed by the Clinical Global 
Impression – Imminent Suicide Risk (CGI-SR-I) from the Suicide Ideation and Behavior Assessment 
Tool (SIBAT) at 4 hours and 24 hours post first dose and through the end of the Double-Blind 
Treatment phase (Day 25).
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JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
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Status: Approved, Date: 22 November 2020

To evaluate the efficacy of single and repeated doses of intranasal esketamine compared with 
psychoactive placebo in reducing suicidal thoughts, as assessed by the following:

Change from baseline in SIBAT Module 3 (My Current Thinking) and Module 5 (My Risk) 
Question 3 (patient-reported frequency of suicidal thinking) through the end of the Double-Blind 
Treatment phase (Day 25) and during the 6-month Post-Treatment Follow-Up phase. 

To characterize the pharmacokinetics of intranasal esketamine and its metabolite noresketamine.

To evaluate the safety and tolerability of intranasal esketamine through the end of the Double-Blind 
Treatment phase (Day 25) using the following assessments:

Effects on suicidal ideation and behavior using the SIBAT 

Effects on dissociative symptoms using the Clinician-Administered Dissociative States Scale 
(CADSS)

Occurrence of psychosis-like side effects using a 4-item positive symptom subscale (consisting 
of: suspiciousness, hallucinations, unusual thought content, and conceptual disorganization) of 
the Brief Psychiatric Rating Scale, positive symptom subscale (BPRS+)

Occurrence of potential treatment-emergent symptoms of mania using the Young Mania Rating 
Scale (YMRS)

Effects on cognitive function as measured by the Cogstate® computerized cognitive battery

Effect on sedation using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) 
scale

Local nasal tolerability, using targeted nasal examinations coupled with a nasal symptom 
questionnaire

To evaluate the safety and tolerability of intranasal esketamine at specified times through the initial 
25 day double-blind treatment period (Day 25), the 8-week post-treatment follow-up (Day 81) and 
6-month post-treatment follow-up, with special attention given to the following assessments:

Effects on suicidal ideation and behavior using the SIBAT

Effects on cognitive function as measured by the Cogstate computerized cognitive battery

To evaluate potential withdrawal symptoms during the post-treatment follow-up as measured by the 
Physician Withdrawal Checklist (PWC-20) on Days 25, 28, 32, 35 and 39.

To evaluate the potential for ketamine or phencyclidine (PCP) abuse during the follow-up as measured 
by the Timeline Follow-Back (TLFB).

To evaluate whether pretreatment concentrations of MDD-related biomarkers (eg, 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.

To explore the change in MDD-related biomarkers in relation to clinical response or non-response to 
intranasal esketamine.
Endpoints
The primary efficacy evaluation will be the change from baseline (Day 1, predose) at 24 hours post first 
dose in depressive symptoms, including suicidal ideation, as measured by the CDRS-R total score.
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JNJ-54135419 (esketamine)
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Status: Approved, Date: 22 November 2020

Other efficacy endpoints will be evaluated throughout the study, as follows:

CDRS-R 
o
Dose response at 24 hours post first dose and Day 25.
o
Changes from baseline, post single and repeated doses, at 4 hours post first dose, through the 
end of the Double-Blind Treatment phase (Day 25), and during the 6-month Post-Treatment 
Follow-Up phase.

MADRS
o
Changes from baseline, post single and repeated doses, at 4 hours and 24 hours post first 
dose, through the end of the Double-Blind Treatment phase (Day 25), and during the 
6-month Post-Treatment Follow-Up phase. 

CGI-SS-R from SIBAT
o
Changes from baseline, post single and repeated doses, at 4 hours and 24 hours post first 
dose, through the end of the Double-Blind Treatment phase (Day 25).

CGI-SR-I from SIBAT
o
Changes from baseline, post single and repeated doses, at 4 hours and 24 hours post first 
dose, through the end of the Double-Blind Treatment phase (Day 25).

SIBAT
o
Changes from baseline, post single and repeated doses, through the end of the Double-Blind 
Treatment phase (Day 25) and during the 6-month Post-Treatment Follow-Up phase in 
depressive symptoms and suicidal ideation (subject-completed modules 3, 4, and 5) and 
clinician impression of suicidality and judgment about management of suicidal thinking 
(clinician-completed modules 7 and 8).

CDI 2:SR (S)
o
Changes from baseline, post single and repeated doses, at 24 hours post first dose and 
through the end of the Double-Blind Treatment phase (Day 25). 

Safety endpoints will be evaluated throughout the study, as follows: 

Monitoring of treatment-emergent adverse events (TEAEs) 

Clinical laboratory tests, physical examination, nasal examination and nasal symptom 
questionnaire, 12-lead electrocardiogram (ECG), vital signs, pulse oximetry and body weight

SIBAT 

BPRS+ score 

CADSS 

Cogstate computerized cognitive battery

YMRS score

Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score

Physician Withdrawal Checklist (PWC-20)

TLFB methodology to evaluate use of ketamine or PCP.
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JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 22 November 2020

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. Plasma concentrations of other esketamine metabolites and midazolam may also be 
measured, if warranted.

Biomarkers

Characteristics of esketamine mechanism of action or biological predictors of inter-individual 
variability.
Refer to Section 9, Study Evaluations, for evaluations related to endpoints.
Hypothesis
The primary hypothesis of this study is that, in addition to standard of care, intranasal esketamine is superior 
to psychoactive placebo in rapidly reducing the symptoms of MDD, including suicidal ideation, as assessed 
by the change from baseline in CDRS-R at 24 hours post first dose in subjects 12 to <18 years of age who 
are assessed to be at imminent risk for suicide.
OVERVIEW OF STUDY DESIGN
This Phase 2 study is a randomized, double-blind, double-dummy, psychoactive placebo-controlled, 
multicenter trial with 45 anticipated global sites. A target of 145 pediatric subjects, 12 to <18 years of age, 
will be enrolled in this study and randomized in a 1:1:1:2 ratio to one of 3 doses of intranasal esketamine 
(28, 56 or 84 mg) or a psychoactive placebo (oral midazolam 0.125 mg/kg), with approximately 29 subjects 
assigned to each dose of intranasal esketamine and approximately 58 subjects assigned to psychoactive 
placebo. All eligible subjects will have a diagnosis of MDD and will have presented to an emergency room 
(ER) or other permitted setting and been assessed to be at imminent risk for suicide. Given the vulnerability 
of the population, this study will be conducted in the context of standard of care treatment. This includes 
initial hospitalization in an inpatient psychiatric unit or other permitted setting for a recommended duration 
of 5 days counted from randomization, with shorter or longer hospitalizations permitted if clinically 
warranted per local standard of care; initiation or optimization of allowed antidepressant medication 
therapy, participation in a specific psychological intervention (individual cognitive behavioral therapy 
[CBT]), interpersonal therapy, family therapy or psychodynamic psychotherapy), and close outpatient 
follow-up.
There is only 1 approved antidepressant for the treatment of MDD in children and adolescents in both the 
United States (US) and European Union (EU): fluoxetine; however, if treatment with fluoxetine is 
unsuccessful or is not tolerated because of side effects, guidelines recommend treatment with escitalopram 
and sertraline. Escitalopram (the S-enantiomer of citalopram) is also approved for use in adolescents in the 
US. Therefore, this multi-national study will permit the use of fluoxetine, escitalopram or sertraline as the 
standard of care antidepressants.
The study will be conducted in 4 phases: a screening evaluation performed within 48 hours prior to Day 1 
intranasal dose (if possible, screening should occur within 24 hours prior to the Day 1 intranasal dose); a 
25-day Double-Blind Treatment phase (Days 1-25), during which study drug will be administered 2 times 
per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25; an 8-week initial post-treatment follow-up
phase (Days 25-81); and a subsequent phase to complete a full 6-month post-treatment follow-up 
(Days 81-200). During post-treatment follow-up phases, no study drug will be administered. The duration 
of the subject’s participation will be approximately 29 weeks. The study is considered completed with the 
last study assessment for the last subject participating in the study.
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Clinical Protocol ESKETINSUI2002 Amendment 4
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Status: Approved, Date: 22 November 2020
Efficacy, safety, pharmacokinetic, biomarker, and pharmacogenomic (DNA and RNA) evaluations will be 
performed as described in the Time and Events Schedule.

The primary efficacy evaluation is the CDRS-R; other efficacy evaluations are SIBAT/CGI-SS-R and 
CGI-SR-I, MADRS, CDI 2:SR(S).

Safety evaluations include monitoring and collection of adverse events and concomitant therapies, 
physical examination, nasal examination and nasal symptom questionnaire, measurements of body 
weight and vital signs, 12-lead electrocardiogram (ECG), pulse oximetry, clinical laboratory tests, 
SIBAT, MOAA/S, CADSS, BPRS+, YMRS, PWC-20, TLFB, Cogstate computerized cognitive
battery.

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.

Blood samples for DNA and RNA analyses will be collected from subjects who consent/assent 
separately to this component of the study (where local regulations permit). Subject participation in 
DNA and RNA 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.
Key Inclusion Criteria

Male and female adolescents (12 to <18 years of age).

Subject must meet DSM-5 diagnostic criteria for MDD, without psychotic features, based upon 
clinical assessment and confirmed by the Mini International Neuropsychiatric Interview for 
Children and Adolescents (MINI-KID).

Subject must have current suicidal thinking with intent at the time of screening, confirmed by “Yes” 
responses to both MINI-KID Question B3 (Think about hurting yourself with the possibility that 
you might die. Or did you think about killing yourself?)  AND Question B10 (Expect to go through 
with a plan to kill yourself?). 
Note: the response to B3 must refer to the present, whereas the response to B10 may reflect the past 
24 hours. If screening is longer than 24 hours, the assessment of questions B3 and B10 for the MINI-
KID must be repeated to confirm eligibility.

In the physician’s opinion, acute psychiatric hospitalization is clinically warranted due to subject’s 
imminent risk of suicide.

Subject must have a CDRS-R total score of ≥ 58 predose on Day 1.

As part of standard of care treatment, subject must agree 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). 

As part of the newly initiated or optimized standard of care treatment, subject must agree to take 
one of the prescribed non-investigational antidepressants medications (fluoxetine, escitalopram, 
sertraline) during the Double-Blind Treatment phase (Day 25).
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JNJ-54135419 (esketamine)
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Status: Approved, Date: 22 November 2020

As part of standard of care treatment, subject must agree to participate in a specific psychological 
intervention (individual cognitive behavioral therapy [CBT], interpersonal therapy, family therapy 
or psychodynamic psychotherapy) at least through the initial 8-week follow-up period (Day 81).
Key Exclusion Criteria

Subject has a current DSM-5 diagnosis of bipolar (or related disorders), intellectual disability, 
autism spectrum disorder, conduct disorder, anorexia nervosa, oppositional defiant 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 or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychosis.

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 a history of seizure disorder.

Subject has a history or current signs and/or symptoms of liver or renal insufficiency; has a current 
diagnosis of clinically significant cardiac (eg, congenital heart disease, cardiomyopathy, or 
tachyarrhythmias), 
vascular, 
pulmonary, 
gastrointestinal, 
endocrine
(including 
severe 
dehydration/hypovolemia), neurologic, hematologic, rheumatologic, or metabolic disturbances; 
based on investigator judgment.

On Day -1 (screening) or Day 1 of the double-blind phase prior to randomization, a supine or semi-
supine SBP and/or DBP ≥ the 95th percentile for sex, age and height is exclusionary. Subjects who 
fall below the 5th or above the 95th percentile for their age, sex, and height should be evaluated using 
the parameters for the 5th or 95th percentile. Note that subjects whose SBP and/or DBP values are ≥ 
the 95th percentile for sex, age and height may be reevaluated with a repeated measure once after 
5 minutes of rest to assess eligibility.
Subjects with conditions in which blood pressure elevation could pose a serious risk (including 
severe cardiovascular disease, recent cerebral injury, increased intracranial pressure / intracranial 
mass lesion, intracranial bleeding or acute stroke, primary developmental or secondary acquired 
glaucoma or perforating eye injury) are excluded.
DOSAGE AND ADMINISTRATION
Intranasal Study Drug 
For each intranasal esketamine or placebo dose, 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. Sprays to each nostril should be 
delivered in rapid succession at each of the 3 scheduled time points. A total of 3 devices will be used by all 
subjects to administer 3 doses of esketamine or placebo.
Oral Study Drug
Oral midazolam solution (2mg/ml) will be provided as a psychoactive placebo at a dose of 0.125mg/kg to 
all subjects randomized to intranasal placebo. A designated pharmacist (or other qualified healthcare 
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JNJ-54135419 (esketamine)
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CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 22 November 2020
professional) will be unblinded in order to prepare the oral study drug. Subjects randomized to oral 
psychoactive placebo (midazolam) will receive a weight-based dose using a 2mg/mL solution; those 
randomized to intranasal esketamine will receive an oral placebo solution in an equivalent volume to that 
which they would receive if randomized to the psychoactive placebo.
EFFICACY EVALUATIONS
The primary efficacy evaluation will be the CDRS-R total score. 
The other efficacy evaluations include SIBAT, MADRS, and CDI 2:SR(S).
PHARMACOKINETIC EVALUATIONS
Venous blood samples will be collected for measurement of plasma concentrations of esketamine, 
noresketamine, and other metabolites (if warranted).
BIOMARKER AND PHARMACOGENOMIC (DNA AND RNA) EVALUATIONS
Blood samples will be collected for exploratory analysis of biomarkers (protein and metabolites) 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.
Blood samples for DNA and RNA analyses will be collected from subjects who consent/assent separately 
to this component of the study (where local regulations permit). Subject participation in DNA and RNA 
research is optional.
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, nasal 
examination and nasal symptom questionnaire, MOAA/S, CADSS, BPRS+, YMRS, TLFB, Cogstate
computerized cognitive battery, and PWC-20. 
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.
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 receive at least 1 dose 
of double-blind study medication and have both a baseline and a postdose evaluation for the CDRS-R 
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 sample size for this study was calculated assuming an effect size of 0.65 between any dose of 
esketamine and psychoactive placebo for the change from baseline at 24 hours postdose for the CDRS-R 
total score and a 2-sided significance level of 0.05. A total of 145 subjects will be randomized in this study. 
Using a 1:1:1:2 randomization ratio (esketamine 28 mg: esketamine 56 mg: esketamine 84 mg: 
psychoactive placebo), approximately 58 subjects will need to be randomized to psychoactive placebo and
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JNJ-54135419 (esketamine)
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Status: Approved, Date: 22 November 2020
29 subjects will need to be randomized to each esketamine treatment group to achieve 94% power for the 
comparison of the pooled doses of esketamine 56 mg and esketamine 84 mg versus psychoactive placebo
and 92% power for at least one of the 2 esketamine higher doses (56-mg and 84-mg) versus psychoactive 
placebo. The effect size of 0.65 is based on results from study ESKETINSUI2001 (mean difference between 
treatment groups of -7.2 and a pooled SD of 11.02) for MADRS total score.
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 CDRS-R 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 CDRS-R total scores collected at Day 2 
(24 hours post first dose). 
Primary Efficacy Analysis
The primary analysis will be based on the full analysis set. The primary efficacy variable, change from 
baseline in CDRS-R total score at 24 hours post first dose, will be analyzed using an analysis of covariance 
(ANCOVA) model. The model will include factors for treatment and center, and baseline CDRS-R total 
score as a covariate A pooled sequential multiple testing procedure will be implemented to control for 
Type I error. The esketamine 56-mg and 84-mg treatment groups will be pooled and compared with 
psychoactive placebo at a 2-sided significance level of 0.05. If this comparison achieves statistical 
significance in favor of esketamine, the 56-mg dose and the 84-mg dose will each be simultaneously tested 
versus psychoactive placebo at the 2-sided significance level of 0.05 based on the closed testing procedure.
The esketamine 28-mg dose will be tested only if both the individual doses of 56-mg and 84 mg are shown 
to be significant. Point estimates and 95% confidence intervals for treatment differences 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 CDRS-R 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. Missing 
data will be closely monitored throughout the trial.
Other Efficacy Analyses
A dose response analysis for the change from baseline in CDRS-R total score at 24 hours post first dose 
and at Day 25 will be conducted with various dose response models being explored. Details of the dose 
response analysis will be provided in the statistical analysis plan (SAP).
Changes from baseline over time in CDRS-R total score, MADRS total score, and CDI 2:SR[S]TM score 
will be analyzed based on last observation carried forward (LOCF) data using an ANCOVA model with 
treatment and center as factors and baseline value as a covariate. Additionally, the change from baseline in 
CDRS-R total score at Day 25 will be analyzed using a mixed model for repeated measures (MMRM) 
analysis with baseline CDRS-R total score as a covariate, and treatment, center, day, and day-by-treatment 
interaction as fixed effects, and a random subject effect. Comparison of each esketamine dose versus 
placebo will be performed using the appropriate contrast. Point estimates and 95% confidence intervals for 
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JNJ-54135419 (esketamine)
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Status: Approved, Date: 22 November 2020
treatment differences will be provided. Missing data will be closely monitored and additional sensitivity 
analyses will be specified in the SAP, if necessary.
The ranks of changes from baseline over time for both CGI-SS-R and CGI-SR-I will be analyzed using an 
ANCOVA model using LOCF data with factors for treatment and center and baseline CGI-SS-R and
CGI-SR-I (unranked) as a covariate. Treatment differences 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
and CGI-SR-I.
SIBAT Module 3 (My Current Thinking) and Module 5 (My Risk) Question 3 (patient-reported frequency 
of suicidal thinking) 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.
Pharmacokinetic Analyses
Data will be listed for all subjects with available plasma concentrations per treatment group. Subjects will 
be excluded from the pharmacokinetic (PK) analysis if their data do not allow for accurate assessment of 
the PK (eg, incomplete administration of the study drug; missing information of dosing and sampling times; 
concentration data not sufficient for PK parameter calculation). 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.
The plasma concentration-time data of esketamine (and noresketamine, if warranted) will be analyzed using 
population PK 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. 
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. In addition to the final population PK parameter estimates, the corresponding 
standard errors and 95% confidence intervals will be provided.
The relationship between CDRS-R total score (and possibly other efficacy endpoints such as MADRS and 
selected adverse events and additional pharmacodynamic parameters), and PK metrics of esketamine may 
be evaluated. The results of such analyses may be reported separately.
Biomarker and Pharmacogenomic Analyses
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 be performed for additional biomarkers. Results may be presented in a separate 
Biomarkers report. 
Pharmacogenomic analyses (DNA and RNA) may include candidate gene analyses or genome-wide 
association analyses, and gene transcription analyses in relation to treatment response, non-response, and 
MDD. Additional exploratory analyses may be performed.
Safety Analyses
The primary population for safety analysis will consist of all randomized subjects who receive at least one 
dose of double-blind study medication. The safety data from the follow-up phase will be summarized 
separately.
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Status: Approved, Date: 22 November 2020
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). Treatment-
emergent adverse events are adverse events with onset during the Double-Blind Treatment phase or that 
are a consequence of a pre-existing condition that has worsened since baseline. All reported adverse events 
with onset during the Double-Blind Treatment phase (ie, TEAEs 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. In addition, 
comparisons between treatment groups will be provided if appropriate. Adverse events during the follow-
up phase will be summarized separately.
The TEAEs of special interest will be examined separately grouped in the following Medical Dictionary 
for Regulatory Activities (MedDRA) based categories: drug abuse, dependence and withdrawal 
(standardized MedDRA queries [MedDRA SMQ]), transient dizziness/vertigo, impaired cognition, anxiety, 
cystitis, and suicidality. Treatment-emergent adverse events of special interest will be further listed in the 
SAP.
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. A listing of subjects with any markedly abnormal laboratory results will also be provided.
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 (the predose ECG 
will be used as baseline).
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). 
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, >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.)
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.
Changes in findings from the baseline nasal examination (including the upper respiratory tract/throat) will 
be listed by treatment group. Examinations will provide ratings of severity 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.
Scoring from the nasal symptom questionnaire will be summarized descriptively by treatment group.
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Sedation data from the MOAA/S and dissociative symptoms data from the CADSS will be summarized 
descriptively at each scheduled visit by treatment group. Data on suicidal ideation and behavior from the 
SIBAT; psychosis-like side effects from the BPRS+; and potential treatment-emergent symptoms of mania 
from the YMRS will be summarized descriptively at each scheduled visit by treatment group. Cognitive 
function data from the Cogstate computerized cognitive battery, and withdrawal symptom data from the 
PWC-20 will be summarized descriptively at designated scheduled visits by treatment group.
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Footnotes:  
a
Day -1 and Day 1 visits may occur on the same day. If done on same day, vital signs to determine eligibility must be performed both as part of the screening visit 
and as part of the Day 1 visit (predose).
b
Subject should be screened within 48 hrs (if possible, 24 hrs) prior to study drug dosing on Day 1.
c
Visit can be performed +/- 1 day. During the DB phase, study drug administration should not occur on consecutive days.
d
Discharge visit is performed on the actual day of discharge from inpatient hospitalization. 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.
e
Subjects who discontinue from the DB phase for reasons other than lost to follow up, death, or withdrawal of consent/assent will have the DB EW visit conducted at 
the time of discontinuation. In addition, if the DB EW visit occurs on Day 1 to Day 21, subjects will  have remote contact visit (eg, by telephone) on Day 25 to 
assess PWC-20, CDRS-R and MADRS, and for collection of concomitant therapies and AEs (Refer to Sections 9.1.5 and 10.2).
f
If the DB EW visit occurs on or after Day 22 (assuming dose administered), D25 RC visit is not required, however, RC D+5 (5 days after last dose) should be 
performed. If subjects discontinue anytime between Day 25 postdose and Day 28 RC of the PT phase, the PT EW visit is not required; however, Day 28 RC should 
be performed.
g
For subjects who discontinue DB treatment for reasons other than lost to follow up, death, or withdrawal of consent/assent, a remote contact visit will be conducted 
5 days (+/-2 days) after the last dose of study medication. If RC D+5 occurs within 2 days of the EW visit, use the +2 day window to conduct the RC D+5 visit.
h
Day 1, 4-hr assessments should be performed within a 30 min window. Day 2, 24-hr assessments should be performed within a 2 hr window.
i
Not applicable for subjects admitted directly into the inpatient psychiatric unit or other permitted setting (refer to Section 3.1).
j
It is recommended that subjects dosed in the ER not be transferred to the inpatient psychiatric unit or other permitted setting until after the 4-hr postdose assessments 
are completed.
k 
Refer to Section 3.1.
l
Subjects requiring psychiatric re-hospitalization may be eligible to continue in the study.
m Antidepressant medication should be initiated or optimized on Day 1. If starting 2 medications simultaneously is not consistent with local clinical practice, initiating 
SOC antidepressant medication up to 7 days after Day 1 is permitted (refer to Section 6).
n 
Outpatient psychotherapy should be initiated as soon as possible upon discharge from the hospital.
o 
In addition to the scheduled time points, additional pregnancy tests can be performed during the study at the investigator’s discretion (refer to Section 5).
p 
Due to the need to preserve the integrity of the study blind, a urine drug screen (UDS) should not be performed during the DB period unless medically necessary. If 
deemed medically necessary, the medical monitor should be contacted and UDS should be performed predose on dosing days.
q 
Subjects will be asked to respond to Questions B3 and B10 of the MINI-KID regarding their current state. Response to B3 must refer to the present, response to B10 
may reflect the past 24 hrs. If screening is longer than 24 hrs prior to first dose, the B3 and B10 MINI-KID assessment must be repeated to confirm eligibility.
r 
CDRS-R and BP should be performed prior to randomization in order to evaluate eligibility.
s
Refer to Section 6.
t
Performed predose.
u 
Blood pressure, heart rate, and respiratory rate performed at predose (should be performed between t = -15 min and t = 0) and at t = 40 mins, 1 hr, and 1.5 hrs 
postdose; temperature at predose only (tympanic recommended).
v 
At screening, the ECG tracing will be sent to the central ECG laboratory, but the investigator or sub-investigator is required to review the ECG locally to determine 
subject eligibility.
w Performed 1 hr postdose.
x 
On each dosing day, continuous arterial oxygen saturation monitoring by pulse oximetry (SpO2) should be monitored and documented once predose between 
t = -15 min and t = 0 (first spray), and then every 15 mins postdose for approximately 1.5 hrs (see Section 9.6).
y
Only weight will be recorded at the Day 25 and the DB EW visit.
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z 
On each dosing day, MOAA/S should be performed once predose between t = -15 min and t = 0 (first spray), and every 15 min for approximately 1.5 hrs postdose 
(longer, if necessary; refer to Section 9.6).
aa On each dosing day, CADSS and BPRS+ to be performed predose and at 40 minutes and 1.5 hours postdose. If any CADSS items are scored zero at 40 mins, these 
items will not be repeated at 1.5 hrs postdose.
bb Cogstate computerized cognition battery will be performed between Day 4 and Day 8, prior to subject’s discharge from the inpatient unit. On a dosing day, complete 
predose.
cc Nasal symptom questionnaire performed predose and at 1 hr postdose.
dd If a dose is administered, SIBAT is performed predose. Not all modules are completed at every visit; see SIBAT Time &Events Schedule.
ee
MADRS and CDRS-R will be performed at both predose and 4-hr postdose on Day 25 (visit 10) of the DB phase.
ff
CDI 2:SR[S] Completed predose at all timepoints. A 24-hr recall period applies on Day 2; a 2-week recall period applies at Day 1 and Day 25 or DB EW.
gg Samples will be collected for analysis by local laboratory (for eligibility) and central laboratory (refer to Section 9.6)
hh Window for PK collection as follows: 30-50 mins; 1.5 hr to 2.5 hrs; and 4 hrs to 12 hrs on Day 1 and Day 4.
ii
These samples will be collected along with the 1.5 to 2.5 hour PK collection.
jj 
Visit can be performed +/- 3 days.
kk Visit can be performed +/- 5 days.
ll
Visit can be performed +/- 7 days.
mm Subjects who discontinue from the PT phase for reasons other than lost to follow up, death, or withdrawal of consent/assent will have the PT EW visit conducted at 
the time of discontinuation. If subjects discontinue anytime between Day 25 postdose and Day 28 RC of the PT phase, the PT EW visit is not required; however, 
Day 28 RC should be performed. If the PT EW visit occurs prior to completion of the Day 81 visit, a remote contact will be performed on Day 81 for PWC-20,
CDRS-R and MADRS, and for collection of concomitant therapies and AEs. (refer to Sections 9.1.5 and 10.2).
nn If the PT EW visit occurs within ±5 days window of Day 81 (visit 18) of the PT phase, then EW visit will be adequate, and the Day 81 RC visit is not required.
oo Subjects who discontinue from the PT Follow-up Phase for reasons other than lost to follow up, death, or withdrawal of consent/assent after completion of the 
Day 81 visit will have the PT EW visit conducted at the time of discontinuation (refer to Section 10.2).
pp Hematology, chemistry and urinalysis are done only if the subject has withdrawn from the study prior to the Day 81 visit.
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ABBREVIATIONS
AAP
American Academy of Pediatrics
AD
antidepressant
ADHD
Attention-deficit hyperactivity disorder
AE
adverse event
ANCOVA
analysis of covariance
BP
blood pressure
BPRS+
Brief Psychiatric Rating Scale, positive symptom subscale 
CADSS
Clinician-Administered Dissociative States Scale 
CBT
cognitive behavioral therapy
CDI 2:SR
Children’s Depression Inventory 2 Self-Report
CDI 2:SR(S)
Children’s Depression Inventory 2: Self-Report (short version) 
CDRS-R
Children’s Depression Rating Scale-Revised
CGI-SR-I
Clinical Global Impression – Imminent Suicide Risk
CGI-S
Clinical Global Impression Severity Scale
CGI-SS
Clinical Global Impression Severity of Suicidality
CGI-SS-R
Clinical Global Impression of Severity of Suicidality, revised version 
eCRF
electronic case report form 
DB
double-blind
DBP
diastolic blood pressure
D/C
hospital discharge
DCF
data clarification form
DSM-5
Diagnostic and Statistical Manual of Mental Disorders (5th edition)
ECG
electrocardiogram
eDC
electronic data capture
ER
emergency room
EU
European Union
EW
early withdrawal
FDA
Food and Drug Administration
GCP
Good Clinical Practice
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IM
intramuscular
IND
Investigational New Drug
InterSePT
International Suicide Prevention Trial
IRB
Institutional Review Board
IV
intravenous
IVRS
interactive voice response system
IWRS
interactive web response system
LAR
Legally acceptable representative
LC-MS/MS
liquid chromatography/mass spectrometry/mass spectrometry
MADRS
Montgomery-Asberg Depression Rating Scale 
MADRS-SI
Montgomery-Asberg Depression Rating Scale – Suicidal Ideation
MedDRA
Medical Dictionary for Regulatory Activities
MDD
major depressive disorder
MINI
Mini International Neuropsychiatric Interview
MINI-KID
Mini International Neuropsychiatric Interview for Children and Adolescents
MOAA/S
Modified Observer's Assessment of Alertness/Sedation 
NICE
National Institute for Health and Clinical Excellence
NSAID
non-steroidal anti-inflammatory drug
PD
pharmacodynamic(s)
PDCO
Paediatric Committee
PWC-20
Physician Withdrawal Checklist 
PK
pharmacokinetic(s)
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PCP
phencyclidine
PQC
Product Quality Complaint
PRO
patient-reported outcome(s) (paper or electronic as appropriate for this study)
RC
remote contact
RNA
ribonucleic acid
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SIBAT
Suicide Ideation and Behavior Assessment Tool 
SoC
standard of care
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
TMS
Trans-cranial magnetic stimulation
TLFB
Timeline Follow-Back 
UDS
urine drug screen
US
United States
USP
United States Pharmacopeia
YMRS
Young Mania Rating Scale 
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1.
INTRODUCTION
Esketamine is the S-enantiomer of ketamine, which has been widely used for the induction and 
maintenance of anesthesia since the 1970s. Because of its ability to block the N-methyl-D-
aspartate (NMDA) glutamate receptor, ketamine has shown efficacy in the treatment of symptoms 
of major depressive disorder (MDD).85 This study is intended to evaluate the efficacy, safety and 
dose response of 3 doses of esketamine in subjects 12 to <18 years of age with MDD who are 
assessed to be at imminent risk for suicide.
Major depressive disorder is one of the most prevalent mental health conditions and the psychiatric 
diagnosis most commonly associated with suicide.54,91 Epidemiology studies estimate that the
12-month prevalence of MDD is 2% in children and 4% to 8% in adolescents,2 that MDD is the 
main predictor of suicidal ideation among children and adolescents,37,93 and that 40% to 80% of 
adolescents meet the diagnostic criteria for depression at the time of suicide attempt.10,37 Similar 
to adults, there is a substantial link between clinical depression and suicide in adolescents with up 
to 60% of adolescent suicide victims having a depressive disorder at the time of death.14,107
Therefore, MDD with imminent risk for suicide is a serious, potentially lethal condition that 
requires immediate intervention.
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 for depressed 
adolescents at imminent risk for suicide is hospitalization and treatment with antidepressant 
medication combined with psychotherapy.91 However, hospitalization is temporary and not 
completely effective, and the risk for suicide remains high in the weeks after discharge. For 
example, one study found that 13.9% of hospitalized adolescents (12-15 years of age) reattempted 
suicide within 3 months of discharge.102
According to several treatment guidelines, 3 antidepressants are recommended as pharmacological 
treatment options in children and adolescents with MDD: fluoxetine (Prozac®), escitalopram 
(Lexapro®), and sertraline (Zoloft®).20,21 However, because standard of care antidepressants may 
take up to 4 to 6 weeks to exert their full effect,109,114 there is a significant unmet need for a drug
therapy with a rapid onset of effect to decrease depressive symptomatology, including suicidal 
ideation.30
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 desired analgesic-anesthetic effects of esketamine are attributed to the 
blockade of ionotropic NMDA glutamate receptors.112 Affinity for the NMDA receptor is 
approximately 3- to 4-fold greater for esketamine than for its enantiomer, arketamine (R-ketamine, 
the R-enantiomer of ketamine).58,94
Given the evidence that glutamate pathways are involved in the pathophysiology of depression, 
IV-administered ketamine has been investigated for antidepressant properties.68,88 In animal 
models, blockage of NMDA receptors was shown to result in antidepressant-like effects3; and in 
humans, a single subanesthetic dose infusion of ketamine has been shown to have rapid, potent 
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antidepressant effects in patients with TRD.4,84,85,100 Several pilot studies using IV ketamine in 
subjects with MDD or bipolar depression also suggested that ketamine may reduce suicidal 
ideation within hours of administration.4,31,60,101,103,123 In addition, 2 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).5,87  
The mechanism of action of esketamine is distinct from conventional antidepressant treatments, 
which target modulatory monoaminergic neurotransmitters (serotonin, norepinephrine, and/or 
dopamine), 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. 
Administered intranasally, esketamine is rapidly and well-absorbed, and can offer patients better 
convenience. Janssen Research & Development is developing intranasal esketamine both for TRD 
and for the rapid reduction of the symptoms of MDD, including suicidal ideation, in adult patients 
who are assessed to be at imminent risk for suicide. As part of the pediatric development program, 
this study is evaluating the efficacy, safety and dose response of esketamine in subjects 12 to 
<18 years of age with MDD who are assessed to be at imminent risk for suicide.
For the most comprehensive nonclinical and clinical information regarding esketamine
(JNJ-54135419), refer to the latest version of the Investigator's Brochure for esketamine, and 
associated addenda.48,49,50
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.48,49,50 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.55 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.55
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. No adverse 
effects were noted up to the highest dose tested (ie, 9 mg/day in rats, and 72 mg/day in dogs).48,49,50
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The Cmax-based exposure ratios for esketamine compared to the 84 mg human dose ranged from
1.3- and 0.7-fold. The AUC-based exposure ratios for esketamine compared to the 84 mg human 
dose ranged from 0.7- to 1.1-fold.48,49,50
Neurotoxicity: Racemic ketamine has been reported to induce neurotoxicity in animal fetuses, and 
in juvenile, adolescent, and adult animals, as evidenced by histopathological brain lesions and 
functional sequelae. The precise thresholds for dose and duration of ketamine exposure causing 
neurotoxicity in animals remain to be established. The relevance to humans of ketamine’s 
neurotoxic action in animals is unknown.
In animal studies with intranasally-administered esketamine no evidence of neurotoxicity was 
found. In single-dose and 14-day repeat-dose neurotoxicity studies in rats, no histopathological 
brain lesions were noted up to 54 mg/day in the 14-day study, and 72 mg as a single intranasal 
dose. In the 14-day rat study the Cmax- and AUC-based safety margins for esketamine compared 
to the 84 mg human dose were approximately 17- and 11-fold, respectively. At a single intranasal 
dose of 72 esketamine the Cmax- and AUC-based safety margins compared to the 84 mg human 
dose were approximately 60- and 86-fold, respectively48,49,50 In the 6-month rat and 9-month dog 
repeat-dose toxicity studies with intranasally-administered esketamine, where the animals were of 
adolescent age at initiation of treatment, and in the pre- and postnatal developmental toxicity study 
in rats, no morphological or functional evidence of neurotoxicity was observed either.48,49,50  
Reproductive and Developmental Toxicity: In a fertility and early embryonic developmental 
study, no adverse effects of intranasal esketamine on the fertility and reproductive capacities of 
adult male and female rats were observed.48,49,50 Rat and rabbit embryo-fetal developmental 
toxicity studies with intranasally-administered racemic ketamine did not reveal evidence of 
reproductive toxicity.48,49,50 High dose levels of racemic ketamine, however, induced neuronal cell 
death in the brain when administered to early postnatal rat pups.48,49,50 Also, when monkey fetuses 
were exposed in utero to high dose levels of racemic ketamine, neuronal cell death was found in 
the brain.48,49,50 Ketamine anesthesia during the first week of life caused long-lasting cognitive
deficits in monkeys.48,49,50
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.48,49,50
Abuse potential: The results of self-administration and withdrawal experiments in several animal 
models suggest that esketamine would have abuse potential in humans.9,24,25,57,77,120,121
1.1.2.
Clinical Studies
1.1.2.1.
Completed and Ongoing Clinical Studies with Intranasal Esketamine
A total of 10 Phase 1 studies with intranasal esketamine have been completed and reported, 
including 7 studies in healthy younger adult subjects, 2 studies in healthy elderly and younger adult 
subjects, and 1 study in subjects with a history of allergic rhinitis. In total, 320 subjects have been 
exposed to intranasal esketamine in the completed Phase 1 studies that have been reported.48,49,50
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Two 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, 
subjects with renal impairment, and subjects with MDD.
One Phase 2 study has been completed in adult 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 TRD, with 107 subjects exposed to intranasal esketamine.48,49,50 In 
addition, one Phase 2 study in subjects with TRD is ongoing in Japan.
In the clinical development program for intranasal esketamine, 6 Phase 3 clinical trials are ongoing 
in adult subjects with TRD: 2 short-term double-blind, randomized, active-controlled studies, 
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.48,49,50
1.1.2.2.
Human Pharmacokinetics and Product Metabolism
Racemic Ketamine
The pharmacokinetics of IV ketamine has been examined in several studies with pediatric patients 
1.5 to 14 years of age who were administered single doses of 1 to 6 mg/kg.38,41,66 The PK estimates 
of key parameters, namely clearance and distribution volume, in children were similar relative to 
estimates in adult patients who received IV ketamine after standardization for body size. The 
absolute bioavailability of intranasally administered esketamine was estimated to be 50%, which 
is similar to the 42% and 45% bioavailability estimated in adults.98,119
It is evident from the published studies that racemic ketamine and esketamine are metabolized in 
children (1-9 years of age) to norketamine and noresketamine, respectively, based on the measured 
concentrations of each in plasma. A population PK analysis which included norketamine 
concentration-time data from 57 pediatric patients (1.5-14 years of age) and adults who received 
IV ketamine indicated that estimates were indistinguishable from each other when standardized to 
a 70 kg person.42
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 has a half-life in plasma of approximately 5 hours in humans.40 The 
major human hepatic cytochromes that catalyze ketamine N-demethylation in vitro were CYP2B6 
and CYP3A4,43,99,118 and those that were responsible for the formation of norketamine metabolites 
included CYP2A6 and CYP2B6.99 Pharmacokinetic (PK) results after IV administration of 
racemic ketamine and esketamine to human subjects suggest that inversion of esketamine to 
arketamine (the R-enantiomer of ketamine) does not occur.36
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.115
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Intranasal Esketamine
The PK of intranasal esketamine have been characterized in healthy adult subjects (elderly and 
younger adults), subjects with a history of allergic rhinitis, subjects with treatment-resistant 
depression (TRD),48,49,50 and subjects with MDD at imminent risk for suicide. In healthy adult 
subjects, intranasally-administered esketamine (28 mg 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).48,49,50 When administered in healthy adult subjects via 
the intranasal route, esketamine was rapidly absorbed and had an absolute bioavailability of 
approximately 48% (ESKTINTRD1009).48,49,50 In a Phase 2 study in adult 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.48,49,50 Furthermore, the mean esketamine concentrations in plasma samples 
collected at corresponding time points on Days 1, 11, and 25 were similar suggesting that the PK 
was consistent after repeated intranasal administration.48,49,50 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.
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.67 Further, results from Panel A, part of 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 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.48,49,50 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 (mean differences [SE] between each esketamine group and the placebo group 
were -4.2 [2.09], p=0.021; -6.3 [2.07], p=0.001; and -9.0 [2.13], p<0.001 for esketamine 28, 56, 
and 84 mg, respectively). Additionally, there was a significant relationship between esketamine 
dose and change in MADRS total score (p<0.001).48,49,50 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.48,49,50 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 (least squares 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).48,49,50 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 
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interpreted with caution due to a significant treatment by baseline MADRS total score interaction 
during the first week of treatment (p=0.052).48 49,50
Several pilot studies using IV ketamine in subjects with MDD or bipolar depression also suggested 
that ketamine may reduce suicidal ideation within hours of administration.31,60,101,103,123 In addition, 
2 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).5,87
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. Adult subjects with a diagnosis
of MDD assessed to be at imminent risk for suicide from the US 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. Statistical significance for this proof-of-concept study was based on a 
two-sided significance level of 0.20. Esketamine 84 mg, compared to placebo, demonstrated 
evidence for a clinically meaningful and statistically significant reduction of depressive symptoms 
as assessed by changes from baseline in MADRS total score at 4 hours after the first dose (primary 
endpoint; least squares mean difference [SE] between esketamine 84 mg and placebo: -5.3 [2.10]; 
p=0.015), at approximately 24 hours after the first dose (least squares mean difference [SE]: -7.2 
[2.85]; p=0.015). At the end of the double-blind phase esketamine 84 mg, compared to placebo, 
demonstrated evidence for a potential therapeutic effect (least squares mean difference [SE]: -4.5 
[3.14]; p=0.159).16 The changes from baseline in suicidal thoughts based on the MADRS-SI score 
also favored esketamine 84 mg at 4 hours after the first dose (p=0.002), at approximately 24 hours 
after the first dose (p=0.129), and at the end of the double-blind phase (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 support the hypothesis that esketamine, 
administered intranasally, is an efficacious treatment for the rapid reduction of the symptoms of 
MDD, including suicidality, 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.39,56,105,110 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.55
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 
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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.48,49,50 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).48,49,50 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).48,49,50 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 this event 
not related to the study medication based on the short half-life of esketamine and the onset of the 
event of syncope. 
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.23 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 
postdose, with the majority returning within the normal range by 2 hours postdose.23 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 CADSS. Dissociative symptoms peaked 
at approximately 40 minutes after dosing and typically resolved by 2 hours after dosing.23 The 
magnitude of postdose dissociative symptoms decreased over time with repeated consecutive 
doses for all esketamine doses.
Short-term Use of Intranasal Esketamine in Adult Subjects with MDD at Imminent Risk 
for Suicide
In the Phase 2 study in adult subjects with MDD at imminent risk for suicide (ESKETINSUI2001, 
esketamine 84 mg versus placebo), 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. 
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 
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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, dyspnea, 
aggression and agitation. In total, 3 of 35 subjects in the esketamine group had dose reductions 
from 84 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 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.29,78,80,89
Overall, infrequent use did not appear to be associated with long-term cognitive impairment.89 The 
most robust findings were that frequent ketamine users (more than 5 times a week) exhibited 
impairments in both short- and long-term memory.80 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.81
A controlled study of short-term esketamine use in patients with TRD demonstrated a decline in 
cognitive function shortly after a single 84-mg dose administration (40 minutes postdose) that 
returned to comparable baseline levels by 2 hours postdose.82
Ketamine-induced ulcerative cystitis is also an identified complication.79 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.
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Abuse Liability, Dependence and Withdrawal
There are reports of ketamine dependence in the literature but no large-scale studies.46,52,79,76,95
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.83 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.27,63,79
1.2.
Psychoactive Placebo Control
Midazolam 
Oral midazolam solution, 0.125 mg/kg, will be used as a psychoactive placebo in a double-dummy 
study design. Given the transient dissociative and sedative side effects of esketamine, midazolam 
was selected as a psychoactive placebo in order to maintain blinding.86 Midazolam is a short-acting 
benzodiazepine central nervous system depressant, with pharmacokinetic characteristics similar to 
those of ketamine; that is, fast onset of action and short elimination half-life. It also possesses 
psychoactive effects such as sedation and disorientation.72,73 Oral midazolam is indicated for use 
in pediatric subjects for sedation, anxiolysis, muscle relaxation, and amnesia prior to a medical 
procedure, and before induction of anesthesia. Common reported effective doses range from 
0.25 mg/kg to 1 mg/kg in children 6 months to <16 years of age.71 While midazolam is anxiolytic, 
it has not been shown to be efficacious as a treatment for depression. Midazolam has been 
previously used as a psychoactive placebo in studies of ketamine.86
The midazolam dose of 0.125 mg/kg is based on a study of IV ketamine in adult subjects with 
TRD in which midazolam 0.045 mg/kg IV was used.86 Assuming 36% bioavailability of the oral 
formulation in pediatric patients,104 an oral dose of 0.125 mg/kg was calculated to be equivalent to 
the IV dose of 0.045 mg/kg. The midazolam dose selected for this study is approximately 25% of 
that recommended for pre-anesthetic use in pediatric populations.
Midazolam exhibits linear pharmacokinetics between oral doses of 0.25 to 1 mg/kg (up to a 
maximum dose of 40 mg) across the age groups ranging from 6 months to <16 years. The 36% 
absolute bioavailability of orally administered midazolam in pediatric patients is not affected by 
pediatric age or weight. Midazolam is rapidly absorbed after oral administration with tmax occurring 
between approximately 0.5 and 3 hours. The half-life of midazolam ranges between 2 and 6 hours. 
Midazolam is primarily metabolized to 1 hydroxymidazolam by CYP3A4 and is considered a 
sensitive probe of CYP3A4 activity. Fluoxetine, escitalopram or sertraline are not expected to 
influence the metabolic clearance of midazolam. 
The sedative effects of midazolam are accentuated by any concomitantly administered medications 
that depress the central nervous system, particularly narcotics, secobarbital and droperidol. 
Caution is also advised when midazolam is administered with drugs that are known to inhibit the
P450-3A4 enzyme system such as (not ranitidine), diltiazem, verapamil, ketoconazole, and 
itraconazole. These drug interactions may result in prolonged sedation due to a decrease in plasma 
clearance of midazolam.70
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Adverse events associated with midazolam administration include sedation, vomiting, nausea, 
hypoxia, laryngospasm, respiratory depression, rhonchi, congestion, agitation, involuntary 
movements (including tonic-clonic movements and muscle tremor), bradycardia, bigeminy, and 
skin rash.71 Benzodiazepines, including midazolam, are contraindicated in patients with acute 
narrow-angle glaucoma. Flumazenil is a specific reversal agent for midazolam.70
1.3.
Overall Rationale for the Study
The current study is being conducted to evaluate the efficacy, safety and dose response of 3 fixed 
doses of intranasal esketamine (28, 56 and 84 mg) compared with a psychoactive placebo, each 
given in addition to comprehensive standard of care in subjects 12 to <18 years of age with MDD 
who are at imminent risk for suicide in support of regulatory agency requirements for registration 
of intranasal esketamine.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objective
The primary objective is to assess the efficacy of a single (first) dose of 3 fixed doses of intranasal 
esketamine (28 mg, 56 mg, and 84 mg) compared with psychoactive placebo (oral midazolam) in 
rapidly reducing the symptoms of MDD, including suicidal ideation, in subjects 12 to <18 years
of age who are assessed to be at imminent risk for suicide. Efficacy will be assessed by the change 
from baseline in Children’s Depression Rating Scale, Revised (CDRS-R) total score at 24 hours 
post first dose (Day 2).
Other Objectives
The other objectives are the following: 

To evaluate the dose response of intranasal esketamine compared with psychoactive placebo 
in reducing the symptoms of MDD, including suicidal ideation, as assessed by the change 
from baseline in CDRS-R total score at 24 hours post first dose (Day 2) and at Day 25.

To evaluate the efficacy of single and repeated doses of intranasal esketamine compared with 
psychoactive placebo in reducing symptoms of suicidal ideation, as assessed by the Clinical 
Global Impression of Severity of Suicidality, revised version (CGI-SS-R) from the Suicide 
Ideation and Behavior Assessment Tool (SIBAT) 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 single and repeated doses of intranasal esketamine compared with 
psychoactive placebo in reducing symptoms of MDD as assessed by the following:
-
CDRS-R total score at 4 hours post first dose, through the end of the Double-Blind 
Treatment phase (Day 25), and during the 6-month Post-Treatment Follow-Up phase.
-
MADRS total score at 4 hours and 24 hours post first dose, through the end of the Double-
Blind Treatment phase (Day 25), and during the 6-month Post-Treatment Follow-Up phase.
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-
Children’s Depression Inventory 2: Self-Report (Short) version (CDI 2:SR[S])TM score at 
24 hours post first dose and through the end of the Double-Blind Treatment phase (Day 25).

To evaluate the efficacy of single and repeated doses of intranasal esketamine compared with 
psychoactive placebo in reducing symptoms of suicidal ideation, as assessed by the Clinical 
Global Impression – Imminent Suicide Risk (CGI-SR-I) from the SIBAT 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 single and repeated doses of intranasal esketamine compared with 
psychoactive placebo in reducing suicidal thoughts, as assessed by the following:
-
Change from baseline in SIBAT Module 3 (My Current Thinking) and Module 5 (My Risk) 
Question 3 (patient-reported frequency of suicidal thinking) through the end of the Double-
Blind Treatment phase (Day 25) and during the 6-month Post-Treatment Follow-Up phase.

To characterize the pharmacokinetics of intranasal esketamine and its metabolite 
noresketamine.

To evaluate the safety and tolerability of intranasal esketamine through the end of the Double-
Blind Treatment phase (Day 25) using the following assessments:
-
Effects on suicidal ideation and behavior using the SIBAT 
-
Effects on dissociative symptoms using the Clinician-Administered Dissociative States 
Scale (CADSS)
-
Occurrence of psychosis-like side effects using a 4-item positive symptom subscale 
(consisting of: suspiciousness, hallucinations, unusual thought content, and conceptual 
disorganization) of the Brief Psychiatric Rating Scale, positive symptom subscale (BPRS+)
-
Occurrence of potential treatment-emergent symptoms of mania using the Young Mania 
Rating Scale (YMRS)
-
Effects on cognitive function as measured by the Cogstate computerized cognitive battery 
-
Effect on sedation using the Modified Observer's Assessment of Alertness/Sedation 
(MOAA/S) scale
-
Local nasal tolerability, using targeted nasal examinations coupled with a nasal symptom
questionnaire

To evaluate the safety and tolerability of intranasal esketamine at specified times through the 
initial 25 day double-blind treatment period (Day 25), the 8-week post-treatment follow-up 
(Day 81) and 6-month post-treatment follow-up, with special attention given to the following 
assessments:
-
Effects on suicidal ideation and behavior using the SIBAT
-
Effects on cognitive function as measured by the Cogstate computerized cognitive battery 

To evaluate potential withdrawal symptoms during the post-treatment follow-up as measured 
by the Physician Withdrawal Checklist (PWC-20) on Days 25, 28, 32, 35 and 39.

To evaluate the potential for ketamine or PCP abuse during the follow-up as measured by the 
Timeline Follow-Back (TLFB).
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
To evaluate whether pretreatment concentrations of MDD-related biomarkers (eg, 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.

To explore the change in MDD-related biomarkers in relation to clinical response or non-
response to intranasal esketamine.
2.1.2.
Endpoints
The primary efficacy evaluation will be the change from baseline (Day 1, predose) at 24 hours 
post first dose in depressive symptoms, including suicidal ideation, as measured by the CDRS-R 
total score.

Other efficacy endpoints will be evaluated throughout the study, as follows:
-
CDRS-R
o
Dose response at 24 hours post first dose.
o
Changes from baseline, post single and repeated doses, at 4 hours post first dose, 
through the end of the Double-Blind Treatment phase (Day 25), and during the 
6-month Post-Treatment Follow-Up phase.
-
MADRS
o
Changes from baseline, post single and repeated doses, at 4 hours and 24 hours post 
first dose, through the end of the Double-Blind Treatment phase (Day 25), and during 
the 6-month Post-Treatment Follow-Up phase.
-
CGI-SS-R from SIBAT
o
Changes from baseline, post single and repeated doses at 4 hours and 24 hours post 
first dose, through the end of the Double-Blind Treatment phase (Day 25).
-
CGI-SR-I from SIBAT
o
Changes from baseline, post single and repeated doses at 4 hours and 24 hours post 
first dose, through the end of the Double-Blind Treatment phase (Day 25).
-
SIBAT
o
Changes from baseline, post single and repeated doses, through the end of the 
Double-Blind Treatment phase (Day 25) and during the 6-month Post-Treatment 
Follow-Up phase in depressive symptoms and suicidal ideation (subject-completed 
modules 3, 4, and 5) and clinician impression of suicidality and judgment about 
management of suicidal thinking (clinician-completed modules 7 and 8).
-
CDI 2:SR (S)
o
Changes from baseline, post single and repeated doses, at 24 hours post first dose 
and through the end of the Double-Blind Treatment phase (Day 25).

Safety endpoints will be evaluated throughout the study, as follows:
-
Monitoring of TEAEs
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-
Clinical laboratory tests, physical examination, nasal examination and nasal symptom 
questionnaire, 12-lead ECG, vital signs, pulse oximetry and body weight
-
SIBAT
-
BPRS+ score 
-
CADSS 
-
Cogstate computerized cognitive battery 
-
YMRS score
-
Modified Observerʼs Assessment of Alertness/Sedation (MOAA/S) score
-
Physician Withdrawal Checklist (PWC-20)
-
TLFB methodology to evaluate use of ketamine or PCP.

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. Plasma concentrations of other esketamine metabolites 
and midazolam may also be measured, if warranted.

Biomarkers
-
Characteristics of esketamine mechanism of action or biological predictors of inter-
individual variability.
Refer to Section 9, Study Evaluations, for evaluations related to endpoints.
2.2.
Hypothesis
The primary hypothesis of this study is that, in addition to standard of care, intranasal esketamine 
is superior to psychoactive placebo in rapidly reducing the symptoms of MDD, including suicidal
ideation, as assessed by the change from baseline in CDRS-R at 24 hours post first dose in subjects 
12 to <18 years of age who are assessed to be at imminent risk for suicide.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This Phase 2 study is a randomized, double-blind, double-dummy, psychoactive placebo-
controlled, multicenter trial with 45 anticipated global sites. A target of 145 male and female 
subjects, 12 to <18 years of age, will be enrolled in this study and randomized in a 1:1:1:2 ratio to 
one of 3 doses of intranasal esketamine (28, 56 or 84 mg) or a psychoactive placebo (oral 
midazolam 0.125 mg/kg), with approximately 29 subjects assigned to each dose of intranasal 
esketamine and approximately 58 subjects assigned to psychoactive placebo. All eligible subjects 
will have a diagnosis of MDD, and will have presented to an emergency room (ER) or other 
permitted setting and been assessed to be at imminent risk for suicide. Given the vulnerability of 
the population, this study will be conducted in the context of standard of care treatment. This
includes initial hospitalization in an inpatient psychiatric unit or other permitted setting for a 
recommended duration of 5 days counted from randomization, with shorter or longer 
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hospitalizations permitted if clinically warranted per local standard of care; initiation or 
optimization of allowed antidepressant treatment; participation in a specific psychological
intervention (individual cognitive behavioral therapy [CBT]), interpersonal therapy, family 
therapy or psychodynamic psychotherapy); and close outpatient follow-up.
There is only 1 approved antidepressant for the treatment of MDD in children and adolescents in 
both the United States (US) and European Union (EU): fluoxetine; however, if treatment with 
fluoxetine is unsuccessful or is not tolerated because of side effects, guidelines recommend treatment 
with citalopram and sertraline.20,22,61,91 Escitalopram (the S-enantiomer of citalopram) is also 
approved for use in adolescents in the US. Therefore, this multi-national study will permit the use 
of fluoxetine, escitalopram or sertraline as the standard of care antidepressants.
The study will be conducted in 4 phases: a screening evaluation performed within 48 hours prior 
to Day 1 intranasal dose (if possible, screening should occur within 24 hours prior to the Day 1 
intranasal dose); a 25-day Double-Blind Treatment phase (Days 1-25), during which study drug 
will be administered 2 times per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25; an
8-week initial post-treatment phase (Days 25-81); and a subsequent phase to complete a full 
6-month post-treatment follow-up (Days 81-200). During post-treatment follow-up phases, no 
study drug will be administered. The duration of the subject’s participation will be approximately 
29 weeks. 
Efficacy, safety, pharmacokinetic, biomarker, and pharmacogenomic (DNA and RNA) 
evaluations will be performed as described in the Time and Events Schedule.

The primary efficacy evaluation is the CDRS-R; other efficacy evaluations are 
SIBAT/CGI-SS-R and CGI-SR-I, MADRS, CDI 2:SR(S).

Safety evaluations include monitoring and collection of adverse events and concomitant 
therapies, physical examination, nasal examination and nasal symptom questionnaire, 
measurements of body weight and vital signs, 12-lead electrocardiogram (ECG), pulse 
oximetry, clinical laboratory tests, SIBAT, MOAA/S, CADSS, BPRS+, YMRS, PWC-20, 
TLFB, and Cogstate computerized cognitive battery.

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.

Blood samples for DNA and RNA analyses will be collected from subjects who consent/assent 
separately to this component of the study (where local regulations permit). Subject 
participation in DNA and RNA research is optional.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study (refer 
to Section 11.7, Data Monitoring Committee, for details).
A diagram of the study design is provided in Figure 1.
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Figure 1:
Schematic Overview of the Study
Abbreviations: AD, antidepressant; SoC, standard of care.
a
Antidepressant medication should be initiated or optimized on Day 1. However, initiating standard of care
antidepressant medication up to 7 days after the first dose of study medication (Day 1), is permitted if starting 
two medications simultaneously is not consistent with local clinical practice.
b
If possible, screening should be performed within 24 hours prior to Day 1 intranasal dose.
c
Hospital discharge before 5 days (from randomization) must be discussed with 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.
d 
Remote contact.
3.2.
Study Design Rationale
3.2.1.
Study Population
This study will enroll subjects 12 to <18 years of age with MDD presenting with suicidal ideation 
who are assessed to be at imminent risk for suicide. MDD is the most prevalent mental health 
condition and the psychiatric diagnosis most commonly associated with suicide.54,91 Depression is 
the main predictor of suicidal ideation.37,93 In the US, the age standardized suicide rate increased 
24.2% over the 12-year period from 2000 to 2012, rising from 9.8% to 12.1% per 
100,000 individuals. Young people are among those most affected. Globally, suicide accounts for 
8.5% of all deaths among young adults (15−29 years of age) and is ranked as the second leading 
cause of death.92 In the US, suicide is the third leading cause of death for young people between the 
ages of 10 and 24, and results in approximately 4,600 deaths each year.17 Data from the cross-
national World Mental Health survey indicate that the risk of first onset of suicidal ideation increases 
sharply during adolescence and young adulthood.92 Older adolescents (13 – 18 years) are at higher 
risk of MDD than those younger than 13 years (overall point prevalence estimates [±SE] 5.6±0.3% 
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versus 2.8±0.5%, respectively).17,117 The age range of subjects 12 to < 18 was chosen due to the 
significant unmet need for effective treatment in this particularly vulnerable population. 
The MINI-KID 7.0.2 will be utilized to identify adolescents with a primary diagnosis of MDD 
without psychotic features. Affirmative responses to questions B3 and B10 of the MINI-KID, 
along with clinical need for hospitalization, will confirm that subjects are experiencing active 
suicidal ideation with intent, and thus are considered to be at imminent risk for suicide. A 
requirement for a CDRS-R total score of ≥58 will ensure that subjects have level of depressive 
symptomatology that is moderate to severe.
Subjects with a current diagnosis of bipolar disorder, intellectual disability, autism spectrum 
disorder, conduct disorder, anorexia nervosa, oppositional defiant disorder, obsessive compulsive 
disorder, borderline personality disorder, or those who meet Diagnostic and Statistical Manual of 
Mental Disorders (5th edition) (DSM-5) severity criteria of moderate or severe substance or alcohol 
use disorders within the 6 months before screening will be excluded to ensure the subject’s 
depression is not attributed to a disorder other than MDD, and 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 antidepressant53 and post-
hospitalization.11,102,114 The dosing regimen in this study includes administration of esketamine 
twice a week 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 duration of follow-up in this study covers the period of greatest risk 
for recurrent suicidality post initial attempt and/or hospitalization.11,15,102
The follow-up after the 25-day double-blind treatment period is through Day 200 and will allow 
for the exploration of the continued effects of esketamine on depression and suicidal symptoms. 
No study medication will be administered during the follow-up phase. Visits will continue to occur 
twice a week for the first 2 weeks (Days 28, 32, 35, 39), after which visits will occur weekly (Days 46 
and 53), then every 2 weeks (Days 67 and 81). The Day 28 and 35 visits are remote contact visits. 
After the Day 81 visit, subjects will enter the extended Post-Treatment Follow-Up phase 
(Days 81-200), during which they will have monthly visits to assess safety. Investigators may add 
follow-up visits as dictated by the subject’s clinical condition and the investigator’s clinical 
judgment. Additionally, throughout the follow-up period, suicide attempts, hospital re-admissions 
for suicidality, and ER visits will be followed and noted as part of safety outcomes.
3.2.3.
Control, 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. Randomization will be stratified by study center.
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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, a psychoactive placebo, midazolam, 
will be used. Midazolam has been used as a psychoactive placebo in previous studies of ketamine88
because of its similar onset of action and side effect profile.
The effect of a placebo response is of particular concern in clinical trials of MDD.97 Because a 
lower likelihood of randomization to placebo has been shown to be associated with placebo 
response,97 a treatment allocation of 1:1:1:2 for 28 mg: 56 mg: 84 mg: psychoactive placebo is 
being used to minimize expectancy bias and to mitigate placebo response.
A double-dummy design will be used in order to preserve the blind since the active study drug 
(intranasal esketamine) and the psychoactive placebo (oral midazolam) are administered via 
different routes. Therefore, 2 matching placebo formulations, intranasal and oral, will be included 
in the treatment regimen. In order to maintain the blind, subjects randomized to intranasal 
esketamine will also receive an oral placebo, and subjects randomized to oral midazolam will also 
be administered an intranasal placebo. 
3.2.4.
Esketamine Dose
In a Phase 2 study, ESKETINTRD2003,23 the efficacy of intranasal esketamine at 28 mg, 56 mg, 
and 84 mg doses was assessed in adult subjects with TRD. Data from the double-blind phase 
showed that intranasal esketamine had a rapid onset of effect, and repeated treatment sessions 
sustained the response throughout the study duration. A clear dose response was observed for the 
28-, 56- and 84-mg doses, with the most robust and sustained efficacy observed at the 84 mg dose. 
The primary efficacy endpoint (change in MADRS total score from baseline to Day 8) 
demonstrated statistically significant improvement in all 3 esketamine dose groups.
In this study, the same intranasal esketamine doses of 28, 56, and 84 mg will be evaluated to 
establish optimal dose, taking into consideration benefits and tolerability, in young subjects with 
major depressive disorder with imminent suicidality (MDSI). A population PK analysis which 
included esketamine and its active metabolite, norketamine, concentration-time data from 
57 pediatric subjects (1.5 to 14 years old) and adults who received IV ketamine indicated that 
estimates were indistinguishable from each other when standardized to a 70 kg person.42 Therefore, 
standard allometric scaling was applied using the population pharmacokinetic model developed 
with adult data after intranasal administration of esketamine in order to simulate esketamine 
systemic exposure in pediatric subjects. Simulations (based on standard allometric scaling) of the 
exposure of 56 and 84 mg of esketamine after intranasal administration in the 12 to <18 years of 
age show a similar exposure as in adults.
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3.2.5.
Psychoactive Placebo 
Midazolam 
Oral midazolam solution, 0.125 mg/kg, will be used as a psychoactive placebo in a double-dummy 
study design. Given the transient dissociative and sedative side effects of esketamine, midazolam 
was selected as a psychoactive placebo in order to maintain blinding.86 Midazolam is a short-acting 
benzodiazepine central nervous system depressant, with pharmacokinetic characteristics similar to 
those of ketamine; that is, fast onset of action and short elimination half-life. It also possesses 
psychoactive effects such as sedation and disorientation.72,73
The midazolam dose of 0.125 mg/kg is based on a study of IV ketamine in adult subjects with 
TRD in which midazolam 0.045 mg/kg IV was used.86 Assuming 36% bioavailability of the oral 
formulation in pediatric patients,104 an oral dose of 0.125 mg/kg was calculated to be equivalent to 
the IV dose of 0.045 mg/kg, approximately 25% of the pediatric dose recommended for pre 
anesthetic use (0.2-0.5 mg/kg).72,73
For further information regarding midazolam refer to the package insert72 or Summary of Product 
Characteristics.73
3.2.6.
Efficacy Measures
Children’s Depression Rating Scale, Revised (CDRS-R)
The primary outcome measure in this study will be the CDRS-R, a validated 17-item, clinician-
rated instrument developed to assess depressive symptomatology in children that measures the
severity of a patient’s depressive symptoms.69 CDRS-R has been used in previous pivotal trials of 
selective serotonin reuptake inhibitors (SSRIs) in children and adolescents. It was selected as the 
primary outcome measure since it reflects the core symptoms of MDD, as defined by DSM-5, 
including a suicide-related item. The scale has demonstrated good reliability and validity in 
adolescents with depression.69
This study is aimed at evaluating the rapid reduction of symptoms of MDD, including suicidality, 
in subjects 12 to <18 years of age 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 CDRS-R 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 
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 time point is 
relevant to current clinical practice as patients at imminent risk for suicide are typically 
hospitalized for at least 24 hours. 
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 the antipsychotic 
medications clozapine and olanzapine to reduce suicidal behaviors in patients with schizophrenia 
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or schizoaffective disorder who are known to be at high risk for suicide. 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 of the InterSePT 
Scale for Suicidal Thinking (ISST). 
A revised version of the CGI-SS (CGI-SS-R) with a 7-point scale will be used in this study. 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 is currently 
undergoing validation in adults and children as part of the SIBAT.
The CGI-SS-R, assessed at 4 hours and 24 hours post first dose and through the end of the Double-
Blind Treatment phase, will be used to evaluate other objectives by assessing:

Change in severity of suicidality at 4 and 24 hours post first dose 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 post first dose on Day 1, 24 hours post 
first dose on Day 2, and through the end of the Double-Blind Treatment phase

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 (Section 9.2.2). 
The CGI-SR-I will be used to evaluate other objectives by 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
Montgomery-Asberg Depression Rating Scale (MADRS)
The MADRS has been used as an efficacy outcome parameter in several adolescent treatment 
trials.32,113 A 10-item clinician-administered scale that was designed to be used in subjects with 
MDD to measure the overall severity of depressive symptoms in adults.74,75 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 
ideation5,31,60,87,100,101 as well as in the sponsor’s Phase 2 adult studies of esketamine in MDD with 
imminent risk for suicide (ESKETINSUI2001) and in TRD (ESKETINTRD2003 and the Phase 3 
studies of esketamine in TRD). 
Although not validated in children, the MADRS has been included in previous pediatric trials of 
antidepressants.19,33,51 The MADRS will be used to evaluate the change from baseline in MADRS 
total score at 4 hours post first dose and 24 hours post first dose, through the end of the Double-
Blind Treatment phase (Day 25), and through the 6-month Post-Treatment Follow-Up phase. The 
MADRS is included as an additional efficacy measure because in previous trials of esketamine 
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and ketamine in depression, it has been shown to be sensitive to rapid change in symptoms of 
depression and suicidal thoughts.
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, developed by a team of experts in suicide and psychometrics
will be used. The SIBAT is presently undergoing validation in adults and children.
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 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.
The SIBAT builds on prior work used to develop scales which are available for assessing 
suicidality; for example, the ISST,65 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), as well as a Clinical Global 
Impression of Imminent Suicide Risk (CGI-SR-I), which will be used to evaluate other objectives 
(further details are provided above). In addition, Module 3 (My Current Thinking) and Module 5 
(My Risk) Question 3 (patient-reported frequency of suicidal thinking) from the SIBAT will be 
used to evaluate the other objective of assessing patient-reported suicidality through the end of the 
Double-Blind Treatment phase and during the 6-month Post-Treatment Follow-Up phase.
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Children’s Depression Inventory 2, Self-Report (Short Form) (CDI 2:SR[S])
The CDI 2:SR(S) assessment is a patient rated assessment of depressive symptoms in youth aged 
7 to 17 years and an efficient screening measure that contains 12 items and takes 5 to 10 minutes 
to administer. The CDI 2:SR(S) has excellent psychometric properties and yields a total score that 
is generally very comparable to the one produced by the full-length version, CDI 2, a validated 
screening instrument for depression in children.59
3.2.7.
Safety Evaluations
Physical examination, nasal examination, nasal symptom questionnaire, 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 girls of childbearing potential), urine drug screen, and evaluation of TEAEs and 
concomitant therapies will be performed during the study per the Time and Events Schedules to 
monitor subject safety. 
The TEAEs of special interest will be examined separately grouped in the following Medical 
Dictionary for Regulatory Activities (MedDRA) based categories: drug abuse, dependence and 
withdrawal (standardized MedDRA queries [MedDRA SMQ]), 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 time 
points on dosing days. Specific guidance to be followed on intranasal dosing days is provided in 
Section 6.3.
In order to help investigators identify signs and events suggestive of withdrawal, the sponsor has 
included remote (eg, by telephone) contact 3 and 10 days after the last dose of study drug to assess
adverse events. 
As described further in Section 2.1.1, the following assessments will be used at the time points 
defined in the Time & Events Schedule to evaluate safety and tolerability, assess the severity and 
duration of any sedation, and detect any treatment-emergent worsening of psychiatric symptoms 
or cognition: MOAA/S, CADSS, BPRS+, YMRS, and Cogstate computerized cognitive battery. 
The PWC-20 and TLFB will be used to assess for signs and/or symptoms of withdrawal and abuse, 
respectively. A nasal examination and nasal symptom questionnaire will monitor for any signs of 
adverse effects on the nasal mucosa.
Although the SIBAT will be an efficacy evaluation, it will also be used as a safety evaluation to 
detect any worsening of suicidal ideation and behavior throughout the study.
On all outpatient 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 post dose monitoring is 1.5 hours. Subjects should be accompanied 
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when released from the clinical study site. Subjects must not drive a car or work with machines 
for 24 hours after receiving study drug.
3.2.8.
Pharmacokinetic Assessments
The concentration-time data to be obtained in the present study will allow for estimation of 
individual PK parameters of esketamine (and noresketamine, if warranted) in adolescent subjects 
using a population modeling approach. The time and days of plasma sampling were chosen to 
gather maximal information about the PK properties of esketamine while minimizing subject 
burden regarding blood sampling.
3.2.9.
Biomarker and Pharmacogenomic (DNA and RNA) Evaluations 
3.2.9.1.
Biomarker
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, and 
serum) will be collected to evaluate the mechanism of action of esketamine or help to explain inter-
individual 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.
3.2.9.2.
Pharmacogenomic/Epigenetic (DNA and RNA)
It is recognized that genetic variation can be an important contributory factor to inter-individual
differences in drug distribution and response and can also serve as a marker for disease 
susceptibility and prognosis. Pharmacogenomic research may help to explain inter-individual
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 and RNA 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 in patients with MDD assessed 
to be at imminent risk for suicide.
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.
4.
SUBJECT POPULATION
Screening for eligible subjects will 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). Note: Subjects with acute alcohol intoxication or other 
ingestion should not be screened but can be screened once sober. Requests to rescreen an individual 
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subject must be evaluated and approved by the sponsor representative or medical monitor on a 
case-by-case basis.
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 permitted. 
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, Sample 
Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
Male and female adolescents (12 to <18 years of age) 
2.
Subject must meet DSM-5 diagnostic criteria for MDD, without psychotic 
features, based upon clinical assessment and confirmed by the Mini
International Neuropsychiatric Interview for Children and Adolescents 
(MINI-KID).108
3.
Subject must have current suicidal thinking with intent at the time of 
screening, confirmed by “Yes” responses to both MINI-KID Question B3 
(Think about hurting yourself with the possibility that you might die. Or did 
you think about killing yourself?)  AND Question B10 (Expect to go through 
with a plan to kill yourself?). 
Note: the response to B3 must refer to the present, whereas the response to 
B10 may reflect the past 24 hours. If screening is longer than 24 hours, the 
assessment of questions B3 and B10 for the MINI-KID must be repeated to 
confirm eligibility.
4.
In the physician’s opinion, acute psychiatric hospitalization is clinically 
warranted due to subject’s imminent risk of suicide.
5.
Subject must have a CDRS-R total score of ≥58 predose on Day 1.
6.
As part of standard of care treatment, subject must agree 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).
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7.
Criterion modified per Amendment 2:
7.1 As part of the newly initiated or optimized standard of care treatment, 
subject must agree to take one of the prescribed non-investigational 
antidepressants medications (fluoxetine, escitalopram, sertraline) at least 
during the Double-Blind Treatment phase (Day 25).
8.
As part of standard of care treatment, subject must agree to participate in a 
specific psychological intervention (individual cognitive behavioral therapy 
[CBT], 
interpersonal 
therapy, 
family 
therapy 
or 
psychodynamic 
psychotherapy) at least through the initial 8-week post-treatment follow-up 
period (Day 81).
9.
Subject is comfortable with self-administration of intranasal medication and 
able to follow instructions provided.
10.
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.
11.
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.
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12.
Criterion modified per Amendment 1
12.1.
During the Double-Blind Treatment phase and for at least 6 weeks after 
the last dose of study drug, contraception is required. Sexual abstinence 
is strongly recommended; however heterosexually active female 
subjects must practice a highly effective method of contraception 
(failure rate of <1% per year when used consistently and correctly).
Examples of highly effective contraceptives include: implantable 
progestogen-only hormone contraception associated with inhibition of 
ovulation; intrauterine device (IUD); intrauterine hormone-releasing 
system (IUS); vasectomized partner; 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. For each subject, 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.
During the Double-Blind Treatment phase (from Day 1 through the day 
of the last dose of study drug) and for a minimum of 1 spermatogenesis 
cycle, defined as approximately 90 days after receiving the last dose of 
study drug, sexual abstinence is strongly recommended; however,
heterosexually active male subjects must:
-
practice 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).
-
use a condom if his partner is pregnant.
-
agree not to donate sperm.
Contraceptive use by males or females should be consistent with local 
regulations regarding the use of contraceptive methods for subject 
participating in clinical studies and should be discussed in detail with 
the subject by the study investigator. 
13.
A female subject of childbearing potential must have a negative urine 
pregnancy test at screening, baseline, and end of double-blind phase.
14.
Subject must be willing and able to participate in all study activities and to 
adhere to the prohibitions and restrictions specified in this protocol
(Section 4.3).
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15.
Criterion modified per Amendment 3
15.1 Subject’s parent(s) or legally acceptable representative(s) [(LAR(s)]
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 allow the subject to participate in the study. Assent is also 
required of subjects
as described in Section 16.2.3, Informed 
Consent/Pediatric Assent.
16.
Criterion modified per Amendment 3
16.1 Subject’s parent(s) or legally acceptable representative(s) [(LAR(s)]
must sign a separate informed consent form if he or she agrees to have 
the subject provide an optional DNA/RNA sample for research (where 
local regulations permit). Assent is also required from the subject as 
described in Section 16.2.3 Informed Consent/Pediatric Assent. Refusal 
to give consent/assent for the optional DNA/RNA 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), intellectual 
disability, autism spectrum disorder, conduct disorder, anorexia nervosa, oppositional 
defiant 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 or prior DSM-5 diagnosis of a psychotic disorder or MDD with 
psychosis.
4.
Criterion modified per Amendment 1
4.1. 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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5.
Subject has a history of seizure disorder.
6.
Criterion modified per Amendment 1
6.1.
Subject has a history or current signs and/or symptoms of liver or renal 
insufficiency; has a current diagnosis of clinically significant cardiac 
(eg, congenital heart disease, cardiomyopathy, or tachyarrhythmias), vascular, 
pulmonary, 
gastrointestinal, 
endocrine 
(including 
uncontrolled 
hyperthyroidism), neurologic, hematologic, rheumatologic, or metabolic 
(including severe dehydration/hypovolemia) disease based on investigator 
judgment.
7.
Criterion modified per Amendment 1
7.1. Subject has uncontrolled hypertension (SBP and/or DBP that is greater than or 
equal to the 95th percentile for sex, age, and height) despite diet, exercise or a stable 
dose of an allowed anti-hypertensive treatment at screening; or any past history of 
hypertensive crisis. See Attachment 2 for pediatric blood pressure tables with 
percentile ranking by age, sex, and height for determination of hypertensive status.
Criterion modified per Amendment 3
7.2. On Day -1 (screening) or Day 1 of the double-blind phase prior to randomization, 
a supine or semi-supine SBP and/or DBP ≥ the 95th percentile for sex, age and 
height is exclusionary (see Attachment 3). Subjects who fall below the 5th or above 
the 95th percentile for their age, sex, and height should be evaluated using the 
parameters for the 5th or 95th percentile. Note that subjects whose SBP and/or DBP 
values are ≥ the 95th percentile for sex, age and height may be reevaluated with a 
repeated measure once after 5 minutes of rest to assess eligibility.
Subjects with conditions in which blood pressure elevation could pose a serious 
risk (including severe cardiovascular disease, recent cerebral injury, increased 
intracranial pressure / intracranial mass lesion, intracranial bleeding or acute 
stroke, primary developmental or secondary acquired glaucoma or perforating eye 
injury) are excluded.
8.
Criterion modified per Amendment 1
8.1.
Subject has a positive urine test result(s) for phencyclidine (PCP), cocaine, 
methamphetamines, or amphetamines/3,4-methylenedioxy-methamphetamine 
(MDMA) at screening. Subjects known to be using heroin should be excluded 
from the study.
Note: Subjects who have a positive test due to the appropriate use of prescribed 
opiates, methadone, benzodiazepines, barbiturates, or attention-deficit 
hyperactivity disorder (ADHD) medications may be eligible for study 
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participation per clinician judgment. In addition, subjects who have a positive 
test of 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 who have a positive test due to cannabinoids may be eligible provided 
they do not meet DSM-5 criteria for a moderate to severe substance abuse 
disorder.
Subjects who have a positive test due to opiates, including 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.
9.
Subject has a history of malignancy within 5 years before screening, with the exception 
of a malignancy that, in the opinion of the investigator and in concurrence with the 
sponsor's medical monitor, is considered to have minimal risk of recurrence.
10.
Subject has anatomical or medical conditions that may impede delivery or absorption 
of intranasal study medication.
11.
Subject has an abnormal or deviated nasal septum with any 1 or more of the following 
symptoms: blockage of 1 or both nostrils, nasal congestion (especially 1-sided), 
frequent nosebleeds, and frequent sinus infections (and at times has facial pain, 
headaches, and postnasal drip with the sinus infection).
12.
Subject has known allergies, hypersensitivity, intolerance or contraindications to 
midazolam, esketamine or ketamine, or their excipients. 
13.
Subject has taken any disallowed therapy(ies) as noted in Section 8, Prestudy and 
Concomitant Therapy and Attachment 1.
14.
Subject has received an investigational drug (including esketamine, ketamine, or 
investigational vaccines) or used an invasive investigational medical device within 
60 days before the first dose of study drug or is currently enrolled in an investigational 
study.
15.
Subject is a female who is pregnant, breastfeeding, or planning to become pregnant 
while enrolled in this study or within 3 months after the last dose of study drug.
16.
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.
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17.
Subject, parent or legal guardian 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. 
If a subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 17.4, Source Documentation, describes the required 
documentation to support meeting the enrollment criteria.
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. Subjects should be accompanied by a responsible adult 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 details regarding prohibited and restricted therapy during the study.
4.
Subjects may not receive electroconvulsive therapy (ECT), trans-cranial magnetic 
stimulation (TMS), ketamine or other antidepressant therapies (aside from those 
allowed) during the study.
5.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria.
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 4 treatment groups, in a 1:1:1:2 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. The interactive 
web response system (IWRS) will assign a unique treatment code, which will dictate the treatment 
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assignment. 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
Because the routes of administration differ between the active study drug and the psychoactive 
placebo, to maintain the study blind, 2 matching placebo formulations (intranasal and oral) will be
used. A designated pharmacist (or other qualified healthcare professional), who has no 
involvement otherwise with either the study conduct or data collection, will be unblinded in order 
to prepare the oral study drug. Further details can be found in the investigational product 
preparation instructions, as part of the pharmacy manual. When possible, it is requested that 
different raters perform safety and efficacy ratings.
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 (ie, 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.
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. However, an analysis is planned after the last subject completes the 
Day 25 visit. Randomization codes will be disclosed to the sponsor in order to plan for Phase 3 
studies. Subjects, site personnel, external medical monitors and external vendors will remain 
blinded to individual subject treatment assignments until the end of the study when the last subject 
completes the Day 200 visit.
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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.
To maintain the blinding of oral study medication, the midazolam and placebo solutions will be 
indistinguishable. Additionally, the final dose of midazolam or equivalent oral placebo volume 
will be prepared by a designated pharmacist (or other qualified healthcare professional).
To maintain the integrity of the study blind, a urine drug screen (UDS) should not be performed 
during the DB period unless medically necessary. If deemed medically necessary, the medical 
monitor should be contacted and UDS should be performed predose on dosing days.
6.
DOSAGE AND ADMINISTRATION
All subjects will be treated in the context of comprehensive standard clinical care, including the 
initiation or optimization of antidepressant treatment with one of 3 antidepressants allowed per 
protocol during double-blind treatment: fluoxetine, escitalopram, and sertraline. Treatment with a 
psychological intervention is also required, at least through the initial 8-week Post-Treatment 
Follow-Up phase (Day 81). The specific antidepressant and type of psychological intervention 
selected for a given subject will be based on the treating physician(s) clinical judgment, knowledge 
of the subject’s prior treatment history, and practice guidelines. Acceptable types of psychological 
interventions include individual cognitive behavioral therapy (CBT), interpersonal therapy, family 
therapy, and psychodynamic psychotherapy. Other evidence-based psychotherapies may be 
allowed after consultation with the medical monitor.  The frequency of psychotherapy visits should 
be determined based on clinical need, at the discretion of the treatment team. Unless clinical 
judgment dictates otherwise, it is recommended that subjects who have not previously been treated 
with an antidepressant receive standard of care antidepressant treatment with fluoxetine, as this is 
the only antidepressant approved in both the US and EU. Antidepressant medication should be 
initiated or optimized on Day 1. However, initiating standard of care antidepressant medication up 
to 7 days after the first dose of study medication (Day 1), is permitted if starting two medications 
simultaneously is not consistent with local clinical practice.
All study medication will be self-administered under the direct supervision of the investigator or 
designee. Instructions for use of the intranasal spray device will be provided as a separate
document. On Day 1 of the Double-Blind Treatment phase, subjects will be randomized in a 
1:1:1:2 ratio to treatment with one of 3 doses of intranasal esketamine (28, 56, or 84 mg) or oral 
psychoactive placebo (midazolam 0.125 mg/kg), administered 2 times per week for 4 weeks. Study 
medication dosing sessions should not take place on consecutive days. Randomization will be 
stratified by study center. 
A double-dummy design will be used, with each subject receiving 1 dose of oral study drug 
followed closely by intranasal study drug (3 devices) as described below (Table 1) for each dosing 
event. Thus, subjects randomized to intranasal esketamine will also receive an oral placebo, and 
subjects randomized to oral midazolam will also be administered an intranasal placebo (3 devices).
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See Section 9.1.3 for further details on dosing procedures during the Double-Blind Treatment 
phase.
6.1.
Oral Study Drug
Oral midazolam solution (2 mg/ml) will be provided as a psychoactive placebo at a dose of 
0.125 mg/kg to all subjects randomized to intranasal placebo. A designated pharmacist (or other 
qualified healthcare professional) will be unblinded in order to prepare the oral study drug. 
Subjects randomized to oral psychoactive placebo (midazolam) will receive a weight-based dose 
using a 2 mg/mL solution; those randomized to intranasal esketamine will receive an oral placebo 
solution in an equivalent volume to that which they would receive if randomized to the 
psychoactive placebo.
6.2.
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 study medication dosing days, a 
site staff member with basic life support training that is up to date per local regulations must be 
present with the subject during the dosing of study medication and the postdose observation period. 
In addition, a hand-held bag valve mask (Ambu bag) for manual ventilation support must be 
available. 
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. For each 
intranasal esketamine or placebo dose, 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. Sprays to each nostril 
should be delivered in rapid succession at each of the 3 scheduled time points. Table 1 describes 
how esketamine or placebo will be administered in the Double-Blind Treatment phase. A total of 
3 devices will be used by all subjects to administer 3 doses of esketamine or placebo.
A physical description of the study drugs is provided in Section 14.
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Table 1:
Dose administration of Intranasal Esketamine 28, 56, 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
Esketamine 56 mg
1 spray of esketamine to 
each nostril
1 spray of esketamine to 
each nostril
1 spray of
placebo to each nostril
Esketamine 28 mg
1 spray of esketamine to 
each nostril
1 spray of
placebo 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).
6.3.
Guidance on Blood Pressure Monitoring on Study Medication Dosing Days
Elevated blood pressure in children is defined as SBP and/or DBP ≥ the 95th percentile for sex, age 
and height. Attachment 2 (Growth Charts: Stature-for-Age Percentiles for Use in Blood Pressure 
Assessments) and Attachment 3 (95th Percentile Blood Pressure Levels For Sex by Age and 
Height) will be used to determine the 95th percentile for both the systolic (SBP) and diastolic blood 
pressures (DBP) by sex, age and height percentile (refer to Attachment 3 for instructions).
If the predose SBP and/or DBP is elevated on any dosing day, blood pressure measurement should 
be repeated after the subject rests for at least 5 minutes in a supine or semi-supine position to 
confirm the measurement. If SBP and/or DBP remain ≥ the 95th percentile for sex, age and height 
(Attachment 3), 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 should be 
scheduled for a consultation by cardiologist, other specialist, or primary care physician prior to 
further dosing. Any elevation in blood pressure after dosing is expected to be transient. If an 
elevation is observed, continue monitoring until blood pressure returns to normal.
On any dosing day, if either the postdose SBP or DBP levels are equal to or greater than the sex, 
age and height values in Attachment 4 (Postdose Blood Pressure: Withdrawal Criteria Levels for 
Sex by Age and Height), the blood pressure should be repeated after the subject rests for at least 
5 minutes (ie, sitting or supine). If the values are still equal to or greater than the sex, age and 
height values in Attachment 4, the subject should be withdrawn from the study and appropriate 
follow-up clinical care should be initiated.
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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. 
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 pre-existing therapy should not be made for the explicit purpose of entering a 
subject into the study.
A list of concomitant therapies that are prohibited, permitted, and permitted with restrictions is 
provided in Attachment 1 for general guidance for the investigator; 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 may not receive electroconvulsive therapy (ECT), TMS, ketamine or other antidepressant 
therapies (aside from those allowed) during the study. 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 (DNA and RNA), and safety measurements applicable to this study.
If multiple assessments are scheduled for the same time point, 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 serum or urine 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 or alcohol tests may be performed as determined necessary by the investigator or 
required by local regulation.
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Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
Subjects will be instructed that study drug will not be made available to them after they have 
completed/discontinued study drug.
If a subject dies, the date and cause of death will be collected and documented on the eCRF.
9.1.2.
Screening Phase
Prior to conducting any study procedure, the investigator (or designated study personnel) will 
review and explain the written pediatric assent to each potential subject, and the ICF to the
subject’s parent(s) or their legally acceptable representative(s)/[LAR(s)]. Potential subjects are 
aged 12 to <18 years with MDD presenting to an ER, psychiatric unit or other permitted setting 
and assessed to be at imminent risk for suicide (See Section 16.2.3). 
After the ICF is signed by the subject’s LAR, and the subject’s assent is obtained, potential subjects 
will be screened under close supervision within 48 hours of intranasal dosing on Day 1 to 
determine eligibility for study participation. 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 or other permitted 
setting 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-KID. In addition, the subject must have a CDRS-R 
total score of ≥58 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 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. However, if the screening phase is longer than 24 hours, Question B3 and B10 
from MINI-KID (current status) must be repeated 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.
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On Day 1 of the Double-Blind Treatment phase, approximately 145 subjects will be randomly 
assigned in a 1:1:1:2 ratio to 1 of 3 doses of intranasal esketamine (28, 56 or 84 mg) or a 
psychoactive placebo (oral midazolam 0.125 mg/kg), with approximately 29 subjects assigned to 
each dose of intranasal esketamine and approximately 58 subjects assigned to psychoactive 
placebo. Study drug will be administered two times per week for 4 weeks (Days 1, 4, 8, 11, 15, 
18, 22, and 25). Study medication dosing should not take place on consecutive days.
All subjects will be treated in the context of comprehensive standard clinical care, including 
hospitalization and the initiation or optimization of antidepressant treatment with one of 
3 antidepressants allowed per protocol during double-blind treatment: fluoxetine, escitalopram, 
and sertraline. Treatment with a psychological intervention is also required, at least through the 
initial 8-week post-treatment phase (Day 81). The specific antidepressant and type of 
psychological intervention selected for a given subject will be based on the treating physician(s) 
clinical judgment, knowledge of the subject’s prior treatment history, and practice guidelines. 
Acceptable types of psychological interventions include individual CBT, interpersonal therapy, 
family therapy, and psychodynamic psychotherapy. Other evidence-based psychotherapies may 
be allowed after consultation with the medical monitor. The frequency of psychotherapy visits 
should be determined based on clinical need, at the discretion of the treatment team. Unless clinical 
judgment dictates otherwise, it is recommended that subjects who have not previously been treated 
with an antidepressant receive standard of care antidepressant treatment with fluoxetine, as this is 
the only antidepressant approved in both the US and EU. Antidepressant medication should be 
initiated or optimized on Day 1. However, initiating standard of care antidepressant medication up 
to 7 days after the first dose of study medication (Day 1), is permitted if starting two medications 
simultaneously is not consistent with local clinical practice. 
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 (initiated <2 weeks prior) 
may continue taking the antidepressant at the current dose through the end of the double-blind 
phase (Day 25), if deemed clinically appropriate by the treating physician. During the Double-
Blind Treatment phase, the investigator should consult with the sponsor’s medical monitor in
advance if additional changes on antidepressant treatment are clinically indicated. Any changes to 
the standard of care antidepressant treatment, that is different from what was planned at the time 
of randomization, should be clearly documented including the reason for the change.
The first dose of study medication will be administered in the ER, inpatient psychiatric unit or 
other permitted setting that has appropriate staffing to manage acutely suicidal subjects and 
perform postdose study-related procedures. 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 or 
other permitted setting until after the postdose assessments (approximately 4 hours in length) are 
completed. Subjects who have been admitted directly into the inpatient psychiatric unit or other
permitted setting due to imminent risk for suicide or transferred from a medical unit (following 
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medical stabilization for recent suicide attempt) will receive their first dose of study medication in 
the inpatient psychiatric unit or other permitted setting. 
Subjects will remain in the inpatient psychiatry unit or other permitted setting for a recommended 
duration of 5 days (4 nights) from randomization, with shorter or longer hospitalizations permitted 
if clinically warranted per local standard of care. The decision to discharge a subject from the 
hospital should be 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 or other permitted 
setting, subsequent visits for the Double-Blind Treatment phase will be conducted twice-weekly 
at an outpatient psychiatric facility through Day 25. 
On all outpatient dosing days, subjects must remain at the clinical site until study procedures have 
been completed and the subject is ready for discharge, per the clinician’s assessment. The 
minimum time required for postdose monitoring is 1.5 hours. Subjects should be accompanied by 
a responsible adult when released from the clinical site. Subjects must not drive a car or work with 
machines for 24 hours after study drug dosing.
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).
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.
After the first dose on Day 1, whole blood samples (up to 6 samples, 2 mL each, from each subject) 
will be collected from a peripheral vein using an indwelling intravenous catheter at the time points 
specified in the TIME AND EVENTS SCHEDULE – Double-Blind Treatment Phase. The 
concentrations of esketamine and noresketamine in plasma will be measured using a validated 
bioanalytical method under the supervision of the sponsor’s bioanalytical laboratory.
Efficacy, safety, pharmacokinetic, biomarker, and pharmacogenomics (DNA and RNA) 
evaluations will be performed as described in the TIME AND EVENTS SCHEDULE – Double-
Blind Treatment Phase. 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

Patient Portion

Clinician Portion
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
MADRS and CDRS-R 

CDI 2-SR(S)
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 if 
electronic entry is not functioning (refer to Section 15, Study-Specific Materials).
MADRS and CDRS-R will be performed at both predose and 4-hour postdose assessments on 
Day 25 (visit 10) of the Double-Blind Treatment phase.
9.1.4.
Post-Treatment Follow-up Phases
Upon completion of the double-blind phase, subjects will enter a Post-Treatment Follow-Up phase. 
Visits will continue to occur twice a week for the first 2 weeks (Days 28, 32, 35, 39), after which 
visits will occur weekly (Days 46 and 53), then every 2 weeks (Days 67 and 81). The Day 28 and 35 
visits are remote contact visits to assess the PWC-20, CDRS-R and MADRS, and collect 
concomitant therapies and AEs. After the Day 81 visit, subjects will enter the extended Post-
Treatment Follow-Up phase (Days 81-200), during which they will have monthly visits to assess 
safety. Investigators may add follow-up visits as dictated by the subject’s clinical condition and the 
investigator’s clinical judgment. Evaluations will be performed as described in the TIME AND 
EVENTS SCHEDULE – Post-Treatment Follow-Up Phase.
9.1.5.
Early Withdrawal
Subjects who discontinue Double-Blind Study treatment for reasons other than withdrawal of 
consent/assent, lost to follow-up or death will have the DB EW visit conducted at the time of 
discontinuation. In addition, if the DB EW visit occurs on Day 1 to Day 21, a remote contact visit 
(eg, by telephone) will be conducted 5 days (+/-2 days) after the last dose of study medication. If 
remote contact D+5 occurs within 2 days of the early withdrawal visit, +2 day window should be 
used to conduct the remote contact D+5 visit. A remote contact visit will also be conducted on Day 
25 to assess PWC-20, CDRS-R and MADRS, and for collection of concomitant therapies and AEs. 
If the DB EW visit occurs on or after Day 22 (assuming dose administered), D25 RC visit is not 
required, however, RC D+5 (5 days after last dose) should be performed.
Subjects who discontinue from the Post-Treatment Follow-Up phase for reasons other than 
withdrawal of consent/assent, lost to follow-up or death will have the Post-Treatment Early 
Withdrawal visit conducted at the time of discontinuation. In addition, if the PT EW visit occurs 
prior to completion of the Day 81 visit, a remote contact (eg, by telephone) will be performed on 
Day 81 for PWC-20, CDRS-R and MADRS, and for collection of concomitant therapies and AEs.
If the PT EW visit occurs within ±5 days window of Day 81 (Visit 18), then early withdrawal visit 
will be adequate, and the Day 81 RC visit is not required. If subjects discontinue anytime between 
Day 25 postdose and Day 28 RC of the PT phase, the PT EW visit is not required; however, Day 28 
RC should be performed.
The investigator must ensure the subject is appropriately transitioned and/or followed for any 
additional care required when a subject discontinues participation in the study for any reason.
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For information obtained via remote contact, written documentation of the communication must 
be available for review in the source documents. During remote contact visits with the subject by 
site personnel, concomitant therapies and adverse event information will be obtained, and CDRS-R 
and MADRS assessments will be performed by appropriately qualified staff. 
9.2.
Efficacy Evaluations
9.2.1.
Children’s Depression Rating Scale, Revised (CDRS-R)
The primary outcome measure in this study will be the CDRS-R, a validated 17-item, clinician-
rated instrument developed to assess depressive symptomatology in children that measures the 
severity of a patient’s depressive symptoms. The scale has demonstrated good reliability and 
validity in adolescents with depression.69
The typical recall period for the CDRS-R is 7 days. In this study, the CDRS-R will be administered 
using 4 recall periods: a 7-day recall on Day 1 (predose); a 4-hour recall at the 4-hour postdose 
assessment on Days 1 and 25; a 24-hour recall at the postdose assessment on Day 2; and a “since 
last assessment” recall predose on Day 4 through Day 25 dosing days. “Since last assessment” 
recall will also be used in Post-Treatment Follow-up assessments on Days 28, 32, 35 and 39. A 
7-day recall will be used for Post-Treatment Follow-up assessments on Days 46-200. The sleep 
item score is not assessed at the 4-hour postdose time point on Day 1 and Day 25. For the CDRS-
R performed at 4 hours postdose on Days 1 and 25, the CDRS-R scores for the sleep item recorded 
predose on the same day will be carried forward to calculate the total score. 
9.2.2.
Suicide Ideation and Behavior Assessment Tool (SIBAT)
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 a semi-structured interview, clinical global impressions of 
current severity of suicidality and imminent suicide risk, clinical global impression of long-term 
suicide risk, and clinical judgment of optimal suicide management. 
The 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 reduction of 
suicidal ideation 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. Also included in this module is the CGI-SR-I, 
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which 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.
Montgomery-Asberg Depression Rating Scale
The MADRS will be performed using the Structured Interview Guide for the Montgomery-Asberg 
Depression Rating Scale.116
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.74,75 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 be administered 
using 4 recall periods: a 7-day recall on Day 1 (predose); a 4-hour recall at the 4-hour postdose 
assessment on Days 1 and 25; a 24-hour recall at the postdose assessment on Day 2; and a “since 
last assessment” recall predose on Day 4 through Day 25 dosing days. “Since last assessment” 
recall will also be used in Post-Treatment Follow-up assessments on Days 28, 32, 35, and 39. A 
7-day recall will be used for Post-Treatment Follow-up assessments on Days 46-200. The sleep 
item score is not 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 to calculate the 
total score.
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.
9.2.4.
Children’s Depression Inventory 2: Self-Report (Short) 
The CDI 2:SR(S) assessment is based on the Children’s Depression Inventory 2 (CDI 2) and 
Children’s Depression Inventory 2 Self-Report (CDI 2:SR). 
The CDI 2:SR is a 12-item self-reported assessment that yields a total score, 2 scale scores 
(emotional problems and functional problems), and 4 subscale scores (negative mood, negative 
self-esteem, ineffectiveness, interpersonal problems). 
The CDI 2 SR(S), which will be used in this study, is a shortened version of the CDI 2:SR and is 
an efficient screening measure that contains 12 items and takes about half the time of the full-
length version to administer (5–10 minutes). The CDI 2:SR(S) has excellent psychometric 
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properties and yields a total score that is generally very comparable to the one produced by the 
full-length version.1
9.3.
Pharmacokinetics
Whole blood samples will be used to evaluate the PK of esketamine (and noresketamine, if 
warranted). 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 of pharmacokinetic 
blood sampling must be recorded.
Samples collected for analyses of esketamine plasma concentration may additionally be used to 
evaluate safety or efficacy aspects that address concerns arising during or after the study period or
for the evaluation of additional relevant biomarkers. Genetic analyses will not be performed on 
these plasma samples. Subject confidentiality will be maintained. Additional information about 
the collection, handling, and shipment of biological samples can be found in the Laboratory 
Manual.
9.3.2.
Analytical Procedures
Pharmacokinetics
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 
esketamine metabolites or midazolam 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. 
Based on the individual plasma concentration-time data, using the actual dose taken and the actual 
sampling times, PK parameters and exposure information of esketamine will be derived using 
population PK modelling. Baseline covariates (eg, body weight, age, sex, CrCL, race) may be 
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included in the model, if relevant. The results of population PK analyses may be reported 
separately. 
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations
The relationship between CDRS-R total score (and possibly other efficacy endpoints such as 
MADRS and 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 and RNA) Evaluations
Biomarker Evaluations
Blood samples will be collected as indicated in the Time and Events Schedule for exploratory 
analysis of biomarkers (protein and metabolites) 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.
If possible, blood samples should be collected under fasting conditions (minimum 8 hours prior to 
biomarker sample collection, water is permitted). When fasting is not feasible, subjects should 
follow a low fat diet for at least 8 hours prior to sample collection, if possible. Subjects should 
refrain from exercise/strenuous physical activity and the use of non-steroidal anti-inflammatory 
drugs (NSAIDs) for 24 hours prior to blood collection. Not following these recommendations will 
not constitute a protocol violation.
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.
Per the Time and Events Schedule, information on menstrual cycle (date of first day of last period, 
average length of cycle) will be recorded at each visit when blood samples for biomarker analysis 
are collected.
Pharmacogenomics, Epigenetics, and Gene Transcription Evaluations
Subject participation in pharmacogenomics/epigenetic/gene transcription evaluations is optional. 
Whole blood samples for DNA and RNA analyses will be collected from all subjects who provide 
consent/assent for pharmacogenomic research at the time points indicated in the Time and Events 
Schedule.
DNA and RNA samples will be analyzed for the assessment of genetic variation and transcription 
of 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 and RNA 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 
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consist of the analysis of one or more candidate genes or of the analysis of genetic markers 
throughout the genome (as appropriate) in relation to esketamine or MDD clinical endpoints.
All genetic data obtained during this study may be included in ongoing cross-study analyses to 
investigate the relationship between depression severity and phenotypes and biomarkers.
9.6.
Safety Evaluations
Details regarding the IDMC are provided in Section 11.7.
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
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the subject's 
LAR) 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 Section 3.2.7 and Section 11.6
for further details).
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and a 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 
72 hours prior to the screening visit (ie, signing of the ICF), results for those laboratory tests 
required per protocol at screening can be used for determination of subject eligibility. 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.
At Day -1 (screening), following ICF process, central laboratory samples must also be collected.
A central laboratory will be used at screening and during the study.
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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 performed at central laboratory
-specific gravity
Sediment (if central laboratory dipstick result 
is abnormal)
-pH
-glucose
-red blood cells
-protein
-white blood cells
-blood
-epithelial cells
-ketones
-crystals
-bilirubin
-casts
-urobilinogen
-bacteria
-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.
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 at the study site:

Urine Pregnancy Testing (for female subjects of childbearing potential only)
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
Urine drug test will screen for amphetamine, barbiturates, benzodiazepines, cocaine, 
marijuana (THC), methadone, methamphetamine, methylenedioxymethamphetamine 
(MDMA), opiates, phencyclidine, and tricyclic antidepressants. To maintain the integrity of 
the study blind, a urine drug screen (UDS) should not be performed during the DB period 
unless medically necessary. If deemed medically necessary, the medical monitor should be 
contacted and UDS should be performed predose on dosing days. 
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. 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.
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 required to review the ECG locally to determine subject eligibility.
Physical Examination, Body Weight and Height
Physical examinations and measurement of body weight and height will be performed per the Time 
and Events Schedule.
Young Mania Rating Scale (YMRS) 
YMRS will be administered to assess treatment-emergent occurrence and severity of manic 
episodes. The YMRS is an eleven-item multiple choice questionnaire which is used to measure 
the severity of manic episodes in children and young adults. It is based on the patient’s subjective 
report of his or her clinical condition over the previous hours. Additional information is based 
upon clinical observations made during the clinical interview. The scale is completed by a clinician 
or other trained rater and takes 15–30 minutes to complete. The symptom items were selected 
based upon published descriptions of the core symptoms of mania; the YMRS is a reliable, valid 
and sensitive rating scale to measure the severity of mania.122
Physician Withdrawal Checklist (PWC-20)
The PWC-20 will be administered by the clinician to assess potential withdrawal symptoms 
following cessation of intranasal esketamine treatment. The PWC-20 is a 20-item simple and 
accurate method to assess potential development of discontinuation symptoms after stopping of 
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study medication. The PWC-20 is a reliable and sensitive instrument for the assessment of 
anxiolytic discontinuation symptoms.106 Discontinuation symptoms occur early and disappear 
rather swiftly, depending upon speed of taper, daily medication dose, and drug elimination half-
life.106
Cogstate computerized cognitive battery
The Cogstate computerized cognitive battery is a validated set of assessments which will be 
performed to assess verbal learning and memory and evaluate cognitive function.12,28,64 There are 
4 in-study assessment times for these: between Day 4 and Day 8 (prior to discharge; predose if 
performed on dosing day), Day 25 predose, DB EW, Day 81, Day 200, PT EW.
The battery will provide assessment of multiple cognitive domains, including attention, visual 
learning and memory, and executive function. The tests use culture neutral stimuli, enabling use 
in multilingual/multicultural settings. The computerized battery includes:

Simple and choice reaction time tests; scored for speed of response:
o
Detection (DET; Psychomotor Function)
o
Identification (IDN; Attention)

Visual episodic memory; visual recall test:
o
One Card Learning (OCL; Visual Learning)

Working memory (n back task); scored for seed of correct response:
o
One Back (ONB; Working Memory)

Verbal learning and memory assessment 
o
International Shopping List Task (ISLT)

Executive function; maze/sequencing test, scored for total number of errors:
o
The Groton Maze Learning Test (GML; Executive Function)
All measures in the cognitive battery have been validated against traditional neuropsychological 
tests and are sensitive to the effects of various drugs on cognitive performance, including alcohol 
and benzodiazepines. The subject completed Cogstate computerized cognitive battery has been 
used for cognitive assessment in several child and adolescent research trials including attention 
deficit hyperactivity disorder,7 and demonstrates good reliability and validity in child and 
adolescent populations.6 The ISLT has also been used in adolescent trials, demonstrating 
sensitivity, reliability and validity. The subject completed cognitive battery requires approximately 
25 minutes; the clinician administered ISLT requires approximately 15 minutes in total.
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All assessments are completed by the subject except the verbal learning and memory assessment, 
the ISLT, that will be administered by the clinician. The ISLT is a 12-word three-trial verbal list-
learning test. The word lists used in the ISLT consist of foodstuffs common to the culture or 
language group. The verbal presentation of the word list and the recording of responses are done 
by the rater and controlled by a laptop computer or tablet. For each 12-word list that is used, the 
software selects at random the order in which words are presented to subjects. After the third trail 
is completed, the subject will also complete a series of other tasks for 15-20 minutes, before being 
asked to recall the 12 words from the ISLT again – this is called a Delayed Recall trial. The subject 
will also be shown a list of words and asked to recognize previously presented words, a Word 
Recognition trial.
Timeline Follow-Back (TLFB)
The TLFB will be used to assess the potential for ketamine and PCP abuse during the follow-up 
phase. The Timeline Follow-Back (TLFB),35 a clinical and research tool used to obtain a variety 
of quantitative estimates of alcohol and drug use, will be used to evaluate the potential for ketamine 
or PCP abuse during the follow-up. The Timeline Follow-Back method has been used in studies 
to quantify ketamine use in adults, as well as to evaluate substance use in various adolescent 
populations.62
Dosing Day Assessments
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). Blood pressure, heart rate, and 
respiratory rate performed at predose (should be performed between t = -15 min and t = 0) and at 
t = 40 mins, 1 hr, and 1.5 hrs postdose; temperature at predose only.
For further details regarding blood pressure monitoring, please see Guidance on Blood Pressure 
Monitoring on Study Medication Dosing Days (Section 6.3).
Tympanic temperature is recommended. The method used for obtaining temperature should be 
documented.
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 should be monitored and documented 
once predose between t = -15 minutes and t = 0 (first spray) and then every 15 minutes postdose
for approximately 1.5 hours. 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. If oxygen saturation 
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levels are <95% predose, dosing should be postponed, and the subject should be evaluated by an 
appropriate practitioner to determine suitability to continue in the study.
Targeted Nasal Examination and Nasal Symptom Questionnaire
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 examinations 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 
the presence and severity of symptoms will be graded. Any treatment-emergent change or 
worsening from baseline examination will be recorded as an adverse event.
In addition, a clinician or designated study staff will complete a nasal symptom questionnaire.
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.96 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 dosing day, the MOAA/S should be performed once predose between t = -15 minutes and 
t = 0 (first spray), and every 15 minutes for approximately 1.5 hours postdose (or longer, if 
necessary).
If the score is ≤3 at any time during the 90-minute postdose interval, the MOAA/S should 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 symptoms13 and 
will be administered to assess treatment-emergent dissociative symptoms. On each dosing day, the 
CADSS should be performed 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.
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.
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Brief Psychiatric Rating Scale, Positive Symptom Subscale (BPRS+)
The BPRS+ is an instrument that uses a 4-item positive symptom subscale (consisting of: 
suspiciousness, hallucinations, unusual thought content, and conceptual disorganization) to assess 
psychosis-like side effects. On each dosing day, BPRS+ to be performed predose and at 40 minutes 
and 1.5 hours postdose.
9.7.
Other Evaluations
MINI International Neuropsychiatric Interview for Children and Adolescents (MINI-KID)
The MINI-KID 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. The MINI-KID follows the structure and format of the adult version of the 
interview (MINI) but was revised and validated for use in children aged 6 to 17 years. It is 
administered to the child or adolescent together with their parents(s), or can be administered 
without a parent present for adolescents.108 It has an administration time of approximately 15 to 
30 minutes and provides an accurate structured psychiatric interview for multicenter clinical trials. 
The MINI-KID 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-KID
Current suicidal ideation with intent will be evaluated at screening using Question B3 (Think about 
hurting yourself with the possibility that you might die. Or did you think about killing yourself?)
AND B10 (Expect to go through with a plan to kill yourself?) from the MINI-KID. Subjects will 
be asked to answer these questions (Yes or No) 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 screening 
is longer than 24 hours prior to randomization, the B3 and B10 MINI-KID assessment must be 
repeated to confirm eligibility.
9.8.
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 Treatment 
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 Week 29 (Day 200).
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study
Discontinuation of Study Treatment During the Double-blind Phase 
A subject's study treatment will be discontinued for any of the following reasons:

Lost to follow-up

Withdrawal of consent/assent

Death 

Subjects whose postdose SBP or DBP measures are equal to or greater than the sex, age and 
height values in Attachment 4 (after a repeated measurement).

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.
Refer to Section 9.1.5 for details on early withdrawal information.
The investigator must ensure the subject is appropriately transitioned and/or followed for any 
additional care required when a subject discontinues participation in the study for any reason.
Withdrawal from the Study During the Post-Treatment 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
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
Withdrawal of consent/assent

Death

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.

Requires treatment with ECT, TMS, ketamine or esketamine
Refer to Section 9.1.5 for details on early withdrawal information.
The investigator must ensure the subject is appropriately transitioned and/or followed for any 
additional care required when a subject discontinues participation in the study for any reason.
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(s):

The collected sample will be retained and used in accordance with the subject and 
parent(s)/LAR(s) original separate pediatric assent/informed consent form for optional 
research sample(s).

The subject or parent(s)/LAR(s) may withdraw pediatric assent/informed consent for optional 
research sample(s), in which case the sample(s) 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 pediatric assent/informed consent for the optional research 
sample(s) 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 or parent(s)/LAR(s) may withdraw pediatric assent/ informed consent for optional 
research sample(s) while remaining in the study. In such a case, the optional research sample(s)
will be destroyed. The sample destruction process will proceed as described above.
Withdrawal from the Use of Samples in Future Research
The subject or parent(s)/LAR(s) may withdraw pediatric assent/ informed 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.
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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.
An analysis of efficacy and safety will be performed after the last subject completes the 25-day 
Double-blind Treatment Period (Day 25). This analysis will enable selection of a dose for the 
planned Phase 3 trial, facilitating Phase 3 trial design and preparation. Database locks will also be 
performed after the last subject completes the Day 81 Visit and Day 200 Visit, respectively.
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 receive at least 
1 dose of double-blind study medication and have both a baseline and a postdose evaluation 
for the CDRS-R 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.
11.2.
Sample Size Determination
The sample size for this study was calculated assuming an effect size of 0.65 between any dose of 
esketamine and psychoactive placebo for the change from baseline at 24 hours postdose for the 
CDRS-R total score and a 2-sided significance level of 0.05. A total of 145 subjects will be 
randomized in this study. Using a 1:1:1:2 randomization ratio (esketamine 28 mg: esketamine 
56 mg: esketamine 84 mg: psychoactive placebo), approximately 58 subjects will need to be 
randomized to psychoactive placebo and 29 subjects will need to be randomized to each 
esketamine treatment group to achieve 94% power for the comparison of the pooled doses of 
esketamine 56 mg and esketamine 84 mg versus psychoactive placebo and 92% power for at least 
one of the 2 esketamine higher doses (56-mg and 84-mg) versus psychoactive placebo. The effect 
size of 0.65 is based on results from study ESKETINSUI2001 (mean difference between treatment 
groups of -7.2 and a pooled SD of 11.02) for MADRS total score.16
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 CDRS-R 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. 
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The primary analysis will be based on the full analysis set and the CDRS-R total scores collected 
at Day 2 (24 hours post first dose).
Primary Efficacy Analysis
The primary analysis will be based on the full analysis set. The primary efficacy variable, change 
from baseline in CDRS-R total score at 24 hours post first dose, will be analyzed using an analysis 
of covariance (ANCOVA) model. The model will include factors for treatment and center, and 
baseline CDRS-R total score as a covariate. A pooled sequential multiple testing procedure will 
be implemented to control for Type I error. The esketamine 56 mg and 84 mg treatment groups 
will be pooled and compared with psychoactive placebo at the 2-sided significance level of 0.05. 
If this comparison achieves statistical significance in favor of esketamine, the 56-mg dose and 
84-mg dose will be simultaneously tested versus psychoactive placebo at the 2-sided significance 
level of 0.05 based on the closed testing procedure. The 28-mg dose will be tested only if both the 
56-mg and 84-mg doses are shown to be significant. Point estimates and 95% confidence intervals 
for treatment differences 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 CDRS-
R 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. Missing data will be closely monitored 
throughout the trial.
Other Efficacy Analyses
A dose response analysis for the change from baseline in CDRS-R total score at 24 hours post first 
dose and at Day 25 will be conducted with various dose response models being explored. Details 
of the dose response analysis will be provided in the SAP.
Changes from baseline over time in CDRS-R total score, MADRS total score, and CDI 2:SR(S)
score will be analyzed based on last observation carried forward (LOCF) data using an ANCOVA 
model with treatment and center as factors and baseline value as a covariate. Additionally, the 
change from baseline in CDRS-R total score at Day 25 will be analyzed using a mixed model for 
repeated measures (MMRM) analysis with baseline CDRS-R total score as a covariate, and 
treatment, center, day, and day-by-treatment interaction as fixed effects, and a random subject 
effect. Comparison of each esketamine dose versus placebo will be performed using the 
appropriate contrast. Point estimates and 95% confidence intervals for treatment differences will 
be provided. Missing data will be closely monitored and additional sensitivity analyses will be 
specified in the SAP, if necessary.
The ranks of changes from baseline over time for both CGI-SS-R and CGI-SR-I will be analyzed 
using an ANCOVA model using last observation carried forward data with factors for treatment 
and center and baseline CGI-SS-R and CGI-SR-I (unranked) as a covariate. Treatment differences 
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 and CGI-SR-I.
SIBAT Module 3 (My Current Thinking) and Module 5 (My Risk) Question 3 (patient-reported 
frequency of suicidal thinking) will be summarized over time.
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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.
Details of the other analyses will be provided in the SAP.
11.4.
Pharmacokinetic Analyses
Data will be listed for all subjects with available plasma concentrations per treatment group. 
Subjects will be excluded from the PK analysis if their data do not allow for accurate assessment 
of the PK (eg, incomplete administration of the study drug; missing information of dosing and 
sampling times; concentration data not sufficient for PK parameter calculation). 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.
The plasma concentration-time data of esketamine (and noresketamine, if warranted) will be 
analyzed using population PK 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. 
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. In addition to the final population PK parameter estimates, 
the corresponding standard errors and 95% confidence intervals will be provided.
The relationship between CDRS-R total score (and possibly other efficacy endpoints such as 
MADRS and selected adverse events and additional pharmacodynamic parameters), and PK 
metrics of esketamine may be evaluated. The results of such analyses may be reported separately.
11.5.
Biomarker and Pharmacogenomic Analyses
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 be performed for additional biomarkers. Results may be presented in a 
separate Biomarkers report. 
Pharmacogenomic analyses (DNA and RNA) may include candidate gene analyses, genome-wide 
association analyses, and gene transcription analyses in relation to treatment response, 
non-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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11.6.
Safety Analyses
The primary population for safety analysis will consist of all randomized subjects who receive at 
least one dose of double-blind study medication. 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). Treatment-emergent adverse 
events are adverse events with onset during the Double-Blind Treatment phase or that are a 
consequence of a pre-existing condition that has worsened since baseline. All reported adverse 
events with onset during the Double-Blind Treatment phase (ie, TEAEs 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. In addition, comparisons between treatment groups will be provided if 
appropriate. Adverse events during the follow-up phase will be summarized separately.
The TEAEs of special interest will be examined separately (refer to Section 3.2.7 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. 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).8,44,47,109
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, 
>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.
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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 and Nasal Symptom Questionnaire
Changes in findings from the baseline nasal examination (including the upper respiratory 
tract/throat) will be listed by treatment group. Examinations will provide ratings of severity 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.
Scoring from the nasal symptom questionnaire will be summarized descriptively 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.
SIBAT, BPRS+, and YMRS
Suicidal ideation and behavior data from the SIBAT, psychosis-like side effect data from the 
BPRS+, and potential treatment-emergent symptoms of mania data from the YMRS will be 
summarized descriptively at each scheduled visit by treatment group.
Cogstate Computerized Cognitive Battery 
Cognitive function data from the Cogstate computerized cognitive battery will be summarized 
descriptively at each scheduled visit by treatment group.
PWC-20
Withdrawal symptoms data from the PWC-20 will be summarized descriptively at designated
scheduled visit by treatment group.106
Time Line Follow-Back (TLFB)
The TLFB, a clinical and research tool used to obtain a variety of quantitative estimates of 
ketamine and PCP abuse, will be summarized descriptively at each scheduled visit by treatment 
group.
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11.7.
Independent Data Monitoring Committee
In addition to investigator judgment concerning standard of care and subject safety, an external 
IDMC, comprised of individuals with appropriate pediatric expertise including pediatric 
psychiatric expertise, 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 periodically to 
review interim safety data. After the review, 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.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events or SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about adverse event
occurrence. For some studies, subjects are not always able to provide valid verbal responses to 
open-ended questions. In these circumstances, certain adverse events are solicited by efficacy and 
safety assessments (see Section 3.2.6 and Section 3.2.7).
Solicited Adverse Events
Solicited adverse events are predefined local and systemic events for which the subject is 
specifically questioned.
Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the subject is specifically not 
questioned.
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 
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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 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.48,49,50 For midazolam,
with a marketing authorization, the expectedness of an adverse event will be determined by 
whether or not it is listed in the package insert or summary of product characteristics.72,73
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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.
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).
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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.
One of the principal aims of this trial is to define safety of intranasal esketamine use in the 
adolescent population. Anticipated events will not be applied to this adolescent trial. There are no 
common causes of hospitalization or serious events collectively in this age group. There is not 
enough information in this age group to define anticipated events due to major depression or major 
depression with suicidal intention at this time.
All events that meet the definition of a serious adverse event will be reported as SAEs, regardless 
of whether they are protocol-specific assessments.
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 
relationship of the adverse event to study therapy. All measures required for adverse event 
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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 SAEs 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 SAEs 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 SAEs 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 hospitalization that extends beyond the protocol-recommended 5 days (not due to 
adverse event; e.g. 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 be promptly withdrawn from the study and 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.
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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, 
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)
Study drug will be manufactured and provided under the responsibility of the sponsor. Refer to the 
Investigator's Brochure for a list of excipients for esketamine,48 and to the midazolam product 
label72,73 for a list of excipients for midazolam.
Intranasal Esketamine and Placebo Solution
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 intranasal 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 
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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.
Oral Midazolam and Placebo
The oral midazolam supplied for this study is available as a clear, colorless solution of midazolam-
ratiopharm® 2 mg/ml. Other ingredients include raspberry flavoring, sodium benzoate, sodium 
cyclamate, hydrochloric acid (0.8%) and distilled water. It is provided in a glass bottle with dropper 
and child-proof plastic cap, measuring cap, and application syringe.
The oral placebo solution will be provided as a clear, colorless oral solution of purified water with 
a preservative (sodium benzoate) at a concentration of 2.36 mg/mL with a buffer (citric acid) at 
3.00 mg/mL. Sucralose (sweetener) is added at a concentration of 1.00 mg/mL and artificial 
raspberry flavor is added at a concentration of 1.00 mg/mL. The oral placebo solution is provided 
in 30-mL amber glass bottles with a child-resistant cap.
14.2.
Packaging
All study drug will be administered under the supervision of site staff.
Intranasal Esketamine and Placebo Solution
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.
Oral Midazolam and Placebo
The oral midazolam (2mg/ml) and oral placebo solutions will be provided in 30-mL amber glass 
bottles with a child-resistant cap and packaged in cartons. Storage conditions are as indicated on 
the label.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
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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. 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. 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.
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

SmPC or Package Insert for midazolam

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
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
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

Visit procedures checklist

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.54,91 Epidemiology studies estimate that the 12-
month prevalence of MDD is 2% in children and 4% to 8% in adolescents,2 that MDD is the main 
predictor of suicidal ideation among children and adolescents,37,93 and that 40% to 80% of 
adolescents meet the diagnostic criteria for depression at the time of suicide attempt.10,37 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 and psychological therapy. However, these therapies are unable to 
rapidly reduce depressive symptoms and suicidal ideation. Thus, subjects remain at risk for 
suicide, with up to 13.9% of subjects reattempting suicide within the 3 months following
hospitalization.102 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.31,60,101,103,123
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. Thus, esketamine treatment for 25 days added to 
standard care for these at-risk adolescents has the potential to reduce MDD symptoms, including
suicidal ideation, while standard therapies are becoming effective.
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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 MDD, including suicidal ideation, in young 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 and parent(s)/LAR(s) in this trial will be providing voluntary pediatric assent/informed 
consent to participate in the study of a potentially efficacious treatment, given in the context of 
standard of care treatment (ie, hospitalization, antidepressant treatment and psychological 
therapy). Thus, ethical concerns regarding subjects’ decision to participate are minimal.
Subjects and parent(s)/LAR(s) may participate in the study only if they have adequate capacity to 
give assent and after fully understanding the potential risks and giving a pediatric assent/informed 
consent. Determination of capacity to provide assent 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. 
Further each subject’s parent(s)/LAR(s), as required by local regulations, must give written consent.
Justification for Using Psychoactive Placebo
Assessment of the potential efficacy of a new compound for the treatment of MDD 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 psychoactive 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, 
psychological therapy and close outpatient follow up) is ethically appropriate. 
The rationale for use of a psychoactive placebo to protect the blind of study medication is discussed 
in Section 3.2.3. As its pharmacokinetic characteristics and transient psychoactive effects are 
similar to ketamine, midazolam has been used as a psychoactive control in studies of ketamine.85
It will be used in doses approximately 25% of those recommended for use in pediatric 
populations.72,73
Subjects and their consenting parent or legal guardian will be informed of the chance of receiving 
esketamine or psychoactive placebo, the rationale for use of a psychoactive placebo, and of the 
potential side effects of midazolam as well as esketamine. 
Precautions to Ensure Subject Safety in the Study
The study will be conducted in the context of standard clinical care, including hospitalization the 
initiation or optimization of antidepressant and psychological treatment, and close outpatient 
follow up. Subjects will remain hospitalized for a recommended period of 5 days and may stay 
longer if clinically warranted. Subjects should receive standard of care antidepressant medication 
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initiated or optimized on Day 1. However, initiating standard of care antidepressant medication up 
to 7 days after the first dose of study medication (Day 1) may be permitted if starting two 
medications simultaneously is not consistent with local clinical practice.
Subjects will be followed closely throughout the study: twice a week during the 25-day treatment 
period, followed by weekly visits through week 8, visits every 2 weeks through week 12 then 
monthly through Week 29. The frequency of visits may be increased as per the judgment of the 
caregiver and needs of the subject. This is consistent with numerous recommendations from 
professional and health authorities. Specific assessments to measure depressive symptoms and 
suicidal ideation are collected at these visits, enabling early identification of any changes in the 
subject’s condition and possible intervention.
If subjects 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.
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 and their parent(s) or LAR(s) 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 respective assent and 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 and 
parent(s)/LAR(s) who are fully able to understand the risks, benefits, and potential adverse events of 
the study, and provide their pediatric assent/informed consent voluntarily will be enrolled.
When referring to the signing of the ICF, the terms legal guardian and legally acceptable 
representative refer to the legally appointed guardian of the child with authority to authorize 
participation in research. For each subject, his or her parent(s) (preferably both parents, if available) 
or LAR(s), as required by local regulations, must give written consent (permission) according to 
local requirements after the nature of the study has been fully explained and before the performance 
of any study-related assessments. Assent must be obtained from children (minors) capable of 
understanding the nature of the study, typically subjects 7 years of age and older, depending on the 
institutional policies. For the purposes of this study, all references to subjects who have provided 
consent (and assent as applicable) refers to the subjects and his or her parent(s) or the subject's legal 
guardian(s) or LAR(s) who have provided consent according to this process. Minors who assent to 
a study and later withdraw that assent should not be maintained in the study against their will, even 
if their parents still want them to participate.
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 based upon European Medicines 
Agency and Food and Drug Administration (FDA) requirements and strategies for pediatric drug 
development.124 Weight and age charts for 12-year-olds in the 5th percentile, show a weight of 
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approximately 30 kg for both girls and boys.26,45,34,111 Assuming a conservative phlebotomy protocol 
that is 1% of total blood volume drawn within 24 hours and a total of 3% total blood volume drawn 
over 30 days, total blood volume for the study population was calculated based on an assumption of 
80 mL/kg, as follows:

Maximum total blood volume per 24 hours = 30 kg x 80 mL/kg x 0.01 = 24 mL

Maximum total blood volume per 30 days = 30 kg x 80 mL/kg x 0.03 = 72 mL
Compensation for any procedure will be fair per local standards and approved by the IECs/IRBs 
for participating sites in order not to offer any undue incentive to participate in the study.
The blood volumes estimated for this study (Section 9.1.1, Table 2) are lower than maximum 
recommended blood volumes.
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 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
The risks and inconveniences related to Study ESKETINSUI2002 participation will be minimal. 
Any risk or inconvenience will be mitigated through strict adherence to study procedures by the 
investigator, and compliance with study procedures by the subject/guardians. To that end, the 
investigator is responsible for ensuring precise study conduct as specified by the protocol, which 
will be achieved through training on the study protocol, review of important supporting documents 
pertaining to risks (see Section 15, Study-Specific Materials), and compliance with all aspects of 
study conduct.
The following are the foreseeable risks to be monitored by the investigator throughout the study, 
and the associated mitigations, as defined in respective protocol sections:   
Voluntary consent/assent 
For this study, both parental consent and subject assent is required. Subjects may participate only if 
their parent(s)/LAR(s) have adequate capacity to give consent and fully understand the potential 
risks. 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. 
Determination of capacity will be made by the study investigator. See Section 4.1, Inclusion Criteria. 
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Clinical management
To ensure appropriate clinical management of this potentially lethal condition in subjects assessed 
to be at imminent risk for suicide, the study will be conducted in the context intensive standard 
clinical care, including hospitalization, the initiation or optimization of antidepressant treatment and 
psychological therapy. Additionally, close outpatient follow up will occur, consistent with practice 
guideline recommendations from the National Institute for Health and Clinical Excellence (NICE)
and the American Academy of Pediatrics (AAP).90 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 or shorter if clinically 
warranted. Very frequent clinical visit and assessments monitoring symptoms of the subject’s MDD, 
including suicidal ideation, occur throughout the study, thus optimizing early identification of 
changes in depressive status. See Section 9.1, Study Procedures.
Post-treatment follow-up period
After the 4-week double-blind phase, no study medication will be administered. During the initial 
8-week follow-up phase, subjects will have visits conducted weekly through Day 53, then every 
other week until Day 81, then monthly safety appointments for the remainder of the 6 months 
(Day 81-200). The duration of follow-up in this study covers the period of greatest risk for 
recurrent suicidality post initial attempt and/or hospitalization.11,102 The follow-up through 
Day 200 will allow for appropriate outpatient monitoring and the exploration of the continued 
effects of esketamine on depression and suicidal symptoms.
Study discontinuation and follow-up
Subjects may discontinue the study at any time for a variety of reasons, including withdrawal of 
consent. If subjects 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. 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. See 
Section 10.
Safety during study
All phlebotomy volumes for this study have been minimized to adhere to the Committee for 
Human Medicinal Products (CHMP)
and Paediatric Committee (PDCO)
guideline 
recommendations.26 To increase subject comfort, an indwelling catheter has been recommended.
Study requirements for frequent and close follow-up, coupled with use of recommended 
pharmacologic and psychological therapies in addition to study drug, assures that adolescents 
participating in the study receive care consistent with recognized guidelines for care of subjects 
with MDD and suicidal ideation.
Based on previous studies, it is known that certain adverse drug reactions occur postdose, peak 
around 40 minutes, and then dissipate, usually within 4 hours. The study includes careful 
monitoring following study drug dosing. Vital signs are performed at predose (should be 
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performed between t = -15 minutes and t = 0) and at 40 minutes, 1 hour, and 1.5 hours postdose.
Oxygenation should be monitored predose (performed between t = -15 minutes and t = 0), and 
every 15 minutes thereafter through to approximately 1.5 hours postdose, or longer, if necessary. 
Additionally, other known side effects of esketamine (eg, dissociation, sedation, conceptual 
disorientation, hallucinogenic behavior, and abnormal thought content) are monitored closely 
during this time using specific assessment tools like CADSS, MOAA/S, and BPRS+. On each 
dosing day, CADSS and BPRS+ should be performed predose and at 40 minutes and 1.5 hours 
postdose; MOAA/S should be performed predose (between t = -15 minutes and t = 0) and every 
15 minutes thereafter through to approximately 1.5 hours postdose, or longer, if necessary.
Other measures
Additional safeguards have also been included to facilitate subject safety; eg, specific guidance 
provided regarding management of elevated blood pressure, pre- and postdose (Section 6.3), and 
intensive post-administration monitoring on outpatient days (Section 10). In addition, an external 
IDMC will be established to monitor unblinded safety data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled in this study. The committee will meet regularly to 
review safety data and determine if it is appropriate for the study to continue (Section 11.7). 
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.
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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

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 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/Pediatric Assent Form
Subject’s parent(s) or LAR(s) must give written consent, granting permission for his/her child to 
participate in the study according to local requirements after the nature of the study has been fully 
explained. Written assent must be obtained from the subject.
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Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects and their parent(s)/LAR(s), the methods, reasonably 
anticipated benefits, and potential hazards of the study, and any discomfort participation in the 
study may entail. This discussion should be documented. Subjects and parent(s)/LAR(s) 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. Subjects and parent(s)/LAR(s) will be told that 
alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, the subject and parent/LAR will be told that the investigator 
will maintain a subject ID 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 pediatric assent/ICF the subject and parent/LAR are authorizing such access, 
including permission to obtain information about his or her survival status, and agree to allow their 
study physician to recontact the subject for the purpose of obtaining consent for additional safety 
evaluations, if needed, and subsequent disease-related treatment, or to obtain information about 
his or her survival status. The subject and parent/LAR will be given sufficient time to read the ICF 
and the opportunity to ask questions. Parent/LAR ICF(s) and the pediatric assent form(s) must be 
signed before performance of any study-related activity. The ICF(s) and assent form(s) that are 
used must be approved by both the sponsor and by the reviewing IEC/IRB and be in a language 
that the parent/LAR and subject can read and understand. The informed consent/assent should be 
in accordance with principles that originated in the Declaration of Helsinki, current ICH and GCP 
guidelines, applicable regulatory requirements, and sponsor policy. After having obtained the 
consent and assent, a copy both must be given to the subject and parent/LAR.
Children (minors) who reach the age of majority during the study will be reconsented using a 
provided adult written ICF per applicable local regulations and the IRB/IEC requirements. 
Subjects and parent(s)/LAR(s) 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 and his or her parent(s)/LAR(s) 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(s)/assent(s) will be given to the subject and parent(s)/LAR(s).
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. 
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Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of subjects confidential.
The informed consent/pediatric assent obtained from the subject and his or her parent(s)/LAR(s)
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(s) or their parent(s)/LARs 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.
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 and suicidality, to understand differential drug responders, and to develop tests/assays 
related to esketamine and depression and suicidality. 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 or their parent(s)/LAR(s) may withdraw their consent 
for their/their child’s samples to be stored for research (refer to Section 10.3, Withdrawal from the 
Use of Research Samples).
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 
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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.
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
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
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 sub-investigator 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
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
number 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/pediatric assent; 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.
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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).
Subject- and investigator-completed scales and assessments designated by the sponsor will be 
considered source data. The CDRS-R, MADRS, SIBAT, CDI 2:SR(S), MOAA/S, YMRS, 
PWC-20, BPRS+, MINI-KID, Cogstate computerized cognitive battery, TLFB (including paper 
calendar), nasal symptom questionnaire, and CADSS will be considered source data.
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 
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 CRF 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.
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All subjective measurements (eg, scale information or other questionnaires) will be completed by 
the same individual who made the initial baseline determinations whenever possible.
The investigator must verify that all data entries in the eCRF 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 an 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.
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.
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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 the 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. 
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.
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Status: Approved, Date: 22 November 2020
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 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 
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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.
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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REFERENCES
1.
Allgaier A, Frühe, B, Pietsch K, Saravo B, Baethmann M, Schulte-Körne, G.  Is the Children's Depression 
Inventory Short version a valid screening tool in pediatric care? A comparison to its full-length version. 
Journal of Psychosomatic Research. 2012;75(5),369-374.
2.
American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of 
children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 2007;46:1503-1526.
3.
Ates-Alagoz Z, Adejare A. NMDA receptor antagonists for treatment of depression. Pharmaceuticals. 
2013;6(4):480-499.
4.
Ballard ED, Ionescu DF, Vande Vort JL, et al. Improvement in suicidal ideation after ketamine infusion: 
relationship to reductions in depression and anxiety. J Psych Res. 2014;58:161-166. 
5.
Ballard ED, Luckenbaugh DA, Richards EM, et al. Assessing measures of suicidal ideation in clinical trials
with a rapid-acting antidepressant. J Psychiatr Res. 2015;68:68-73.
6.
Bangirana P, Sikorskii A, Giordani B, Nakasuija N, Boivin MJ. Validation of the CogState battery for rapid 
neurocognitive assessment in Ugandan school age children. Child Adolesc Psychiatry Ment Health. 2015: 
9(38).
7.
Barnett R, Maruff P, Vance A. An investigation of visuospatial memory impairment in children with attention 
deficit hyperactivity disorder (ADHD), combined type. Psychol Med. 2005; 35(10): 1433-1443.
8.
Bazett HC. An analysis of the time-relationship of electrocardiograms. Heart. 1920;7:353-380.
9.
Beardsley PM, Balster RL. Behavioral dependence upon phencyclidine and ketamine in the rat. J Pharmacol 
Exp Ther. 1987;242:203-211.
10.
Beautrais AL, Joyce PR, Mulder RT. Psychiatric illness in a New Zealand sample of young people making 
serious suicide attempts. N Z Med J. 1998;111(1060):44–48.
11.
Bickley H, Hunt IM, Windfuhr K, Shaw J, Appleby L, Kapur N. Suicide within two weeks of discharge from 
psychiatric inpatient care: a case-control study. Psychiatr Serv. 2013;64(7):653-659.
12.
Bredlau AL, Harel BT, McDermott MP, Dworkin RH, Korones DN, Dolan JG, Adams HR. Neurocognitive 
Changes after Sustained Ketamine Administration in Children with Chronic Pain. J Palliat Care Med. 2015: 2; 
pii 215.
13.
Bremmer JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, Mazure CM. Measurement of 
dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress. 
1998;11(1):125-136.
14.
Brent DA, Baugher M, Bridge J, Chen T, Chiappetta L. Age- and sex-related risk factors for adolescent 
suicide. J Am Acad Child Adolesc Psychiatry. 1999;38(12):1497-1505.
15.
Brent DA, Greenhill LL, Compton S, et al. The Treatment of Adolescent Suicide Attempters study (TASA): 
predictors of suicidal events in an open treatment trial. J Am Acad Child Adolesc Psychiatry. 
2009;48(10):987-996.
16.
Briefing Book JNJ-54135419-AAC (esketamine hydrochloride). Esketamine for Rapid Reduction of 
Symptoms of Major Depressive Disorder, including Suicidality, in Patients who are Assessed to be at 
Imminent Risk for Suicide (25 Aug 2016).
17.
Centers for Disease Control: Suicide Prevention Available from: 
http://www.cdc.gov/violenceprevention/suicide/youth_suicide html. Accessed 12 January 2016.
18.
Chang T, Savory A, Albin M, Goulet R, Glasko AJ. Metabolic disposition of tritium-labelled ketamine 
(Ketalar®, CI-581) in normal human subjects. Clin Res. 1970;18:597.
19.
Cheung A, Emslie G, Mayes TL. Review of the efficacy and safety of antidepressants in youth depression. J 
Child Psychol and Psychiatry. 2005;46(7):735-754.
20.
Cheung A, Zuckerbrot RA, Jensen PS, et al. Guidelines for Adolescent Depression in Primary Care (GLAD-PC): II. 
Treatment and Ongoing Management. PEDIATRICS Volume 120, Number 5, November 2007. e1313-1326. 
NCT03185819


JNJ-54135419 (esketamine)
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21.
Cincinnati Children's Hospital Medical Center. Best Evidence Statement (BESt): Treatment of Children and 
Adolescents With Major Depressive Disorder (MDD) During the Acute Phase. Cincinnati, OH: Cincinnati 
Children's Hospital Medical Center; 2010.
22.
Clark MS, Jansen KL, Cloy JA. Treatment of childhood and adolescent depression. Amer Fam Physician. 
2012; 86(5):442-448.
23.
Clinical Study Report ESKETINTRD2003. A Double-Blind, Doubly-Randomized, Placebo-Controlled Study 
of Intranasal Esketamine in an Adaptive Treatment Protocol to Assess Safety and Efficacy in Treatment-
Resistant Depression (29 Apr 2016).
24.
Collins GT, Woods JH. Drug and reinforcement history as determinants of the response-maintaining effects of 
quinpirole in the rat. J Pharmacol Exp Ther. 2007;323:599-605.
25.
Collins RJ, Weeks JR, Cooper MM, Good PI, Russell RR. Prediction of abuse liability of drugs using IV self-
administration by rats. Psychopharmacology. 1984;82:6-13.
26.
Committee for Medicinal Products for Human Use (CHMP) and Paediatric Committee (PDCO). Guideline on 
the investigation of medicinal products in the term and preterm neonate; London, 25 June 2009. Doc Ref 
EMEA/536810/2008.
27.
Critchlow DG. A case of ketamine dependence with discontinuation symptoms. Addiction. 2006;101:1212-1213.
28.
Crutcher E, Ali M, Harrison J, Sovag J, Gomez-Mancilla B, Schaaf CP. Assessment of Cognitive Outcome 
Measures in Teenagers with 15q13.3 Microdeletion Syndrome. J Autism Dev Disord. 2016: 46(4); 1455-1463.
29.
Curran HV, Morgan C. Cognitive, dissociative and psychotogenic effects of ketamine in recreational users on 
the night of drug use and 3 days later. Addiction. 2000;95:575-590.
30.
Deisenhammer EA, Ing CM, Strauss R, Kemmler G, Hinterhuber H, Weiss EM. The duration of the suicidal 
process: how much time is left for intervention between consideration and accomplishment of a suicide 
attempt? J Clin Psychiatry. 2009; 70(1):19-24.
31.
DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a single infusion 
of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin 
Psychiatry.  2010;71(12):1605-1611.
32.
Emslie GJ, Heiligenstein JH, Wagner KD, et al. Fluoxetine for acute treatment of depression in children and 
adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry. 
2002;41(10):1205–1215.
33.
Emslie GJ, Heiligenstein JH, Wagner KD, et al. Fluoxetine for acute treatment of depression in children and 
adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry. 
2002;41(10):1205-1215.
34.
European Medicines Agency. Ethical considerations for clinical trials on medicinal products with the 
paediatric population. Available from: http://ec.europa.eu/health/files/eudralex/vol-
10/ethical_considerations_en.pdf. Accessed 11 August 2015.
35.
Fals-Stewart W, O’Farrell TJ, Freitas TT, McFarlin SK, Rutigliano P. The timeline followback reports of 
psychoactive substance use by drug-abusing patients: psychometric properties. J Consul Clin Psychol. 2000: 
68(1); 134-144.
36.
Geisslinger G, Hering W, Thomann P, Knoll R, Kamp H-D, Brune K. Pharmacokinetics and 
pharmacodynamics of ketamine enantiomers in surgical patients using a stereoselective analytical method. Br J 
Anaesth. 1993;70:666-671.
37.
Gould MS, King R, Greenwald S, et al. Psychopathology associated with suicidal ideation and attempts among 
children and adolescents. J Am Acad Child Adolesc Psychiatry. 1998;37(9):915–923.
38.
Grant IS, Nimmo WS, McNicol LR, Clements JA. Ketamine disposition in children and adults. Br J Anaesth. 
1983;55(11):1107-1111.
39.
Haas DA, Harper DG. Ketamine: a review of its pharmacologic properties and use in ambulatory anesthesia. 
Anesth Prog. 1992;39:61-68.
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Status: Approved, Date: 22 November 2020
40.
Hagelberg NM, Peltoniemi MA, Saari TI, et al. Clarithromycin, a potent inhibitor of CYP3A, greatly increases 
exposure to oral S-ketamine. Eur J Pain. 2010;14:625-629.
41.
Herd D, Anderson BJ. Ketamine disposition in children presenting for procedural sedation and analgesia in a 
children's emergency department. Paediatr Anaesth. 2007;17(7):622-629.
42.
Herd DW, Anderson BJ, Holford NH. Modeling the norketamine metabolite in children and the implications 
for analgesia. Paediatr Anaesth. 2007;17(9):831-840.
43.
Hijazi Y, Boulieu R. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of 
ketamine in human liver microsomes. Drug Metab Dispos. 2002;30:853-858.
44.
Hodges M, Salerno D, Erlien D. Bazett’s QT correction reviewed: evidence that a linear QT correction for 
heart rate is better. J Am Coll Cardiol. 1983;1:694.
45.
Howie SRC, Blood sample volumes in child health research: review of safe limits. Bull World Health Organ 
2011;89:46-53.
46.
Hurt PH, Ritchie EC. A case of ketamine dependence. Am J Psychiatry. 1994;151:779.
47.
International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use. ICH Harmonized Tripartite Guideline E14: Clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs. ICH 12 May 2005.
48.
Investigator’s Brochure, JNJ-54135419-AAC (esketamine hydrochloride). Edition 4, Janssen Research & 
Development, LLC (12 February 2015).
49.
Investigator’s Brochure, JNJ-54135419-AAC (esketamine hydrochloride). Edition 4, Addendum 1. Janssen 
Research & Development, LLC (21 June 2016).
50.
Investigator’s Brochure, JNJ-54135419-AAC (esketamine hydrochloride). Edition 4, Addendum 2. Janssen 
Research & Development, LLC (14 September 2016).
51.
Jain S, Carmody TJ, Trivedi M, et al. A psychometric evaluation of the CDRS and MADRS in assessing 
depressive symptoms in children. J Am Acad Child Adolesc Psychiatry. 2007;46(9):1204-1212.
52.
Jansen KL. Ketamine--can chronic use impair memory? Int J Addict. 1990;25:133-139.
53.
Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA. 2004;292:338-343.
54.
Kessler RC, Berglund P, Borges G, et al. Trends in suicide ideation, plans, gestures, and attempts in the United
States, 1990-1992 to 2001-2003. JAMA. 2005; 293(20):2487-2495.
55.
Ketalar® (ketamine hydrochloride injection, USP) [United States Prescribing Information]. JHP 
Pharmaceuticals, LLC; March 2012.
56.
Ketanest-S [Summary of Product Characteristics]. Ankeveen, Netherlands: Eurocept BV; 2011.
57.
Koffarnus MN, Hall A, Winger G. Individual differences in rhesus monkeys’ demand for drugs of abuse. 
Addict Biol. 2011;17:887-896.
58.
Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg. 1998;87:1186-1193.
59.
Kovacs M. Children’s Depression Inventory 2 (CDI 2) (2nd edition). J Psychoeducational Assessment. 
2012;30(3)304-308.
60.
Larkin GL, Beautrais AL. A preliminary naturalistic study of low-dose ketamine for depression and suicide 
ideation in the emergency department. Int J Neuropsychopharmacol. 2011;14 (8):1127-1131.
61.
Lewandowski RE, Acri,MC, Hoagwood KE, et al. Evidence for the management of adolescent depression. 
Pediatrics. 2013;132(4):e996-e100.
62.
Lewis-Esquerre JM, Colby SM, Tevyaw TO, Eaton CA, Kahler CW, Monti PM. Validation of the timeline 
follow-back in the assessment of adolescent smoking. Drug Alcohol Depend. 2005: 79(1); 33-43.
63.
Lim DK. Ketamine associated psychedelic effects and dependence. Singapore Med J. 2003;44:31-34.
64.
Lim YY, Prang K H, Cysique L, Pietrzak R H, Snyder PJ, Maruff P. A method for cross-cultural adaptation of 
a verbal memory assessment. Behavior Research Methods. 2009: 41(4); 1190-1200.
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Status: Approved, Date: 22 November 2020
65.
Lindenmayer JP, Czobor P, Alphs L, et al. InterSePT Study Group. The InterSePT Scale for Suicidal Thinking 
reliability and validity. Schizophr Res. 2003;63(2):161-170.
66.
Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M. Ketamine and norketamine plasma concentrations 
after i.v., nasal and rectal administration in children. Br J Anaesth. 1996;77(2):203-207.
67.
Mathew SJ, Shah A, Lapidus K, et al. Ketamine for treatment-resistant unipolar depression: current evidence. 
CNS Drugs. 2012;26 (3):189-204.
68.
Mathew SJ, Shah A, Lapidus K, et al. Ketamine for treatment-resistant unipolar depression: current evidence. 
CNS Drugs. 2012;26:189-204.
69.
Mayes TL, Bernstein IH, Haley CL, Kennard BD, Emslie GJ. Psychometric properties of the Children's 
Depression Rating Scale-Revised in adolescents. J Child Adolesc Psychopharmacol. 2010;20(6):513-516.
70.
Midazolam Injection USP. [United States Prescribing Information]. Sagent Pharmaceuticals; September, 2012.
71.
Midazolam Syrup. Available at http://www.drugs.com/pro/midazolam-syrup.html.
72.
Midazolam-ratiopharm® 2mg/ml Oral Solution: Full Prescribing Information. Ratiopharm GmbH; November, 
2015.
73.
Midazolam-ratiopharm® 2mg/ml Oral Solution: Summary of Product Characteristics. Ratiopharm GmbH; 
November 2015.
74.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 
1979;134:382-389.
75.
Montgomery SA. Clinically relevant effect sizes in depression. Eur Neuropsychopharmacology. 
1994;(4)283-284.
76.
Moore NN, Bostwick JM. Ketamine dependence in anesthesia providers. Psychosomatics. 1999;40:356-359.
77.
Moreton JE, Meisch RA, Stark L, Thompson T. Ketamine self-administration by rhesus monkey. J Pharmacol 
Exp Ther. 1977;203:303-309.
78.
Morgan CJ, Muetzelfeldt L, Curran HV. Ketamine use, cognition and psychological wellbeing: a comparison 
of frequent, infrequent and ex-users with polydrug and non-using controls. Addiction. 2009;104:77-87.
79.
Morgan CJA, Curran HV, Independent Scientific Committee on Drugs. Ketamine use: a review. Addiction. 
2012;107:27-38.
80.
Morgan CJA, Curran HV. Acute and chronic effects of ketamine upon human memory: a review. 
Psychopharmacology. 2006;188:408-424.
81.
Morgan CJA, Muetzelfeldt L, Curran HV. Consequences of chronic ketamine self-administration upon 
neurocognitive function and psychological wellbeing: a 1-year longitudinal study. Addiction. 
2010;105:121-133.
82.
Morrison R, Fedgchin M, Singh J, et al. Effect of intranasal esketamine on cognitive functioning in healthy 
participants: A randomized, double-blind, placebo-controlled study. Poster presented at: Society of Biological 
Psychiatry, May, 2016, Atlanta GA. 
83.
Muetzelfeldt L, Kamboj SK, Rees H, Taylor J, Morgan CJ, Curran HV. Journey through the K-hole: 
phenomenological aspects of ketamine use. Drug Alcohol Depend. 2008;95:219-229.
84.
Murrough J, Perez, A, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine 
infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250-256.
85.
Murrough JW, Iosifescu MD, Chang L, et al. Antidepressant Efficacy of Ketamine in Treatment-Resistant
Major Depression: A Two-Site Randomized Controlled Trial. Am J Psychiatry. 2013;170(10):1134-1142.
86.
Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine 
infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250-256.
87.
Murrough JW, Soleimani L, deWilde KE, et al. Ketamine for rapid reduction of suicide ideation: a randomized 
controlled trial. Psychol Med. 2015;45(16);3571-3580.
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Status: Approved, Date: 22 November 2020
88.
Murrough, JW, Burdick KE, Levitch CF, et al. Neurocognitive effects of ketamine and association with 
antidepressant response in individuals with treatment-resistant depression: A randomized controlled trial. 
Neuropsychopharmacology. 2015;40:1084–1090.
89.
Narendran R, Frankle WG, Keefe R, et al. Altered prefrontal dopaminergic function in chronic recreational 
ketamine users. Am J Psychiatry. 2005;162:2352-2359.
90.
National Institute for Health and Clinical Excellence (NICE) Depression in children and young people: 
identification and management. Clinical Guideline 28. National Collaborating Centre for Mental Health, 
London: March 2015. Available from: https://www.nice.org.uk/guidance/cg28. Accessed 5 December 2016.
91.
National Institute for Health and Clinical Excellence (NICE) Depression in adults: recognition and 
management. Clinical Guideline 90. National Collaborating Centre for Mental Health, London: October 2009. 
https://www.nice.org.uk/guidance/CG90. Accessed 16 September 2016.
92.
Nock MK, Borges G, Bromet EJ, et al. Cross-national prevalence and risk factors for suicidal ideation, plans, 
and attempts in the WHO World Mental Health Surveys. Br J Psychiatry. 2008;192(2):98-105.
93.
Nock MK, Green JG, Hwang I, et al. Prevalence, correlates, and treatment of lifetime suicidal behavior among 
adolescents: results from the National Comorbidity Survey Replication Adolescent Supplement. JAMA 
Psychiatry. 2013;70(3):300-310.
94.
Oye I, Paulsen O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-
aspartate receptors. J Pharmacol Exp Ther. 1992;260:1209-1213.
95.
Pal HR, Berry N, Kumar R, Ray R. Ketamine dependence. Anaesth Intensive Care. 2002;30:382-384.
96.
Pambianco DJ, Vargo JJ, Pruitt RE, Hardi R, Martin JF. Computer-assisted personalized sedation for upper 
endoscopy and colonoscopy: a comparative, multicenter randomized study. Gastrointest Endosc.
2011;73(4):765-772.
97.
Papakostas G, Fava M. Does the probability of receiving placebo influence clinical trial outcome? A meta-
regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol. 2008;19(1):34-40.
98.
Pharmacokinetic Report KET-PK-007. A randomized, open label, single center, single dose, cross-over study 
to determine the absolute bioavailability and the nasopharyngeal absorption of PMI-150 (intranasal ketamine) 
in healthy adult volunteers. Javelin Pharmaceuticals, Inc (31 October 2008).
99.
Portmann S, Kwan HY, Theurillat R, Schmitz A, Mevissen M, Thormann W. Enantioselective capillary 
electrophoresis for identification and characterization of human cytochrome P450 enzymes which metabolize 
ketamine and norketamine in vitro. J Chromatogr A. 2010;1217:7942-7948. 
100. Price RB, Iosifescu DV, Murrough JW, et al. Effects of ketamine on explicit and implicit suicidal cognition: a 
randomized controlled trial in treatment-resistant depression. Depress Anxiety. 2014;31(4):335-343.
101. Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit 
measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009; 66:522-526.
102. Prinstein M, Nock M, Simon V, Aikins JW, Cheah CSL, Spirito A. Longitudinal trajectories and predictors of 
adolescent suicidal ideation and attempts following inpatient hospitalization. J Consult Clin Psychol. 
2008;76(1):92-103.
103. Rasmussen KG, Lineberry TW, Galardy CW, et al. Serial infusions of low-dose ketamine for major 
depression. J Psychopharmacol. 2013; 27(5):444-450.
104. Reed MD, Rodarte A, Blumer JL, et al. The single-dose pharmacokinetics of midazolam and its primary 
metabolite in pediatric patients after oral and intravenous administration. J Clin Pharmacol. 
2001;41(12):1359-1369.
105. Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth. 
1989;36:186-197.
106. Rickels K, Garcia-Espana F, Mandos LA, Case GW. Physician Withdrawal Checklist (PWC-20). Journal of 
Clinical Psychopharmacology. 2008; 28(4):447-451.
107. Shafii M, Steltz-Lenarsky J, Derrick AM, et al. Comorbidity of mental disorders in the post-mortem diagnosis 
of completed suicide in children and adolescents. J Affect Disord. 1988;15(3):227–233.
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Status: Approved, Date: 22 November 2020
108. Sheehan DV, Sheehan KH, Shytle RD, et al. Reliability and validity of the mini international neuropsychiatric 
interview for children and adolescents (MINI-KID). J Clin Psychiatry. 2010;71(3):313-326.
109. Simon GE, Savarino J. Suicide attempts among patients starting depression treatment with medications or 
psychotherapy. Am J Pyschiatry. 2007;164:1029-1034.
110. Sinner B, Graf BM. Ketamine. In: Schüttler J, Schwilden H, eds. Modern Anesthetics: Handbook of 
Experimental Pharmacology. Berlin: Springer-Verlag; 2008;182:313-333.
111. Veal GJ. Blood volumes in pediatric clinical trials: a review of current regulations and guidance for research 
studies. Clin Invest (Lond) 2014;4(11):1005-1011.
112. Vesierra® [Summary of Product Characteristics]. Sandwich, Kent, United Kingdom: Pfizer Limited; 2014.
113. Vitiello B, Brent D, Greenhill LL, et al. Depressive symptoms and clinical status during the treatment of 
adolescent suicide attempters study (TASA). J Am Acad Child Adolesc Psychiatry 2009;48(10):997-1004.
114. Wasserman D, Rihmer Z, Rujescu D, et al. The European Psychiatric Association (EPA) guidance on suicide 
treatment and prevention. Eur Psychiatry. 2012;27:129-141.
115. Wieber J, Gugler R, Hengstmann JH, Dengler HJ. Pharmacokinetics of ketamine in man. Anaesthesist. 
1975;24:260-263.
116. Williams JB, Kobak KA. Development and reliability of a structured interview guide for the Montgomery 
Asberg Depression Rating Scale (SIGMA). Br J Psychiatry. 2008;192:52-58.
117. World Health Organization (WHO 2014). Preventing suicide: A global imperative. Available from: 
http://www.who.int/mental_health/suicide-prevention/world_report_2014/en/. Accessed 20 December 2015.
118. Yanagihara Y, Kariya S, Ohtani M, et al. Involvement of CYP2B6 in N-demethylation of ketamine in human 
liver microsomes. Drug Metab Dispos. 2001;29:887-890.
119. Yanagihara Y, Ohtani M, Kariya S, et al. Plasma concentration profiles of ketamine and norketamine after 
administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Disp. 
2003;24(1):37-43.
120. Young AM, Herling S, Winger GD, Woods JH. Comparison of discriminative and reinforcing effects of 
ketamine and related compounds in the rhesus monkey. NIDA Res Monogr. 1981;34:173-179.
121. Young AM, Woods JH. Maintenance of behavior by ketamine and related compounds in rhesus monkeys with 
different self-administration histories. J Pharmacol Exp Ther. 1981,218:720-727.
122. Young RC, Biggs JT, Ziegler VE, Meyer, DA. A rating scale for mania: reliability, validity and sensitivity. 
British Journal of Psychiatry (1978), 133, 429-435.
123. Zarate C, Brutsche NE, Ibrahim L, et al. Replication of ketamine’s antidepressant efficacy in bipolar 
depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71: 939-946.
124. Zisowski J, Krause A, Diingemanse J. Druge development for pediatric populations: Regulatory aspects. 
Available from: http://www.ncbi nlm.nih.gov/pmc/articles/PMC3967144/. Accessed 20 December 2016.
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Attachment 1: Prohibited/Permitted Concomitant Medications 
This list of medications is not all-inclusive; it is intended for general guidance.  Please contact the medical 
monitor for any questions regarding medications.
The pharmacotherapies listed below are permitted (Y), permitted with restrictions (Y*) with additional 
guidance or restrictions in the “Comments” column, 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 table below, the prohibited therapies listed in this table are prohibited 
from screening until at least 1 day (24 hours) after the last dose of study medication.
Drug Class
Episodic Use (as 
needed)
Continuous 
Use
Comments
ADHD medications
Atomoxetine
N
N
Amphetamines
N
Y
On dosing days, should be held until at least 2 
hours postdose.
If, for a given subject, it is not clinically 
appropriate to delay dosing of these medications 
for at least 2 hours after study medication is 
given, the investigator should contact the medical 
monitor to discuss an alternate plan regarding the 
timing of dosing of these medications, relative to 
study drug. 
Methylphenidate
N 
Y
Clonidine
Y
Y
Dose as usual
Guanfacine
Y
Y
Dose as usual
Aldehydes and Derivatives
Chloral hydrate
N
N
Anorexiants 
Phentermine
N
N
Phendimetrazine
N
N
Anticonvulsants
Y*
N
Use of anticonvulsants as adjunctive treatment 
for major depressive disorder (MDD) is 
prohibited. 
-
Note: Anticonvulsants used for indications 
other than seizures (eg valproate for 
migraine) may be permitted upon discussion 
with medical monitor 
Antidepressants 
(other than the three (3) 
specific antidepressants 
permitted as SoC per 
protocol)
N
N
Taper 
and/ 
or 
Washout 
from 
prohibited 
antidepressant(s) will be per clinician’s judgment 
on or before screening visit day. Antidepressants 
that are not permitted during the double-blind
period may be started on Day 25 following the last 
assessment (eg, 4-hour postdose assessment).
Note the exception of the use of Monoamine 
Oxidase Inhibitors (MAOIs see below).
Antidepressant medications used for indications 
other than depression (eg trazodone for sleep) 
may be permitted upon discussion with the 
medical monitor. Trazodone should not be used 
within 8 hours prior to the start of study drug 
administration.
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Drug Class
Episodic Use (as 
needed)
Continuous 
Use
Comments
Antidepressants
Monoamine Oxidase 
Inhibitors
N
N
Prohibited from within 2 weeks prior to study 
drug administration on Day 1, and throughout the 
study.
Antihistamines
First Generation
Y*
Y*
Should not be used within 8 hours prior to study 
drug administration.
Second Generation 
Non-sedating
Y
Y
Antihypertensive Agents
Ketanserin
N
N
Antipsychotics
Y
N
Low dose antipsychotic medications used for 
indications other than psychosis, bipolar disorder 
or antidepressant augmentation (eg, quetiapine for 
sleep) may be permitted upon discussion with the 
Medical Monitor; however, they may not be used 
prior to the completion of Day 2 assessments
If clinically necessary, antipsychotics may be 
started on Day 25 following the last assessment 
(eg, 4-hour postdose assessment).
Antivertigo Products 
Scopolamine
N
N
Antivirals
Amantadine
N
N
Anxiolytics and Sleep Aids
Benzodiazepines 
(at dosages equal to or 
less than the equivalent of 
6 mg/day lorazepam) 
Y*
Y*
Anxiolytics and Sleep Aids should not be used 
within 8 hours prior to study drug administration 
and/or cognitive testing. On Day 2, should not be 
used within 8 hours of assessments.
Hydroxyzine
Y*
Y*
Diphenhydramine
Y*
Y*
Zolpidem, Zaleplon, 
Eszopiclone, and 
Ramelteon)
Y*
Y*
Melatonin 
Y
Y
Cyamemazine 
(maximum of 
75 mg/day, in doses no 
larger than 50 mg at a time)
Y*
Y*
Cardiac Preparations
Metyrosine
N
N
Centrally Acting Alpha Agonists
Clonidine
Y
Y
Methyldopa
N
N
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Drug Class
Episodic Use (as 
needed)
Continuous 
Use
Comments
Corticosteroids 
Y*
Y*
Intermittent and continuous use of inhaled, 
intranasal, topical, and ophthalmic 
corticosteroids are permitted.
Continuous use of oral corticosteroids may be 
acceptable for maintenance of stable chronic 
disease states (eg, rheumatologic and respiratory 
conditions) but must be discussed with the 
medical monitor. Likewise, intermittent use of 
IM steroid must be discussed with the medical 
monitor.
Intermittent and continuous use of IV 
corticosteroid use is not permitted. 
Cough/cold 
Preparations/Nasal 
Solutions Containing 
Vasoconstrictors, 
Decongestants (Excluding 
Dextromethorphan) 
Y*
Y*
Intranasally-administered decongestants 
(vasoconstrictors) or saline solution / spray 
should not be used from 1 hour prior to study 
drug administration.
Pseudoephedrine-containing oral products should 
not be used within 12 hours prior to study drug 
administration.
Herbal Supplements (eg, 
Valerian, St. John’s Wort)
N
N
Mood Stabilizers
Lithium
N
N
Non-Opioid Antitussives 
Dextromethorphan
N
N
Opioids
Y*
Y*
Continuous use of oral opioids may be 
acceptable for maintenance of stable chronic 
disease states (eg, sickle cell disease, 
rheumatologic conditions) but must be discussed 
with the medical monitor.
Illicit use is prohibited if criteria for moderate or 
severe substance use disorder are met. 
Oral Anti-Acne Retinoids 
Isotretinoin
N
Y*
May only be used in consultation with the 
medical monitor.
Other Psychostimulants
Armodafanil
N
N
Modafinil
N
N
Rauwolfia Alkaloids 
Reserpine
N
N
Thyroid hormone 
supplement for treatment 
of thyroid condition only 
(not for depression)
N
Y
Abbreviations: ADHD: attention-deficit/hyperactivity disorder, IM: intramuscular, IV: intravenous, N: Prohibited,
Y: permitted, Y*: permitted with restrictions (in the case of “permitted with restrictions”, please refer to the 
column labeled “Comments” for additional guidance or restrictions).
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Attachment 2: Growth Charts: Stature-for-Age Percentiles for Use in Blood Pressure 
Assessments
(Boys, 2 to 20 Years)
To be used to determine individual blood pressure thresholds for eligibility, predose and 
postdose withdrawal criteria.
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Growth Charts: Stature-for-Age Percentiles for Use in Blood Pressure Assessments
(Girls, 2 to 20 Years)
To be used to determine individual blood pressure thresholds for eligibility, predose and 
postdose withdrawal criteria.
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Status: Approved, Date: 22 November 2020
Attachment 3: 95th Percentile Blood Pressure Levels For Sex by Age and Height
Blood Pressure Levels and Growth Charts for Boys to be used for Eligibility and Predose 
Instructions for Use
1. Use Attachment 2 to determine the height percentile. Subjects who fall below the 5th or above the 95th
percentile for their age, sex, and height should be evaluated using the parameters for the 5th or 95th
percentile.
2. Measure and record the blood pressure of the child or adolescent.
3. Use the table below to identify the 95th percentile for both systolic and diastolic blood pressure, by sex, 
according to age and height.
Boys’ 95th Percentile Blood Pressure Levels by Age and Height 
Systolic BP (mmHg)
Diastolic BP (mmHg)
Age 
(Year)
Percentile of Height 
Percentile of Height 
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
9
113
114
116
118
119
121
121
76
77
78
79
80
81
81
10
115
116
117
119
121
122
123
77
78
79
80
81
81
82
11
117
118
119
121
123
124
125
78
78
79
80
81
82
82
12
119
120
122
123
125
127
127
78
79
80
81
82
82
83
13
121
122
124
126
128
129
130
79
79
80
81
82
83
83
14
124
125
127
128
130
132
132
80
80
81
82
83
84
84
15
126
127
129
131
133
134
135
81
81
82
83
84
85
85
16
129
130
132
134
135
137
137
82
83
83
84
85
86
87
17
131
132
134
136
138
139
140
84
85
86
87
87
88
89
95th percentile for blood pressure level is 1.645 SD over the mean.
Adapted from “The fourth report on the diagnosis, evaluation and treatment of high blood pressure in 
children and adolescents. National Institutes of Health. May 2005.”
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
152
Status: Approved, Date: 22 November 2020
Blood Pressure Levels and Growth Charts for Girls to be used for Eligibility and Predose 
Instructions for Use
1. Use Attachment 2 to determine the height percentile. Subjects who fall below the 5th or above the 95th
percentile for their age, sex, and height should be evaluated using the parameters for the 5th or 95th
percentile. 
2. Measure and record the blood pressure of the child or adolescent.
3. Use the table below to identify the 95th percentile for both systolic and diastolic blood pressure, by sex, 
according to age and height.
Girls’ 95th Percentile Blood Pressure Levels by Age and Height
Systolic BP (mmHg)
Diastolic BP (mmHg)
Age 
(Year)
Percentile of Height 
Percentile of Height 
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
9
114
114
115
117
118
119
120
76
76
76
77
78
79
79
10
116
116
117
119
120
121
122
77
77
77
78
79
80
80
11
118
118
119
121
122
123
124
78
78
78
79
80
81
81
12
119
120
121
123
124
125
126
79
79
79
80
81
82
82
13
121
122
123
124
126
127
128
80
80
80
81
82
83
83
14
123
123
125
126
127
129
129
81
81
81
82
83
84
84
15
124
125
126
127
129
130
131
82
82
82
83
84
85
85
16
125
126
127
128
130
131
132
82
82
83
84
85
85
86
17
125
126
127
129
130
131
132
82
83
83
84
85
85
86
95th percentile is 1.645 SD over the mean.
Adapted from “The fourth report on the diagnosis, evaluation and treatment of high blood pressure in 
children and adolescents. National Institutes of Health. May 2005.”
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
153
Status: Approved, Date: 22 November 2020
Attachment 4: Postdose Blood Pressure: Withdrawal Criteria Levels for Sex by Age and Height
Postdose Blood Pressure: Withdrawal Criteria Levels for Boys
If, postdose, either the systolic or diastolic BP levels are equal to or greater than the age and height 
values in the table below, measure blood pressure again after at least five minutes of relaxation (ie, sitting 
or supine). If the values are still equal to or greater than the age and height values in the table, the 
subject should be withdrawn from the study and appropriate follow-up clinical care should be initiated.
Subjects who fall below the 5th or above the 95th percentile for their age, sex, and height should be 
evaluated using the parameters for the 5th or 95th percentile.
Blood pressure withdrawal values below 
represent the 99th percentile for age and 
height plus 1.28 SD over the mean
Blood pressure withdrawal values below 
represent the 99th percentile for age and 
height plus 1.28 SD over the mean
Systolic BP (mmHg)
Diastolic BP (mmHg)
Age 
(Year)
Percentile of Height 
Percentile of Height 
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
9
158
159
161
163
164
166
166
111
112
113
114
115
116
116
10
160
161
162
164
166
167
168
112
113
114
115
116
116
117
11
162
163
164
166
168
169
170
113
113
114
115
116
117
117
12
164
165
167
168
170
172
172
113
114
115
116
117
117
118
13
166
167
169
171
173
174
175
114
114
115
116
117
118
118
14
169
170
172
173
175
177
177
115
115
116
117
118
119
119
15
171
172
174
176
178
179
179
116
116
117
118
119
120
120
16
174
175
177
179
180
182
182
117
118
118
119
120
121
122
17
176
177
179
181
183
184
185
119
120
121
122
122
123
124
Adapted from “The fourth report on the diagnosis, evaluation and treatment of high blood pressure in 
children and adolescents. National Institutes of Health. May 2005.”
NCT03185819


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
154
Status: Approved, Date: 22 November 2020
Postdose Blood Pressure: Withdrawal Criteria Levels for Girls
If, postdose, either the systolic or diastolic BP levels are equal to or greater than the age and height 
values in the table below, measure blood pressure again after at least five minutes of relaxation (ie, sitting 
or supine). If the values are still equal to or greater than the age and height values in the table, the 
subject should be withdrawn from the study and appropriate follow-up clinical care should be initiated.
Subjects who fall below the 5th or above the 95th percentile for their age, sex, and height should be 
evaluated using the parameters for the 5th or 95th percentile.
Blood pressure withdrawal values below 
represent the 99th percentile for age and 
height plus 1.28 SD over the mean
Blood pressure withdrawal values below 
represent the 99th percentile for age and 
height plus 1.28 SD over the mean
Systolic BP (mmHg)
Diastolic BP (mmHg)
Age 
(Year)
Percentile of Height 
Percentile of Height 
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
9
159
159
160
162
163
164
165
111
111
111
112
113
114
114
10
161
161
162
164
165
166
167
112
112
112
113
114
115
115
11
163
163
165
166
167
168
169
113
113
113
114
115
116
116
12
164
165
166
168
169
170
171
114
114
114
115
116
117
117
13
166
167
168
169
171
172
173
115
115
115
116
117
118
118
14
168
168
170
171
172
174
174
116
116
116
117
118
119
119
15
169
170
171
172
174
175
176
117
117
117
118
119
120
120
16
170
171
172
173
175
176
177
117
117
118
119
120
120
121
17
170
171
172
174
175
176
178
117
118
118
119
120
120
121
Adapted from “The fourth report on the diagnosis, evaluation and treatment of high blood pressure in 
children and adolescents. National Institutes of Health. May 2005.”
NCT03185819


NCT03185819


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 16 July 2020
Janssen Research & Development *
COVID-19 Appendix
A Double-blind, Randomized, Psychoactive Placebo-controlled, Study to Evaluate the 
Efficacy and Safety of 3 Fixed Doses (28 mg, 56 mg and 84 mg) 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 Pediatric Subjects Assessed to 
be at Imminent Risk for Suicide
Protocol ESKETINSUI2002; Phase 2b
JNJ-54135419 (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 Pharmaceutica 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 study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2016-004422-42
Status:
Approved
Date:
16 July 2020
Prepared by:
Janssen Research & Development, LLC  
EDMS number:
EDMS-RIM-100193, 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS, INCLUDING 
COUNTRY-SPECIFIC VERSIONS, OF THE PROTOCOL
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.
NCT03185819


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
COVID-19 APPENDIX
Guidance on Study Conduct during the COVID-19 Pandemic
This Appendix applies to all current versions, including country-specific versions, of Protocol 
ESKETINSUI2002.
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by subjects and 
study site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for study-
related subject management in the event of COVID-related disruption to the conduct of the study. 
This guidance does not supersede any local or government requirements or the clinical judgment
of the investigator to protect the health and well-being of subjects/guardians and site staff. If, at 
any time, a subject’s safety is considered to be at risk, study participation will be discontinued, and 
study follow-up will be conducted according to the “Guidance Specific To This Protocol” section 
of this document.
Every effort should be made to adhere to protocol-specified assessments. Modifications addressed 
in the “Guidance Specific To This Protocol” section should be discussed with the subjects/ 
guardians, and documented as described in section entitled “Subject Agreement to Modified 
Study Procedures”.
Additional modifications to protocol-required assessments not addressed in this document may be 
permitted in response to the pandemic emergency after consultation between the subject/ guardian
and investigator, and with the agreement of the sponsor or designee. Missed assessments/visits 
will be captured as protocol deviations.
If re-consenting of subjects/guardians is required during the COVID-19 pandemic, remote
consenting by phone will be acceptable in accordance with local guidance for informed consent.
The sponsor will continue to monitor the conduct and progress of the clinical study in relation to 
the status of the COVID-19 pandemic, and any changes will be communicated to the sites and to 
the health authorities according to local guidance. Modifications made to the study conduct as a 
result of the COVID-19 pandemic will be summarized in the clinical study report.
NCT03185819


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
GUIDANCE SPECIFIC TO THIS PROTOCOL
These provisions are meant to minimize the risk of exposure to COVID-19 and to safely maintain 
subject study visits while site capabilities and subject / guardian travel limitations are compromised 
by COVID-19-related restrictions. As restrictions are lifted, sites should revert to original protocol 
conduct as soon as feasible.
The safety of study subjects and site staff is priority. Each subject’s circumstances and potential 
restrictions should be evaluated by the Principal Investigator. If there is doubt regarding the 
risk/benefit assessment of the participant in relation to these COVID-related modifications, the 
investigator should contact the Sponsor’s Medical Monitor for discussion and / or discontinue the 
participant from the study.
All modifications described in this Appendix should be instituted in accordance with applicable 
(including local) laws, regulations, guidelines, and procedures.
SCREENING AND ENROLLMENT:

Potential study candidates who are currently known to be positive for the COVID-19 virus 
will not be screened for the study.

Potential study candidates who have any symptoms related to the COVID -19 virus or who 
are suspected to be infected with the COVID -19 virus will not be screened for the study.

Potential study candidates who have had the COVID-19 virus and have fully recovered may 
be considered for enrollment following a discussion with the Sponsor’s Medical Monitor.

Prior to enrollment, site should assess current capability for subject / guardian to complete in-
person dosing visits (Double-blind Treatment Phase).

If known travel / site restrictions constrain or prohibit the completion of the Double-blind 
Treatment Phase, the potential candidate should not be screened or enrolled.
DOUBLE-BLIND TREATMENT PHASE:

If needed for COVID-19 mitigation, an enrolled subject may remain as inpatient for the entire 
25 days of the Double-blind Treatment Phase provided that:

Subject and guardian agree

Principal investigator agrees it is in the best interest of the subject

Inpatient bed is available

If subject has been discharged and is an outpatient during the Double-blind Treatment Phase, 
and subject/guardian is restricted from coming back for dosing visits, OR, if the site cannot 
conduct a dosing visit, site should consult the Sponsor’s Medical Monitor to discuss. General 
guidelines are as follows:

Assess risk/benefit of subject remaining in the study
NCT03185819


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4

If >14 days elapse since last dose, subject should be discontinued from the study

If ≤14 days elapse since last dose, dosing should resume. If possible, all 8 doses should 
be administered.

If a dosing visit is missed, the site should call the subject and remotely conduct the following
assessments as applicable and feasible for that Visit Day:

Suicide Ideation and Behavior Assessment Tool (SIBAT), including both patient modules 
and clinician modules

Children’s Depression Rating Scale-Revised (CDRS-R)
/ Montgomery-Asberg 
Depression Rating Scale (MADRS)

Physician Withdrawal Checklist (PWC-20)

International Shopping List Task (ISLT) (from the Cogstate Battery)

Children’s Depression Inventory (CDI)

Evaluation of adverse events (AEs) and concomitant medications
These assessments should be placed in an “Unscheduled Assessment” folder.

If a dosing visit is missed, the Study Visit upon return in the Double-blind treatment phase 
should be resumed as the next visit in the schedule. For example: if Visit Day 8 and Day 11 
are missed, , Day 8 would be filled out when the subject returns, and dosing for the remainder
of the 8 total doses in the Double-blind Treatment Phase would be administered following the 
twice-weekly dosing schedule.

Outpatient standard of care psychological therapy should be initiated/continued per protocol. 
It is recognized that during this time, standard of care psychological therapy sessions may be 
constrained or interrupted. Continued psychological therapy remotely via telephone is 
acceptable/encouraged in this case.
POST-TREATMENT FOLLOW-UP PHASE
The table below provides information on modifications for remote performance of assessments
during the Post-treatment Follow-up Phase.
NCT03185819


NCT03185819


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
VISIT DAY 200
To accommodate potential restrictions, the window for the Day 200 protocol visit may be extended 
by an addition of +7 days. The current protocol window is +/-7 days; this effectively allows for a
– 7/+14 day visit. If neither an in-person or remote Day 200 visit are feasible within the extended 
window of +14 days of Day 200 visit, the subject should be discontinued.
GENERAL:
COVID-19 Related:

If a subject contracts the virus during the Screening or Double-blind Treatment Phase:

PI should contact the Sponsor’s Medical Monitor to discuss the best course of action
based on a risk/benefit assessment.

If a subject contracts the virus during the Post-Treatment Follow-up Phase:

PI should contact the Sponsor’s Medical Monitor; if feasible, the subject, may complete 
assessments remotely until recovered.
Additional Assessment Information:

Clinical lab tests that cannot be performed at the site may be performed locally, for safety, per 
Principal Investigator judgment following a risk/benefit assessment which should be recorded 
in source documentation.

ECGs and other physical assessments (eg, PE, body weight, vital signs) that cannot be 
performed in person at the site will be recorded as ‘missing’ and documented per conventions.

At each contact, subjects (and guardians as necessary) will be interviewed to collect AEs and 
concomitant medication data. Subjects will be questioned regarding their general health status.
Early Withdrawal Information:

Discontinuation of study treatment and withdrawal from the study due to COVID-19 AEs/ 
serious adverse events (SAEs) should be documented as discontinuation due to “Adverse 
Event”. The specific COVID-19-related AE should then be chosen from the corresponding AE 
logline. If a subject dies due to COVID-19, “death” should be selected as the reason for 
discontinuation and the cause of death should be specified as COVID-19-related. 
Discontinuations for other COVID-19 reasons should be documented with the prefix “COVID-
19-related” in the CRF.

Early Withdrawal visit assessments should be conducted as feasible, remotely or in-person.
As a reminder, the investigator must ensure the subject is appropriately transitioned and/or 
followed for any additional care required when a subject discontinues participation in the study for 
any reason.
NCT03185819


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
7
Subject Agreement to Modified Study Procedures
Specific guidance provided in this Appendix in response to the global COVID-19 pandemic may 
influence subject’s and legal guardian(s)’s willingness to continue participating in the study. 
Below is general guidance for an oral consent. Documentation of this should be made within the 
subject’s source documentation (one-time per subject).
General guidance for oral consent is listed below:

Who assented / consented: Name of the study participant and if applicable, the legally 
authorized representative(s).

When they assented / consented: The time and date the conversation took place.

What they were told at the time: What changes or new aspects of the study were agreed 
due to the COVID-19 pandemic (example script: To simplify study participation during 
the COVID-19 pandemic, some of your previously completed and upcoming scheduled 
study visits may be conducted by telephone instead of going into the study doctor’s office. 
Your study doctor will explain which visits you can do by phone and which study visits 
require you to come into the office.).

How they consented: The consent result (e.g., all subject / legal authorized representative 
questions were reviewed and answered, they understand and agree to the modifications), 
the method used (eg, telephone).

Who captured the oral / verbal consent: name and signature of the Investigator or staff 
member who captured the assent / consent from the subject and legally authorized 
representative(s).

Impartial Witness (if applicable): Who was present as impartial witness and how the 
impartial witness was selected.
Sites should refer to their continuity plans and local HA/IRB/EC guidance for appropriate methods 
of documenting evidence for verbal and/or other alternate consent methods. Additionally, 
acceptability of alternate consenting methods will vary by country based upon local/country 
guidance, laws, and regulations, and take precedence over the above general guidance.
Statistical Analysis
The sponsor will evaluate the totality of the impact of COVID-19 on collection of key study data. 
Additional data analyses, if any, will be outlined in the statistical analysis plan.
NCT03185819


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol ESKETINSUI2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
8
Attachment 1:
Cogstate COVID-19 Remote ISLT Administration Guidelines for ESKETINSUI2002
NCT03185819


NCT03185819


NCT03185819

SAP_001.pdf: 
1
Approved, Date: 19 September 2022
Janssen Research & Development *
Statistical Analysis Plan
A Double-blind, Randomized, Psychoactive Placebo-controlled, Study to Evaluate the 
Efficacy and Safety of 3 Fixed Doses (28 mg, 56 mg and 84 mg) 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 Pediatric Subjects Assessed to 
be at Imminent Risk for Suicide
Protocol ESKETINSUI2002; Phase 2b
JNJ54135419 (esketamine)
Status:
Approved
Date:
19 September 2022
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-ERI-147066589
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.
NCT03185819


JNJ54135419  (esketamine)
Statistical Analysis Plan ESKETINSUI2002
2
Approved, Date: 19 September 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 4
LIST OF IN-TEXT FIGURES ........................................................................................................................ 4
CHANGES HISTORY ................................................................................................................................... 5
ABBREVIATIONS ........................................................................................................................................ 6
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Trial Objectives ................................................................................................................................ 7
1.2.
Trial Design ...................................................................................................................................... 9
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 11
1.4.
Sample Size Justification ............................................................................................................... 11
1.5.
Randomization and Blinding .......................................................................................................... 11
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 12
2.1.
Pooling Algorithm for Analysis Centers.......................................................................................... 12
2.2.
Analysis Phases............................................................................................................................. 12
2.2.1.
Analysis Phase Start and End Dates.......................................................................................... 12
2.2.2.
Study Reference Start and End Dates ....................................................................................... 13
2.2.3.
Study Day and Relative Day....................................................................................................... 13
2.3.
Baseline and End Point.................................................................................................................. 13
2.4.
Visit Windows................................................................................................................................. 13
2.5.
Analysis Sets.................................................................................................................................. 23
2.5.1.
All Randomized Analysis Set...................................................................................................... 23
2.5.2.
Full Efficacy Analysis Set............................................................................................................ 23
2.5.3.
Safety Analysis Set..................................................................................................................... 23
2.5.4.
Follow-up Analysis Set ............................................................................................................... 23
2.6.
Analysis for 9 - < 12 Year Old Cohort ............................................................................................ 24
2.7.
Definition of Subgroups.................................................................................................................. 24
2.8.
Incomplete/Missing Dates for Adverse Events .............................................................................. 24
3.
DATA MONITORING COMMITTEE REVIEW................................................................................... 25
4.
SUBJECT INFORMATION................................................................................................................ 26
4.1.
Demographics and Baseline Characteristics ................................................................................. 26
4.2.
Disposition Information................................................................................................................... 27
4.3.
Extent of Exposure......................................................................................................................... 27
4.4.
Protocol Deviations ........................................................................................................................ 28
4.5.
Prior and Concomitant Medications ............................................................................................... 28
5.
EFFICACY ......................................................................................................................................... 28
5.1.
Analysis Specifications................................................................................................................... 29
5.1.1.
Level of Significance................................................................................................................... 29
5.1.2.
Data Handling Rules................................................................................................................... 30
5.1.3.
Imputation Methods for Missing Items........................................................................................ 30
5.1.4.
Change from Baseline ................................................................................................................ 30
5.2.
Primary Efficacy Endpoint.............................................................................................................. 30
5.2.1.
Definition..................................................................................................................................... 30
5.2.2.
Estimand..................................................................................................................................... 31
5.2.3.
Analysis Methods........................................................................................................................ 31
5.3.
Other Efficacy Endpoints................................................................................................................ 33
5.3.1.
Dose Response .......................................................................................................................... 33
5.3.1.1.
Definition.................................................................................................................................. 33
NCT03185819


JNJ54135419  (esketamine)
Statistical Analysis Plan ESKETINSUI2002
3
Approved, Date: 19 September 2022
5.3.1.2.
Analysis Methods .................................................................................................................... 33
5.3.2.
Remission of MDD...................................................................................................................... 38
5.3.2.1.
Definition.................................................................................................................................. 38
5.3.2.2.
Analysis Methods .................................................................................................................... 38
5.3.3.
Responder .................................................................................................................................. 38
5.3.3.1.
Definition.................................................................................................................................. 38
5.3.3.2.
Analysis Methods .................................................................................................................... 38
5.3.4.
MADRS....................................................................................................................................... 38
5.3.4.1.
Definition.................................................................................................................................. 38
5.3.4.2.
Analysis Methods .................................................................................................................... 39
5.3.4.3.
Remission of MDD................................................................................................................... 40
5.3.4.4.
Responder ............................................................................................................................... 40
5.3.4.5.
Dose Response ....................................................................................................................... 40
5.3.5.
CGI-SS-R.................................................................................................................................... 40
5.3.5.1.
Definition.................................................................................................................................. 40
5.3.5.2.
Analysis Methods .................................................................................................................... 40
5.3.6.
Resolution of Suicidality.............................................................................................................. 41
5.3.6.1.
Definition.................................................................................................................................. 41
5.3.6.2.
Analysis Methods .................................................................................................................... 41
5.3.7.
CGI-SR-I ..................................................................................................................................... 41
5.3.7.1.
Definition.................................................................................................................................. 41
5.3.7.2.
Analysis Methods .................................................................................................................... 41
5.3.8.
SIBAT – Module 3 (My Current Thinking), Module 5 (My Risk) Question 3, Module 7 
(Global Clinical Impression) FoST, CGI-SR-LT, and Module 8 (Clinical Judgment of 
Optimal Suicide Management) ................................................................................................... 42
5.3.8.1.
Definition.................................................................................................................................. 42
5.3.8.2.
Analysis Methods .................................................................................................................... 42
5.3.9.
CDI 2:SR[S] ................................................................................................................................ 42
5.3.9.1.
Definition.................................................................................................................................. 42
5.3.9.2.
Analysis Methods .................................................................................................................... 43
6.
SAFETY............................................................................................................................................. 43
6.1.
Adverse Events .............................................................................................................................. 43
6.2.
Clinical Laboratory Tests................................................................................................................ 45
6.3.
Vital Signs, Weight, and BMI ......................................................................................................... 45
6.4.
Nasal Examination and Nasal Symptom Questionnaire................................................................ 46
6.5.
Electrocardiogram.......................................................................................................................... 47
6.6.
Other Safety Parameters ............................................................................................................... 48
6.6.1.
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) .......................................... 48
6.6.2.
Clinician Administered Dissociative States Scale (CADSS)....................................................... 48
6.6.3.
Columbia Classification Algorithm for Suicide Assessment (C-CASA)...................................... 49
6.6.4.
Brief Psychiatric Rating Scale, Positive Symptom Subscale (BPRS+) ...................................... 50
6.6.5.
Young Mania Rating Scale (YMRS) ........................................................................................... 51
6.6.6.
Physician Withdrawal Checklist (PWC-20)................................................................................. 51
6.6.7.
Columbia Suicide Severity Rating Scale (C-SSRS) (9 -< 12 Year Old Chort) ........................... 51
6.6.8.
Cogstate® Computerized Cognitive Battery................................................................................ 52
6.6.9.
Timeline Follow-Back (TLFB) ..................................................................................................... 52
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 52
REFERENCES............................................................................................................................................ 53
ATTACHMENTS......................................................................................................................................... 54
Attachment 1:
Scoring Guide for CDI 2:SR[S]................................................................................... 54
Attachment 2:
Criteria of Markedly Abnormal Laboratory Values ..................................................... 58
Attachment 3:
SIBAT Module 3 Scoring ............................................................................................ 59
Attachment 4:
SIBAT Mapping to the C-CASA 2012 Plus................................................................. 61
Attachment 5:
SAP for Cognition Tests ............................................................................................. 67
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LIST OF IN-TEXT TABLES
Table 1:
Analysis Visits ........................................................................................................................... 14
Table 2:
Demographic Variables and Baseline Characteristics.............................................................. 26
Table 3:
Psychiatric History at Baseline Variables ................................................................................. 26
Table 3a:
Psychiatric History at Baseline Variables for 9- < 12 Year Old ................................................ 27
Table 4:
Efficacy Variables ..................................................................................................................... 28
Table 5:
Criteria for Treatment-emergent Abnormal Vital Signs............................................................. 46
Table 6:
Limits for RR, PR, QRS and QTc Interval Abnormality ............................................................ 47
Table 7:
Criteria for Abnormal QTc Values and Changes From Baseline.............................................. 47
Table 8:
CADSS Scoring Method ........................................................................................................... 49
LIST OF IN-TEXT FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 10
Figure 2:
Dose Response Curves............................................................................................................ 34
Figure 3:
Candidate Models for Dose Response Relationship................................................................ 37
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CHANGES HISTORY
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ABBREVIATIONS
AAP
American Academy of Pediatrics
AD
Antidepressant
ADHD
Attention-deficit hyperactivity disorder
AE
Adverse event
AIC
Akaike Information Criterion
BP
Blood pressure
BPRS+
Brief Psychiatric Rating Scale, positive symptom subscale 
CADSS
Clinician-Administered Dissociative States Scale 
CDI 2:SR
Children’s Depression Inventory 2 Self-Report
CDI 2:SR[S]
Children’s Depression Inventory 2: Self-Report (short version)
CDRS-R
Children’s Depression Rating Scale-Revised
CGI-SS
Clinical Global Impression Severity of Suicidality
CGI-SR-I
Clinical Global Impression of Imminent Suicide Risk
CGI-SS-R
Clinical Global Impression of Severity of Suicidality, revised version 
C-SSRS
Columbia-Suicide Severity Rating Scale
EU
European Union
DB
Double-blind
DBP
Diastolic blood pressure
DSM-5
Diagnostic and Statistical Manual of Mental Disorders (5th edition)
ECG
Electrocardiogram
ER
Emergency room
FDA
Food and Drug Administration
FU
Follow-up
GCP
Good Clinical Practice
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
LOCF
Last observation carried forward
MADRS
Montgomery-Asberg Depression Rating Scale 
MDD
Major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MLE
Maximum likelihood estimates
MMRM
Mixed-effects model using repeated measures
MOAA/S
Modified Observer's Assessment of Alertness/Sedation 
PWC-20
Physician Withdrawal Checklist 
PK
Pharmacokinetic(s)
PCP
Phencyclidine
SAE
Serious AE
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Standard deviation
SE
Standard error
SIBAT
Suicide Ideation and Behavior Assessment Tool 
SoC
Standard of care
TEAE
Treatment-emergent adverse events
TEMA
Treatment emergent markedly abnormal
TLFB
Timeline Follow-Back 
US
United States
YMRS
Young Mania Rating Scale 
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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 ESKETINSUI2002.
An analysis of efficacy and safety will be performed after the last subject completes the 25-day 
double-blind treatment Period (Day 25). This analysis will enable selection of a dose for the 
planned Phase 3 trial, facilitating Phase 3 trial design and preparation.Additional efficacy and 
safety analysis will also be performed after the last subject completes 8-week post-treatment 
follow-up phase (Day 81) and 6-month post-treatment follow-up phase (Day 200).
1.1.
Trial Objectives
Primary Objective
The primary objective is to assess the efficacy of a single (first) dose of 3 fixed doses of intranasal 
esketamine (28 mg, 56 mg, and 84 mg) compared with psychoactive placebo (oral midazolam) in 
rapidly reducing the symptoms of MDD, including suicidal ideation, in subjects 12 to <18 years 
of age who are assessed to be at imminent risk for suicide. Efficacy will be assessed by the change 
from baseline in Children’s Depression Rating Scale, Revised (CDRS-R) total score at 24 hours 
post first dose (Day 2).
Other Objectives
The other objectives are: 

To evaluate the dose response of intranasal esketamine compared with psychoactive placebo 
in reducing the symptoms of MDD, including suicidal ideation, as assessed by the change 
from baseline in CDRS-R total score at 24 hours post first dose (Day 2) and at Day 25.

To evaluate the efficacy of single and repeated doses of intranasal esketamine compared with 
psychoactive placebo in reducing symptoms of suicidal ideation, as assessed by the Clinical 
Global Impression of Severity of Suicidality, revised version (CGI-SS-R) from the Suicide 
Ideation and Behavior Assessment Tool (SIBAT) 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 single and repeated doses of intranasal esketamine compared with 
psychoactive placebo in reducing symptoms of MDD as assessed by the following:
-
CDRS-R total score at 4 hours post first dose, through the end of the double-blind 
Treatment phase (Day 25), and during the 6-month post-treatment follow-up phase.
-
MADRS total score at 4 hours and 24 hours post first dose, through the end of the double-
blind Treatment phase (Day 25), and during the 6-month post-treatment follow-up phase.
-
Children’s Depression Inventory 2: Self-Report (Short) version (CDI 2:SR[S])TM score at 
24 hours post first dose and through the end of the double-blind treatment phase (Day 25).

To evaluate the efficacy of single and repeated doses of intranasal esketamine compared with 
psychoactive placebo in reducing symptoms of suicidal ideation, as assessed by the Clinical 
Global Impression – Imminent Suicide Risk (CGI-SR-I) from the SIBAT at 4 hours and 
24 hours post first dose and through the end of the double-blind treatment phase (Day 25).
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
To evaluate the efficacy of single and repeated doses of intranasal esketamine compared with 
psychoactive placebo in reducing suicidal thoughts, as assessed by the following:

Change from baseline in SIBAT Module 3 (My Current Thinking) and Module 5 (My 
Risk) Question 3 (patient-reported frequency of suicidal thinking) through the end of the 
double-blind Treatment phase (Day 25) and during the 6-month post-treatment follow-up 
phase. 

To characterize the pharmacokinetics of intranasal
esketamine and its metabolite 
noresketamine.

To evaluate the safety and tolerability of intranasal esketamine through the end of the double-
blind treatment phase (Day 25) using the following assessments:

Effects on suicidal ideation and behavior using the SIBAT 

Effects on dissociative symptoms using the Clinician-Administered Dissociative States 
Scale (CADSS)

Occurrence of psychosis-like side effects using a 4-item positive symptom subscale 
(consisting of: suspiciousness, hallucinations, unusual thought content, and conceptual 
disorganization) of the Brief Psychiatric Rating Scale, positive symptom subscale 
(BPRS+)

Occurrence of potential treatment-emergent symptoms of mania using the Young Mania 
Rating Scale (YMRS)

Effects on cognitive function as measured by the Cogstate® computerized cognitive 
battery

Effect on sedation using the Modified Observer's Assessment of Alertness/Sedation 
(MOAA/S) scale

Local nasal tolerability, using targeted nasal examinations coupled with a nasal symptom 
questionnaire

To evaluate the safety and tolerability of intranasal esketamine at specified times through the 
initial 25-day double-blind treatment period (Day 25), the 8-week post-treatment follow-up 
(Day 81) and 6-month post-treatment follow-up, with special attention given to the following 
assessments:

Effects on suicidal ideation and behavior using the SIBAT

Effects on cognitive function as measured by the Cogstatecomputerized cognitive battery

To evaluate potential withdrawal symptoms during the post-treatment follow-up as measured 
by the Physician Withdrawal Checklist (PWC-20) on Days 25, 28, 32, 35 and 39.

To evaluate the potential for ketamine or PCP abuse during the follow-up as measured by the 
Timeline Follow-Back (TLFB).

To evaluate whether pretreatment concentrations of MDD-related biomarkers (eg, 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.
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
To explore the change in MDD-related biomarkers in relation to clinical response or non-
response to intranasal esketamine.
1.2.
Trial Design
This is a randomized, double-blind, double-dummy, psychoactive placebo-controlled, multicenter 
trial with 45 anticipated global sites. A target of 145 pediatric subjects, 12 to <18 years of age, will 
be enrolled in this study and randomized in a 1:1:1:2 ratio to one of 3 doses of intranasal 
esketamine (28, 56 or 84 mg) or a psychoactive placebo (oral midazolam 0.125 mg/kg), with 
approximately 29 subjects assigned to each dose of intranasal esketamine and approximately 58 
subjects assigned to psychoactive placebo. All eligible subjects will have a diagnosis of MDD, and 
will have presented to an emergency room (ER) or other permitted setting and been assessed to be 
at imminent risk for suicide. Given the vulnerability of the population, this study will be conducted 
in the context of standard of care treatment. This includes initial hospitalization in an inpatient 
psychiatric unit or other permitted setting for a recommended duration of 5 days counted from 
randomization, with shorter or longer hospitalizations permitted if clinically warranted per local 
standard of care; initiation or optimization of allowed antidepressant medication therapy, 
participation in a specific psychological intervention (individual cognitive behavioral therapy 
[CBT]), interpersonal therapy, family therapy or psychodynamic psychotherapy), and close 
outpatient follow-up.
There is only 1 approved antidepressant for the treatment of MDD in children and adolescents in 
both the United States (US) and European Union (EU): fluoxetine; however, if treatment with 
fluoxetine is unsuccessful or is not tolerated because of side effects, guidelines recommend 
treatment with escitalopram and sertraline. Escitalopram (the S-enantiomer of citalopram) is also 
approved for use in adolescents in the US. Therefore, this multi-national study will permit the use 
of fluoxetine, escitalopram or sertraline as the standard of care antidepressants.
The study will be conducted in 4 phases: a screening evaluation performed within 48 hours prior 
to Day 1 intranasal dose (if possible, screening should occur within 24 hours prior to the Day 1 
intranasal dose); a 25-day double-blind treatment phase (Days 1 - 25), during which study drug 
will be administered 2 times per week for 4 weeks on Days 1, 4, 8, 11, 15, 18, 22, and 25; an 8 
week initial post-treatment phase (Days 25 - 81); and a subsequent phase to complete a full 6-
month post-treatment follow-up (Days 81 - 200). During post-treatment follow-up phases, no study 
drug will be administered. The duration of the subject’s participation will be approximately 29 
weeks. 
An Independent Data Monitoring Committee will be commissioned for this study.
A diagram of the study design is provided in Figure 1.
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Figure 1:
Schematic Overview of the Study
Abbreviations: AD = antidepressant; SoC = standard of care.
a 
It is recommended that standard of care antidepressant treatment will be initiated or optimized on Day 1, 
however, to reflect differing standard of care antidepressant treatment, antidepressant therapy may be started 
within 7 days after the first dose of study medication.
b 
If possible, screening should be performed within 24 hours prior to Day 1 intranasal dose.
c 
Hospital discharge before 5 days (from randomization) must be discussed with 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.
d 
Remote contact.
An additional age cohort is added in Protocol Amendment 4/USA-2. It is planned in the United 
States (US) to explore the efficacy and safety of 56 mg dose of intranasal esketamine in addition 
to comprehensive standard care for the rapid reduction of the symptoms of major depressive 
disorder, including suicidal ideation, in pediatric subjects aged 9 - < 12 years assessed to be at 
imminent risk for suicide. Subjects aged 9 - <12 years old will be enrolled in this study and 
randomized in a 1:1 ratio to a blinded treatment of 56-mg dose of intranasal esketamine or a 
psychoactive placebo (oral midazolam 0.125 mg/kg). Further details please refer the Protocol 
Amendment 4/USA-2.
No sample size calculation is conducted for this cohort. The number of subjects enrolled in 9 -
<12 years old cohort will not impact the sample size from the main protocol (12 -< 18 year old 
subjects).  There will be no hypothesis testing for the 9 - <12 year old cohort. 
Data collected from this cohort will be presented sperately and for descriptive purposes only.
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1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis of this study is that, in addition to standard of care, intranasal esketamine 
is superior to psychoactive placebo in rapidly reducing the symptoms of MDD, including suicidal 
ideation, as assessed by the change from baseline in CDRS-R at 24 hours post first dose in subjects 
12 to <18 years of age who are assessed to be at imminent risk for suicide.
1.4.
Sample Size Justification
The sample size for this study was calculated assuming an effect size of 0.65 between any dose of 
esketamine and psychoactive placebo for the change from baseline at 24 hours postdose for the 
CDRS-R total score and a 2-sided significance level of 0.05. A total of 145 subjects will be 
randomized in this study. Using a 1:1:1:2 randomization ratio (esketamine 28 mg: esketamine 
56 mg: esketamine 84 mg: psychoactive placebo), approximately 58 subjects will need to be 
randomized to psychoactive placebo and 29 subjects will need to be randomized to each 
esketamine treatment group to achieve 94% power for the comparison of the pooled doses of 
esketamine 56 mg and esketamine 84 mg versus psychoactive placebo and 92% power for at least 
one of esketamine dose (56-mg and 84-mg) versus psychoactive placebo. The effect size of 0.65 
is based on results from study ESKETINSUI2001 (mean difference between treatment groups of 
-7.2 and a pooled SD of 11.02) for MADRS total score.2
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. Randomization will be stratified by study center. 
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, a psychoactive placebo, midazolam, 
will be used. Midazolam has been used as a psychoactive placebo in previous studies of ketamine5
because of its similar onset of action and side effect profile. 
The effect of a placebo response is of particular concern in clinical trials of MDD6. Because a 
lower likelihood of randomization to placebo has been shown to be associated with placebo 
response6, a treatment allocation of 1:1:1:2 for 28 mg: 56 mg: 84 mg: psychoactive placebo is 
being used to minimize expectancy bias and to mitigate placebo response.
A double-dummy design will be used in order to preserve the blind since the active study drug 
(intranasal esketamine) and the psychoactive placebo (oral midazolam) are administered via 
different routes. Therefore, 2 matching placebo formulations, intranasal and oral, will be included 
in the treatment regimen. In order to maintain the blind, subjects randomized to intranasal 
esketamine will also receive an oral placebo, and subjects randomized to oral midazolam will also 
be administered an intranasal placebo. 
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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, small study centers with fewer than 4 subjects in Full 
Efficacy Analysis Set will be combined for the purpose of analysis within each region (North 
America, Europe, and South America). 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). The 
follow-up phase is a full 6-month post-treatment phase, including the 8-week initial post-treatment 
follow-up phase till Day 81 and extended post-treatment follow-up phase (Day 81 – Day 200). 
Each analysis phase has its own analysis reference start and end dates.
2.2.1.
Analysis Phase Start and End Dates
Double-Blind Phase
The double-blind (referred to as, ‘DB’) start date is the date of the first dose of double-blind 
medication. The DB end date is the date of the last visit (excluding remote contact visits) in the 
double-blind phase, or the date of the early withdrawal for patients who discontinued from the
double-blind phase. 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 follow-up (referred to as, ‘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 adverse event data collected 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 of the early withdraw for subjects who discontinue during 
the follow-up phase. For the subjects who discontinued between Day 25 and Day 28 remote contact 
without an early withdrawal visit in the follow-up phase, end date is the date of the Day 28 remote 
contact. Otherwise, it is the maximum of the last follow-up visit date and the end of trial date.
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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 maximum of the date of last visit 
and trial completion/discontinuation.
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. A minus (-) sign indicates days prior to the start of study or prior to the start of the 
analysis phase.
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 and is denoted as ‘Baseline (DB)’. Baseline is defined for 
each parameter/assessment.
For each variable measured over time, the ‘End Point (DB)’ is defined as the last post-baseline 
value assessed during the double-blind phase, and the ‘End Point (F/U)’ is defined as the final 
value assessed during the follow-up 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).
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. If a visit window has 
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no scheduled visits but does have unscheduled visits, then the unscheduled visit closest to the 
scheduled visit will be 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).
Table 1:
Analysis Visits
Parameter
Analysis
Phase
Scheduled
Day
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Time Pointa
(Day)
CDRS-Rb,
MADRSb
DB
1
Baseline (DB)
≤ 1 / predose
1
Day 1 (DB): 4H
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
Day 25 (DB): 4H
DB final 
visit
End Point (DB)
Day 1 (DB): 4H -
end of DB
F/U
28
Day 28 (F/U)
Day 1 (F/U) - 4
3
32
Day 32 (F/U)
5 - 8
7
35
Day 35 (F/U)
9 - 11
10
39
Day 39 (F/U)
12 - 17
14
46
Day 46 (F/U)
18 - 24
21
53
Day 53 (F/U)
25 - 34
28
67
Day 67 (F/U)
35 - 48
42
81
Day 81 (F/U)
49 - 69
56
109
Day 109 (F/U)
70 - 97
84
137
Day 137 (F/U)
98 - 125
112
165
Day 165 (F/U)
126 - 157
140
200
Day 200 (F/U)
158 - end of F/U
175
F/U final 
visit
End Point (F/U)
Day 1 (F/U) - end 
of F/U
SIBAT (Module 1),
Height
DB
1
Baseline (DB)
≤ 1 / predose
1
SIBAT (Module 2)
DB
1
Baseline (DB)
≤ 1 / predose
1
8
Day 8 (DB)
2 - 11
8
15
Day 15 (DB)
12 - 19
15
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Table 1:
Analysis Visits
Parameter
Analysis
Phase
Scheduled
Day
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Time Pointa
(Day)
25
Day 25 (DB)
20 - end of DB
25
DB final 
visit
End Point (DB)
2 - end of DB
F/U
39
Day 39 (F/U)
Day 1 (F/U) - 27
14
67
Day 67 (F/U)
28 - 48
42
81
Day 81 (F/U)
49 - 69
56
109
Day 109 (F/U)
70 - 97
84
137
Day 137 (F/U)
98 - 125
112
165
Day 165 (F/U)
126 - 157
140
200
Day 200 (F/U)
158 - end of F/U
175
F/U final 
visit
End Point (F/U)
Day 1 (F/U) - end 
of F/U
SIBAT (Modules 3 and 5)
DB
1
Baseline (DB)
≤ 1 / predose
1
Day 1 (DB): 4H
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 - 48
42
81
Day 81 (F/U)
49 - 69
56
109
Day 109 (F/U)
70 - 97
84
137
Day 137 (F/U)
98 - 125
112
165
Day 165 (F/U)
126 - 157
140
200
Day 200 (F/U)
158 - end of F/U
175
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
NCT03185819


JNJ54135419  (esketamine)
Statistical Analysis Plan ESKETINSUI2002
16
Approved, Date: 19 September 2022
Table 1:
Analysis Visits
Parameter
Analysis
Phase
Scheduled
Day
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Time Pointa
(Day)
22
Day 22 (DB)
20 - 23
22
25
Day 25 (DB)
24 - end of DB
25
DB final 
visit
End Point (DB)
10 - 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 - 48
42
81
Day 81 (F/U)
49 - 69
56
109
Day 109 (F/U)
70 - 97
84
137
Day 137 (F/U)
98 - 125
112
165
Day 165 (F/U)
126 - 157
140
200
Day 200 (F/U)
158 - end of F/U
175
F/U final 
visit
End Point (F/U)
Day 1 (F/U) - end 
of F/U
SIBAT (Modules 6 and 7)
DB
1
Baseline (DB)
≤ 1 / predose
1
Day 1 (DB): 4H
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
39
Day 39 (F/U)
Day 1 (F/U) - 27
14
67
Day 67 (F/U)
28 - 48
42
81
Day 81 (F/U)
49 - 69
56
109
Day 109 (F/U)
70 - 97
84
137
Day 137 (F/U)
98 - 125
112
165
Day 165 (F/U)
126 - 157
140
200
Day 200 (F/U)
158 - end of F/U
175
F/U final 
visit
End Point (F/U)
Day 1 (F/U) - end 
of F/U
SIBAT (Module 8)
DB
1
Baseline (DB)
≤ 1 / predose
1
2
Day 2 (DB)
2
2
8
Day 8 (DB)
3 - 11
8
NCT03185819


JNJ54135419  (esketamine)
Statistical Analysis Plan ESKETINSUI2002
17
Approved, Date: 19 September 2022
Table 1:
Analysis Visits
Parameter
Analysis
Phase
Scheduled
Day
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Time Pointa
(Day)
15
Day 15 (DB)
12 - 19
15
25
Day 25 (DB)
20 - end of DB
25
DB final 
visit
End Point (DB)
Day 2 (DB)- end 
of DB
F/U
39
Day 39 (F/U)
Day 1 (F/U) - 27
14
67
Day 67 (F/U)
28 - 48
42
81
Day 81 (F/U)
49 - 69
56
109
Day 109 (F/U)
70 - 97
84
137
Day 137 (F/U)
98 - 125
112
165
Day 165 (F/U)
126 - 157
140
200
Day 200 (F/U)
158 - end of F/U
175
F/U final 
visit
End Point (F/U)
Day 1 (F/U) - end 
of F/U
CDI 2:SR
DB
1
Baseline (DB)
≤ 1 / predose
1
2
Day 2 (DB)
2
2
25
Day 25 (DB)
3 - end of DB
25
DB final 
visit
End Point (DB)
Day 2 (DB) - end 
of DB
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
F/U
81
Day 81 (F/U)
Day 1 (F/U) - end 
of F/U
56
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
Nasal symptom 
questionnaire
DB
1
Baseline (DB)
≤ 1 / predose
1
Day 1 (DB): 1H
4
Day 4 (DB): Predose
2 - 7
4
Day 4 (DB): 1H
11
Day 11 (DB): 
Predose
8 - 14
11
Day 11 (DB): 1H
18
Day 18 (DB): 
Predose
15 - 21
18
Day 18 (DB): 1H
25
Day 25 (DB): 
Predose
22 - end of DB
25
Day 25 (DB): 1H
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Statistical Analysis Plan ESKETINSUI2002
18
Approved, Date: 19 September 2022
Table 1:
Analysis Visits
Parameter
Analysis
Phase
Scheduled
Day
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Time Pointa
(Day)
Vital Signs
(TEMP [predose],
BP, HR, RESP [predose, 
40M, 1H and 1.5H]))
DB
Screening
Screening
< 1
< 1
1
Day 1 (DB): Predose
1 / predose
1
Day 1 (DB): 40M
Day 1 (DB): 1H
Day 1 (DB): 1.5H
4
Day 4 (DB): Predose
2 - 5
4
Day 4 (DB): 40M
Day 4 (DB): 1H
Day 4 (DB): 1.5H
8
Day 8 (DB): Predose
6 - 9
8
Day 8 (DB): 40M
Day 8 (DB): 1H
Day 8 (DB): 1.5H
11
Day 11 (DB): 
Predose
10 - 12
11
Day 11 (DB): 40M
Day 11 (DB): 1H
Day 11 (DB): 1.5H
15
Day 15 (DB): 
Predose
13 - 16
15
Day 15 (DB): 40M
Day 15 (DB): 1H
Day 15 (DB): 1.5H
18
Day 18 (DB): 
Predose
17 - 19
18
Day 18 (DB): 40M
Day 18 (DB): 1H
Day 18 (DB): 1.5H
22
Day 22 (DB): 
Predose
20 - 23
22
Day 22 (DB): 40M
Day 22 (DB): 1H
Day 22 (DB): 1.5H
25
Day 25 (DB): 
Predose
24 - end of DB
25
Day 25 (DB): 40M
Day 25 (DB): 1H
Day 25 (DB): 1.5H
DB final 
visit
End Point (DB)
Day 1 (DB): 40M 
- end of DB
F/U
200
Day 200 (F/U)
Day 1 (F/U) - end 
of F/U
175
NCT03185819


JNJ54135419  (esketamine)
Statistical Analysis Plan ESKETINSUI2002
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Approved, Date: 19 September 2022
Table 1:
Analysis Visits
Parameter
Analysis
Phase
Scheduled
Day
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Time Pointa
(Day)
ECG
DB
Screening
Baseline (DB)
< 1
< 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
F/U
200
Day 200 (F/U)
Day 1 (F/U) - end 
of F/U
175
Pulse oximetryc,
MOAA/Sd
DB
1
Baseline (DB)/Day 1
(DB): Predose
≤ 1 / predose
1
Day 1 (DB): 15M
Day 1 (DB): 30M
Day 1 (DB): 45M
Day 1 (DB): 1H
Day 1 (DB): 1.25H
Day 1 (DB): 1.5H
4
Day 4 (DB): Predose
2 - 5
4
Day 4 (DB): 15M
Day 4 (DB): 30M
Day 4 (DB): 45M
Day 4 (DB): 1H
Day 4 (DB): 1.25H
Day 4 (DB): 1.5H
8
Day 8 (DB): Predose
6 - 9
8
Day 8 (DB): 15M
Day 8 (DB): 30M
Day 8 (DB): 45M
Day 8 (DB): 1H
Day 8 (DB): 1.25H
Day 8 (DB): 1.5H
11
Day 11 (DB): 
Predose
10 - 12
11
Day 11 (DB): 15M
Day 11 (DB): 30M
Day 11 (DB): 45M
Day 11 (DB): 1H
Day 11 (DB): 1.25H
Day 11 (DB): 1.5H
NCT03185819


JNJ54135419  (esketamine)
Statistical Analysis Plan ESKETINSUI2002
20
Approved, Date: 19 September 2022
Table 1:
Analysis Visits
Parameter
Analysis
Phase
Scheduled
Day
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Time Pointa
(Day)
15
Day 15 (DB): 
Predose
13 - 16
15
Day 15 (DB): 15M
Day 15 (DB): 30M
Day 15 (DB): 45M
Day 15 (DB): 1H
Day 15 (DB): 1.25H
Day 15 (DB): 1.5H
18
Day 18 (DB):
Predose
17 - 19
18
Day 18 (DB): 15M
Day 18 (DB): 30M
Day 18 (DB): 45M
Day 18 (DB): 1H
Day 18 (DB): 1.25H
Day 18 (DB): 1.5H
22
Day 22 (DB): 
Predose
20 - 23
22
Day 22 (DB): 15M
Day 22 (DB): 30M
Day 22 (DB): 45M
Day 22 (DB): 1H
Day 22 (DB): 1.25H
Day 22 (DB): 1.5H
25
Day 25 (DB): 
Predose
24 - end of DB
25
Day 25 (DB): 15M
Day 25 (DB): 30M
Day 25 (DB): 45M
Day 25 (DB): 1H
Day 25 (DB): 1.25H
Day 25 (DB): 1.5H
DB final 
visit
End Point (DB)
Day 1 (DB): 0H -
end of DB
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
200
Day 200 (F/U)
Day 1 (F/U) - end 
of F/U
175
CADSSe,
BPRS+
DB
1
Day 1 (DB): Predose
≤ 1 / predose
1
Day 1 (DB): 40M
NCT03185819


JNJ54135419  (esketamine)
Statistical Analysis Plan ESKETINSUI2002
21
Approved, Date: 19 September 2022
Table 1:
Analysis Visits
Parameter
Analysis
Phase
Scheduled
Day
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Time Pointa
(Day)
Day 1 (DB): 1.5H
4
Day 4 (DB): Predose
2 - 5
4
Day 4 (DB): 40M
Day 4 (DB): 1.5H
8
Day 8 (DB): Predose
6 - 9
8
Day 8 (DB): 40M
Day 8 (DB): 1.5H
11
Day 11 (DB): 
Predose
10 - 12
11
Day 11 (DB): 40M
Day 11 (DB): 1.5H
15
Day 15 (DB): 
Predose
13 - 16
15
Day 15 (DB): 40M
Day 15 (DB): 1.5H
18
Day 18 (DB): 
Predose
17 - 19
18
Day 18 (DB): 40M
Day 18 (DB): 1.5H
22
Day 22 (DB): 
Predose
20 - 23
22
Day 22 (DB): 40M
Day 22 (DB): 1.5H
25
Day 25 (DB): 
Predose
24 - end of DB
25
Day 25 (DB): 40M
Day 25 (DB): 1.5H
YMRS
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
PWC-20
DB
25
Day 25 (DB)
1 - end of DB
25
F/U
28
Day 28 (F/U)
Day 1 (F/U) - 4
3
32
Day 32 (F/U)
5 - 8
7
35
Day 35 (F/U)
9 - 11
10
39
Day 39 (F/U)
12 - end of F/U
14
F/U final 
visit
End Point (F/U)
Day 1 (F/U) - end 
of F/U
TLFB
F/U
53
Day 53 (F/U)
Day 1 (F/U) - 41
28
NCT03185819


JNJ54135419  (esketamine)
Statistical Analysis Plan ESKETINSUI2002
22
Approved, Date: 19 September 2022
Table 1:
Analysis Visits
Parameter
Analysis
Phase
Scheduled
Day
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Time Pointa
(Day)
81
Day 81 (F/U)
42 - 115
56
200
Day 200 (F/U)
116 - end of F/U
175
F/U final 
visit
End Point (F/U)
Day 1 (F/U) - end 
of F/U
C-SSRS (9 -< 12 year old)
DB
1
Baseline (DB)
≤ 1 / predose
1
Day 1 (DB): 4 H
4
Day 4 (DB)
2 - 5
4
8
Day 8 (DB)
6 - 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): 4 H -
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 - 48
42
81
Day 81 (F/U)
49 - 69
56
109
Day 109 (F/U)
70 - 97
84
137
Day 137 (F/U)
98 - 125
112
165
Day 165 (F/U)
126 - 157
140
200
Day 200 (F/U)
158 - end of F/U
175
F/U final 
visit
End Point (F/U)
Day 1 (F/U) - end 
of F/U
a Time interval and Target time point is relative to the first day of each phase.
b For DB phase, 4-hour postdose time point on Day 1 and Day 25, the sleep item score is not assessed for CDRS-
R and MADRS. Sleep item recorded predose on the same day will be carried forward to calculate the total 
score.
c If oxygen saturation level is < 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.
d If the MOAA/S 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 minutesand 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.
e If any CADSS items are scored zero at 40 minutes, these items will not be repeated at 1.5 hours postdose.
NCT03185819


JNJ54135419  (esketamine)
Statistical Analysis Plan ESKETINSUI2002
23
Approved, Date: 19 September 2022
Table 1:
Analysis Visits
Parameter
Analysis
Phase
Scheduled
Day
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Time Pointa
(Day)
Note: if patients early withdrew in DB phase, analysis visits for the remote contacts conducted after 
discountinuation in DB phase will be assigned using the window defined, however these will be denoted as RC. 
Assessments conducted in follow-up phase will be assigned using the visit from the protocol. If patients early 
withdrew in the F/U phase, analysis visits for the remote contacts which are conducted after discountinuation in 
F/U will be assigned using window defined as above but noted with RC. RC for remote contact will only be 
noted for the visits which are conducted after the early withdrawal. 
2.5.
Analysis Sets
Subjects will be classified into the following analysis sets: all randomized, full efficacy, safety and 
follow-up. These analysis sets will only include12 -< 18 year old subjects.
Subjects from site PL10006 will be excluded from the safety analysis set, full efficacy analysis set 
and follow-up analysis set due to non-compliance with GCP principles. However, data for this site 
will be presented in listings and sensitivity analyses for the primary endpoint will be provided.
2.5.1.
All Randomized Analysis Set
This analysis will include all subjects who were randomized (i.e., subjects who reported a 
randomization date, or were assigned a randomization number) regardless of whether or not 
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 during the double-blind phase and have both a baseline and a 
post dose evaluation for the CDRS-R total score.
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 receive at least 1 dose of study medication 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. Subjects who received an incorrect treatment will be 
analyzed under the planned treatment.
2.5.4.
Follow-up Analysis Set
The follow-up analysis set is defined as all subjects who completed the double-blind phase and 
either entered the follow-up phase or have provided adverse event data after the double-blind 
phase. This analysis set will be used for both efficacy and safety analyses.
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Statistical Analysis Plan ESKETINSUI2002
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2.6.
Analysis for 9 - < 12 Year Old Cohort
All effcacy and safety data from the 9 - < 12 year old cohort will be summarized separately. All 
randomized subjects between 9-<12 years old who receive at least 1 dose of study medication in 
the double-blind phase will be included in these summaries. Descriptive summaries and listings 
will be provided for efficacy and safety variables. Continuous variables will be summarized using 
descriptive statistics (N, mean, standard deviation [SD], median, minimum and maximum) and 
categorical variables will be summarized using frequency distributions with the number and 
percentage of subjects in each category.
2.7.
Definition of Subgroups
Descriptive statistics will be provided for the change from baseline of primary endpoint of CDRS-
R total score, by the following subgroups.

Sex

Race (White, Black, Other)

Country

Region (North America, Europe, South America)

Baseline CDRS-R total score (≤/ > median)

Baseline SIBAT: Prior Suicide Attempt (Yes, No) (Module 1: “I have made one or more 
suicide attempts to end my life”)

Baseline Suicide attempt within the last month (Yes, No)
2.8.
Incomplete/Missing Dates for Adverse Events
Treatment-emergent adverse events (AEs) 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 
adverse events.
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
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Statistical Analysis Plan ESKETINSUI2002
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Approved, Date: 19 September 2022
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.
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.
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)
00:00 if the date is the same as DB start date, but the intranasal study medication in 
the double-blind induction phase was started after the oral antidepressant medication 
in this phase
iii)
The time of intranasal medication start in the double-blind induction phase if the
intranasal medication was started on or before the oral antidepressant medication in 
this phase
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
In addition to investigator judgment concerning standard of care and subject safety, an external 
Independent Data Monitoring Committee (IDMC), comprised of individuals with appropriate 
pediatric expertise including pediatric psychiatric expertise, 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 periodically to review safety data. After the review, the IDMC will make 
recommendations regarding the continuation of the study. The details will be provided in a separate 
IDMC charter.
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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.
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 groupa: 12-14, 15-17

Sex (male, female)

Race (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)

Countrya
a Not requied for 9 - < 12 year old cohort 
b If multiple race categories are indicated, then Race is recorded as “Multiple”.
Table 3:
Psychiatric History at Baseline Variables
Continuous Variables:

Baseline CDRS-R total score

Baseline MADRS total score

Baseline CDI 2:SR[S] total score
Categorical Variables:

Baseline CGI-SS-R

Baseline CGI-SR-I

Baseline SIBAT Module 1 (“I have made one or more suicide attempts to end my life”): 
Prior Suicide Attempt (Yes, No)
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
Baseline SIBAT Module 5 (My Risk) Question 3 “Which of the following ratings best 
describes your thinking about suicide right now” (patient-reported frequency of suicidal 
thinking)

Baseline Suicide attempt within the last month (Y/N)

Module 7: Assessment of Frequency of Suicidal Thinking (FoST)

Baseline MINI: make a suicide attempt in your lifetime
Psychiatric history at baseline below (Table 3a) will be summarized for 9-<12 year old cohort.
Table 3a:
Psychiatric History at Baseline Variables for 9- < 12 Year Old
Continuous Variables:

Baseline CDRS-R total score

Baseline MADRS total score

Baseline CDI 2:SR[S] total score
Categorical Variables:

Baseline CGI-SS-R

Baseline CGI-SR-I

Module 7: Assessment of Frequency of Suicidal Thinking (FoST)

Baseline MINI: make a suicide attempt in your lifetime

C-SSRS Actual attempt

Baseline Suicide attempt within the last month (Y/N)
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 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 complete 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 in 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, minimum and maximum) of total duration will be 
presented by treatment group for the full efficacy and safety analysis sets. The total duration of 
study drug exposure in the double-blind phase will also be presented using the following 
categories: 7 days, 8-14 days, 15-21 days, 22-25 days, >25 days.
A frequency distribution of the total number of dosing sessions with study medication received
during the double-blind phase will be presented by treatment group. Descriptive statistics (mean, 
SD, median, minimum and maximum) of the total number of dosing sessions with study drug will 
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also be displayed. In addition, descriptive statistics (mean, SD, median, minimum and maximum)
will be provided for the midazolam dose.
4.4.
Protocol Deviations
Deviations that occurred during the study will be tabulated by treatment group.  Major deviations 
will be tabulated as they are grouped by the Data Management Group prior to unblinding in the 
following categories: entered but did not satisfy criteria; received a disallowed concomitant 
treatment; received wrong treatment or incorrect dose; other; etc. 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 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 standard of care antidepressant treatment during the double-blind phase 
and the follow-up phase will also be summarized. 
5.
EFFICACY
An analysis of efficacy will be performed after the last subject completes the 25-day double blind 
treatment phase (Day 25), 8-week post-treatment follow-up phase (Day 81) and 6-month post-
treatment follow-up phase (Day 200). The efficacy variables for this study are listed in Table 4.
Table 4:
Efficacy Variables
Efficacy Variable
Endpoint
CDRS-R

Change in CDRS-R from Baseline to 24 hours post first 
dose (Day 2)
Primary

Dose response at 24 hours post first dose (Day 2) and on 
Day 25 
Other

Change in CDRS-R from Baseline to 4 hours post first 
dose (Day 1)
Other

Change in CDRS-R from Baseline through the end of DB 
treatment phase (Day 25)
Other

Change in CDRS-R from Baseline during the 6-month 
post-treatment FU phase
Other

Remission of CDRS-R (CDRS-R total score ≤28) at 4 
hours and 24 hours post first dose, and through the end of 
the DB treatment phase (Day 25) and 6-month post-
treatment FU phase
Other

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 6-month post-
treatment FU phase
Other
MADRS

Change in MADRS from Baseline to 4 hours (Day 1) and 
24 hours (Day 2) post first dose
Other

Change in MADRS from Baseline through the end of the 
DB treatment phase (Day 25)
Other
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
Change in MADRS from Baseline during the 6-month 
post-treatment FU phase
Other

Remission of MADRS (MADRS total score ≤12) at 4 
hours and 24 hours post first dose, and through the end of 
the DB treatment phase (Day 25) and 6-month post-
treatment FU phase
Other

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 6-month post-
treatment FU phase
Other
SIBAT –
CGI-SS-R

Change in CGI-SS-R from Baseline to 4 hours (Day 1) 
and 24 hours (Day 2) post first dose, and through the end 
of the DB treatment phase (Day 25) and 6-month post-
treatment FU phase
Other

Resolution of suicidality over time
Other
SIBAT –
CGI-SR-I

Change in CGI-SR-I from Baseline to 4 hours (Day 1) and 
24 hours (Day 2) post first dose, and through the end of 
the DB treatment phase (Day 25) and 6-month post-
treatment FU phase
Other
CDI 2:SR[R]

Change in CDI 2:SR[R] from Baseline to 24 hours post 
first dose (Day 2)
Other

Change in CDI 2:SR[R] from Baseline through the end of 
the DB treatment phase (Day 25) and 6-month post-
treatment FU phase
Other
SIBAT – Module 3 (My 
Current Thinking) 

Change in SIBAT from Baseline through the end of the 
double-blind treatment phase (Day 25)
Other

Change in SIBAT from Baseline during the 6-month post-
treatment FU phase
Other
SIBAT – Module 5 (My 
Risk) Question 3

Change in SIBAT from Baseline through the end of the 
double-blind treatment phase (Day 25)
Other

Change in SIBAT from Baseline during the 6-month post-
treatment FU phase
Other
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) and 6-month post-
treatment FU phase
Other
SIBAT – Module 7 (Global
Clinical Impression) CGI-
SR-LT

Change in CGI-SR-LT from Baseline through the end of 
the DB treatment (Day 25) and 6-month post-treatment 
FU phase
Other
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 6-month post-
treatment FU phase
Other
5.1.
Analysis Specifications
5.1.1.
Level of Significance
A pooled sequential multiple testing procedure will be implemented to control for type I error.  
The esketamine 56-mg and 84-mg treatment groups will be pooled and compared with 
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psychoactive placebo at a 2-sided significance level of 0.05. If this comparison achieves statistical 
significance in favor of esketamine, the 56-mg dose and the 84-mg dose will each be 
simultaneously tested versus psychoactive placebo at the 2-sided significance level of 0.05 based 
on the closed testing procedure. Esketamine 28 mg will be tested at the 2-sided significance level 
of 0.05 only if both the individual doses of 56 mg and 84 mg are shown to be significant.
There will be no multiplicity adjustment for secondary 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 CDRS-R, MADRS, CGI-SS-R, CGI-SR-I and CDI 2:SR[R] 
for the double-blind phase and follow-up phase. If a subject does not enter the follow-up phase,
double-blind observations will not be carried forward into the follow-up phase.
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 5.3.4.1. 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 CDRS-R total score from Baseline (Day 1, predose) 
to 24 hours post first dose in the double-blind phase. The typical recall period for the CDRS-R is 
7 days. The CDRS-R 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. The CDRS-R is a validated 17-
item, clinician-rated instrument developed to assess depressive symptomatology in children that 
measures the severity of a patient’s depressive symptoms. The 17-item includes 14 best description
items that will be determined by CDRS-R raters based on their scores from interviewing of the
subject and caregiver, and 3 nonverbal behavior ratings. For the CDRS-R performed at 4 hours 
postdose on Days 1 and 25, the CDRS-R scores for the sleep disturbance, impaired schoolwork 
and difficulty having fun recorded predose on the same day will be carried forward to calculate 
the total score. For the CDRS-R performed at 24 hours postdose, the CDRS-R scores for impaired 
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schoolwork recorded at predose Day 1 will be carried forward. The 17 item scores range from 1 
to 5 or 1 to 7, with a possible total score ranging from 17 to 113. A higher score represents a more 
severe condition.
5.2.2.
Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined 
by the following 5 components:

Study Intervention: 
      Experimental: esketamine 28 mg, esketamine 56 mg, esketamine 84 mg
      Control: Placebo 

Population: subjects with MDD who are at imminent risk of suicide;

Variable: change from baseline to 24 hours post first dose (Day 2) in the CDRS-R total score;

Intercurrent event: no intercurrent events to be taken into account;

Population-level summary: difference in mean change from baseline to 24 hours post first dose 
(Day 2) in the CDRS-R total score between treatment conditions.
The primary analysis will be based on the full efficacy analysis set and the CDRS-R total scores 
collected at Day 2 (24 hours post first dose).
5.2.3.
Analysis Methods
ANCOVA
The primary efficacy endpoint, change from Baseline (Day 1, predose) to 24 hours post first dose
(Day 2) in CDRS-R total score, will be analyzed using analysis of covariance (ANCOVA) with 
factors for treatment and analysis center and baseline CDRS-R total score as a continuous 
covariate. First, the pooled esketamine doses of 84 mg and 56 mg will be compared to placebo at 
the 2-sided 0.05 significance level using the appropriate contrast statement in SAS GLM (i.e. 0.5, 
0.5, 0, -1 for esketamine doses of 84 mg, 56 mg 28 mg and placebo) If this comparison achieves 
statistical significance in favor of esketamine, the 56-mg dose and the 84-mg dose will each be 
simultaneously tested versus psychoactive placebo at the two-sided significance level of 0.05 using 
the ANCOVA model specified above with the appropriate contrast statetments in SAS GLM (i.e. 
1, 0, 0, -1 for 84 mg vs. placebo and 0, 1, 0, -1 for 56 mg vs. placebo) Esketamine 28 mg will be 
tested at the two-sided 0.05 significance level using the ANCOVA model specified above with the 
appropriate contrast statement in SAS GLM (0, 0, 1, -1 for 28 mg vs. placebo) only if both the 
individual doses of 56 mg and 84 mg are shown to be significant. The treatment effects will be 
estimated using least square means. Point estimates and 95% confidence intervals for the treatment 
differences, along with the associated p-value 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 CDRS-R 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 (i.e. LOCF). In 
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addition, descriptive statistics (N, mean, SD, median, minimum and maximum) of the primary 
efficacy variable will be provided by analysis center.
Descriptive statistics (N, mean, SD, median, minimum and maximum) for the CDRS-R 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.  An 
additional analysis of “End Point (DB)” including remote contact data for subjects who discontinue 
during the double-blind phase using this ANCOVA model will be performed.
Least square mean changes (SE) from baseline over time will be presented graphically for the 
double-blind and follow-up phases based on LOCF data.
Model Assumptions
The normality and equal variance assumptions underlying the ANCOVA model will be assessed 
graphically for the CDRS-R 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 
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 Day 25 (DB) 
and Day 81 (F/U) in CDRS-R total score. The model will include baseline CDRS-R total score as 
a continuous covariate, and treatment, analysis center, day, 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 each esketamine group versus placebo 
will be performed using the appropriate contrast. Point estimates and 95% confidence intervals for 
the treatment differences will be provided. Least square mean changes (SE) from baseline over 
time will be presented graphically for the double-blind and follow-up phase.
Sensitivity Analysis for Missing Data
If the overall missingness of the primary endpoint at 24 hours is above 15% then sensitivity 
analyses will be performed to assess the impact of a range of non-ignorable missingness patterns 
on the robustness of the ANCOVA results for the primary efficacy measure. One set of sensitivity 
analyses will utilize a model-based multiple imputation approach with different imputation 
parameter values. A range of plausible assumptions for the missing data distribution will be used 
to produce imputed datasets to evaluate the impact on the primary analysis. Another potential set 
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of sensitivity analyses will use a bootstrap-based framework, by constructing a set of missing data 
generating models, evaluating the primary analysis method under each of the data generating 
models and thereby establishing the relationship between selection bias and the missing data 
impact.
Additional Sensitivity Analysis
The primary efficacy endpoint will be analyzed using ANCOVA as described above with the 
inclusion of subjects from site LP10006 as a sensitivity analysis.
Subgroup Analyses
Forest plots will be provided displaying analysis results for each subgroup listed in Section 2.7. 
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, subgroup and treatment-by-
subgroup, and baseline CDRS-R total score as a continuous covariate. Analysis center will not be 
included when modeling the subgroups of country and region. Additionally, the terms in the 
models will be adjusted for the subgroup of baseline CDRS-R total score (≤/>median). Baseline 
CDRS-R total score (as a continuous covariate) will not be included in the model when the 
dichotomized baseline CDRS-R total score is included in the model.
5.3.
Other Efficacy Endpoints
5.3.1.
Dose Response
5.3.1.1.
Definition
The detailed definition of CDRS-R has been described in Section 5.2.1. The other efficacy 
endpoint based on CDRS-R is to evaluate dose response at 24 hours post first dose (Day 2) and on 
Day 25.
5.3.1.2.
Analysis Methods
A dose response analysis for the change from baseline in CDRS-R total score at 24 hours post first 
dose and on Day 25 will be conducted with various dose response models.
Sigmoid Emax Model
In order to provide adequate sensitivity to detect a positive dose response over a range of dose-
response patterns, sigmoid Emax model is being considered. Under the model, the placebo effect is 
parameterized to be zero, and therefore the value at a given dosage represents the effect of that 
dosage compared with placebo.
Under the most favorable scenario with the given dose range, the drug is effective at low dosages 
where ED90 is 28 mg and the sigmoid shape parameter is 1. A more realistic scenario may be the 
one where ED90 is 56 mg with 2 for the shape parameter. For the least favorable scenario with the 
selected dose range, ED90 is 84 mg, with 3.5 for the shape parameter. The dose-response curves 
are shown in Figure 2.
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Figure 2:
Dose Response Curves
A trend test statistic will be derived from an ANCOVA model on the change in CDRS-R total 
score, including terms for a linear trend scale, which is derived from a given dose-response curve, 
a factor for analysis center, and baseline CDRS-R total score as a continuous covariate. For a given 
dose-response curve, an optimal linear trend scale will be derived. This gives rise to 3 trend test 
statistics. A p-value will be derived from the maximum of the 3 trend test statistics and the 
multivariate normal distribution of the 3 trend statistics under the null hypothesis of no dose 
response. The combination test statistic is the weighted sum of the normal inverses of the triple 
trend test p-values.
Best Fit Emax model
Additional dose response analysis will be the estimation of the best fit sigmoidal Emax model 
based on the observed study efficacy data using the full efficacy analysis set, and a bootstrapping 
technique for the calculation of 95% confidence intervals around the estimated treatment effect 
for a pre-specified set of doses, including the study doses.
The sigmoidal Emax model is selected because of its flexibility to capture a wide range of dose-
response relationships and the clear interpretation of its parameters. In this model,
µ() = µ + 

 
.×
 ,
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where μ measures the placebo (dose=0) response and τ measures the maximum effect of the 
drug.
The maximum likelihood estimates (MLE) of μ, τ, ED90, and ρ are determined using a 
discretized approach. It can be shown that given a set of values for the ED90 and ρ parameters it 
is possible to identify the conditional MLE's of μ and τ. This is accomplished by computing a 
trend score for each subject based on the dose received,
(;  !"#; $) =

 
.×
 .
The trend scores  are then used in the ANCOVA model,
% = µ +  + &'( + ,
to identify the conditional MLE’s of μ and τ. In the ANCOVA model Y is the vector of observed 
change in CDRS-R total score, C is the design matrix representing the covariates, and e is the 
vector of error terms, which are independent and identically distributed following a normal 
distribution with mean zero and common standard deviation.
A wide range of ED90 and ρ values are considered, and for each pair in the grid search the 
ANCOVA model will be fit with the corresponding trend scores. The candidate ED0.90 values are 
a sequence from 14 mg [half the lowest dose in this study] to 168 mg [twice the highest dose in 
this study] with an increment of 7 mg [0.25 x lowest dose]. The candidate ρ values are a sequence 
from 0.50 to 15 with an increment of 0.25. The MLE's are obtained from the ANCOVA model 
selecting the one associated with the minimum Akaike’s Information Criteria among all candidate 
models. An estimate of the treatment effect at a particular dose, including those not directly 
evaluated in the study, 
is 
obtained by 
multiplying 
̂*+
by 
the trend score 
,;  !"#,*+; $*+.. 
A single dose response curve will be estimated by the weighted average of the predicted 
treatment effects at each dose from the best fit sigmoid Emax models.
Bootstrapping will be used to construct the confidence intervals for the treatment effect estimates 
of the selected doses3. The original data will be stratified by treatment group, and for each group 
a random sample equal in size to the original one will be drawn. For each subject, all of their 
data will be used. The results will comprise the MLE’s of μ, τ, ED90, and ρ for the sigmoidal Emax
model that best fits the observed data, as well as the treatment effect estimates for the doses in 
the study. The 95% confidence intervals for the treatment effect associated with these doses will 
be computed and plotted against the dose level.
MCP-Mod Method
Additional candidate models for the dose response relationship will be investigated using the 
MCP-Mod procedure1. The set of candidate models includes sigmoid Emax models corresponding 
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to the most favorable and least favorable scenarios for the triple trend test, linear and quadratic.
The quadratic covers the scenario of a non-monotonic relationship (see Figure 3).
The significance of dose response signal associated with each candidate model will be determined 
using trend tests with model-specific optimal contrast coefficients, based on the same ANCOVA 
model described for the triple-trend test. The maximum of the candidate model trend test statistics 
will be used to evaluate the presence of a dose-response signal, properly accounting for 
multiplicity. If the maximum test statistic is not significant, no dose-response relationship will be 
further explored. Otherwise, the model families corresponding to individual candidate models with 
significant trend test statistics will be fit to the observed data (including the same covariates as in 
the ANCOVA model as linear terms) and the one with the smallest Akaike Information Criterion 
(AIC) will be selected to represent the dose response relationship. Using that model a confidence 
interval for the response at each dose will be computed based on a bootstrap approach.
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Yi = f (di) + ei
where i is the subject number, Yi is the value for the primary efficacy endpoint, di is the dose 
level used in the study period, f is an unknown nonparametric function assumed to be smooth 
and ei are independent, zero-mean random errors. The function f is estimated by minimizing the 
penalized least squares function using the penalty term for the thin-plate smoothing spline
method.
The spline model will be used to estimate the response at different dose levels and bootstrap 
confidence intervals will be computed.
5.3.2.
Remission of MDD
5.3.2.1.
Definition
A subject is defined to be in remission of MDD at a given time point if the CDRS-R total score is 
≤28. 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.
5.3.2.2.
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.
5.3.3.
Responder
5.3.3.1.
Definition
The percentage change from baseline at Day X is calculated as 100*(CDRS-R total score at Day 
X – Baseline CDRS-R total score)/(Baseline CDRS-R total score – 17). Negative percent changes
in CDRS-R total score indicate improvement (e.g., percent change ≤-50% indicates improvement
≥50%).
A subject is defined a responder at a given time point if the percent improvement in CDRS-R 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.
5.3.3.2.
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.
5.3.4.
MADRS
5.3.4.1.
Definition
The baseline assessment and assessments during the follow-up phase use a 7 day recall period 
while the Day 1, 4-hour postdose assessment, together with other assessments in the double-blind 
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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 postdose 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.
5.3.4.2.
Analysis Methods
The change from Baseline (Day 1, predose) to 24-hour postdose (Day 2) in MADRS total score
will be analyzed using ANCOVA model, with factors for treatment and analysis center, and 
baseline MADRS total score as a continuous covariate. The treatment effects will be estimated 
using least square means. Point estimates and 95% confidence intervals for the treatment 
differences will be provided.
Descriptive statistics (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. An 
additional analysis will be performed of “End Point (DB)” including remote contact data for 
subjects who discontinue during the double-blind phase using the ANCOVA model will be 
performed.
Additionally, an MMRM analysis based on observed case data will be performed comparing 
treatments for the change from Baseline (Day 1, predose) to Day 25 (DB) and Day 81 (F/U) in 
MADRS total score. The model will include baseline MADRS total score as a continuous 
covariate, and treatment, analysis center, day, 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 each esketamine group versus placebo will be performed 
using the appropriate contrast. Point estimates and 95% confidence intervals for the treatment 
differences will be provided.
Least square mean changes (SE) from baseline will be presented graphically for the double-blind 
and follow-up phases for the ANCOVA LOCF and MMRM analyses.
Correlation between CDRS-R total scores and MADRS total scores during double-blinded 
phasewill be explored. Pearson correlations and 95% CI will be reported over time.
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5.3.4.3.
Remission of MDD
A subject is defined to be in remission of MDD 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.
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.
5.3.4.4.
Responder
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 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. 
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.
5.3.4.5.
Dose Response
A dose response analysis for the change from baseline in MADRS total score at 24 hours post first 
dose and on Day 25 will be conducted with various dose response models as decribed in 
Section 5.3.1.
5.3.5.
CGI-SS-R
5.3.5.1.
Definition
One module of the SIBAT includes a revised version of the Clinical Global Impression – Severity 
of Suicidality. 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).
5.3.5.2.
Analysis Methods
The change from Baseline (Day 1, predose) to 24-hour postdose (Day 2) in CGI-SS-R will be 
analyzed using an ANCOVA model on the ranks of change with factors for treatment and analysis 
center, 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 
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differences for the change from baseline for CGI-SS-R at 24 hours. Ranks of changes from baseline 
over time for CGI-SS-R will be analyzed based on observed case and LOCF data using an 
ANCOVA model with treatment and analysis center as factors, and baseline value (unranked) as 
a covariate. The Hodges-Lehmann estimates and the corresponding 95% CIs for the treatment 
differences will be provided.
CGI-SS-R will be also analyzed using un-ranked data. Changes from baseline over time for CGI-
SS-R will be analyzed based on observed case and LOCF data using an ANCOVA model with 
treatment and analysis center as factors, and baseline value as a covariate. Point estimates and 95% 
confidence intervals for the treatment differences will be provided. At each time point during the 
double-blind and follow-up phases, a frequency distribution of the CGI-SS-R 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.
Both observed case data and LOCF frequency distributions will be presented graphically using 
stacked bar charts for baseline, 4-hour post first dose (Day 1), 24-hour post first dose (Day 2), and 
Day 25.
5.3.6.
Resolution of Suicidality
5.3.6.1.
Definition
A subject is defined to have achieved resolution of suicidality 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.
5.3.6.2.
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.
5.3.7.
CGI-SR-I
5.3.7.1.
Definition
One module of the SIBAT includes the Clinical Global Impression of Imminent Suicide Risk. 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). 
5.3.7.2.
Analysis Methods
CGI-SR-I will be analyzed similarly to CGI-SS-R.
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5.3.8.
SIBAT – Module 3 (My Current Thinking), Module 5 (My Risk) 
Question 3, Module 7 (Global Clinical Impression) FoST, CGI-SR-LT, 
and Module 8 (Clinical Judgment of Optimal Suicide Management)
5.3.8.1.
Definition
Module 3 (My Current Thinking), Question 3 (patient-reported frequency of suicidal thinking) in 
Module 5 (My Risk), Module 7 (Global Clinical Impression) Assessment of Frequency of Suicidal 
Thinking (FoST), CGI-SR-LT and Module 8 (Clinical Judgment of Optimal Suicide Management)
from the SIBAT will be used to assess patient and clinician reported suicidality. 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 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.” 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 10 (Psychiatric hospitalization 
required with constant visual observation and use of physical or chemical restraints.
5.3.8.2.
Analysis Methods
Frequency distributions for Module 5 (My Risk) Question 3, Module 7 (Global Clinical 
Impression) FoST, CGI-SR-LT and Module 8 (Clinical Judgment of Optimal Suicide 
Management) will be summarized over time during the double-blind and follow-up phases. In 
addition, descriptive statistics for these scores and Module 3 (My Current Thinking) total score 
and the changes from baseline will be provided.
5.3.9.
CDI 2:SR[S]
5.3.9.1.
Definition
The CDI 2:SR[S] assessment is a multi-rater assessment of depressive symptoms in youth aged 
7 to 17 years and an efficient screening measure that contains 12 items and takes 5 to 10 minutes 
to administer. The CDI 2:SR[S] has excellent psychometric properties and yields a total score that 
is generally very comparable to the one produced by the full-length version, Children’s Depression 
Inventory 2 (CDI 2), a validated screening instrument for depression in children. Scoring the CDI-
2 involves summing the items to obtain raw scores which are then converted to T scores and 
percentiles based on specific age and gender groups. The groups are separated by gender for two 
age groups: 7–12 and 13–17. A higher score indicates a greater problem. Interpretation of the T-
scores will also fall into five categories: Very Elevated (T -score 70+), Elevated (T -score 65-69), 
High Average (T -score 60-64), and Average or Lower (T -score <=59) (see Attachment 1).
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5.3.9.2.
Analysis Methods
The change from Baseline (Day 1, predose) to 24-hour postdose (Day 2) in CDI 2:SR[S] total 
score will be analyzed using an ANCOVA model, with factors for treatment and analysis center,
and baseline CDI 2:SR[S] score as a continuous covariate. The treatment effects will be estimated 
using least square means.
Descriptive statistics (mean, SD, median, minimum and maximum) for the CDI 2:SR[S] score and 
the change from baseline will be provided for both the observed case and LOCF data during the 
double-blind phase. The ANCOVA model, as described above, will also be used to analyze Day 
25 for both observed case and LOCF data. Frequency distributions for categorized T-scores will 
be summarized.
Least square mean changes (SE) from baseline will be presented graphically for the double-blind
phase.
6.
SAFETY
Safety analyses will be performed after the last subject completes the 25-day double blind 
treatment phase (Day 25), 8-week post-treatment follow-up phase (Day 81) and 6-month post-
treatment follow-up phase (Day 200).
6.1.
Adverse Events
Adverse events (AEs) are coded using the MedDRA dictionary (version 18.1 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. For each AE, 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. Adverse events occurring during the follow up phase will be summarized separately. In 
addition, AEs will be summarized by severity and relationship to study drug using the preferred 
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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. Data listings will also be generated for 
deaths, other SAEs, and discontinuations due to AEs.
Adverse Events of Special Interest
Clinically relevant TEAEs of special interest will be examined separately grouped in the following 
categories: 

drug abuse, dependence and withdrawal (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 abuse, 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);

Suicidality (Completed suicide, Depression suicidal, Intentional overdose, Intentional self-
injury, Multiple drug overdose intentional, Poisoning deliberate, Self-injurious behavior, Self-
injurious ideation, Suicidal behavior, Suicidal ideation, Suicide attempt, Suicide threat)
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In addition, a summary of treatment-emergent AEs of cardiac safety (preferred terms: cardiac 
flutter, electrocardiogram QT prolonged, palpitations, seizure, sudden cardiac death, sudden 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, 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 and follow-up phases. The baseline laboratory result is 
defined as the last result collected prior to Day 1 predose. 
Clinical laboratory tests that meet the criteria for markedly abnormal will be listed by subject for 
the double-blind phase and follow-up phase. 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 2. 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 2. 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 normal limit (ULN) will be 
presented for each study phase. Additionally, incidence of hepatic toxicity (Hy's Law7) defined as 
ALT or AST values >3*ULN AND total bilirubin values >2*ULN will be presented for the double-
blind and follow up phases. 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 change from predose and time of maximum percent change will also be 
presented for blood pressure. 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 frequency of subjects with treatment-emergent abnormal vital signs in the double-blind and 
follow-up phases will be summarized. The identification of treatment-emergent abnormal vital 
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signs is based on the post-baseline value (a value occurring after the first study drug 
administration) being out of range while the baseline (DB) value is either missing or within the 
limits given in Table 5. If post-baseline values are above the upper limits and the baseline (DB) 
value is below the lower limits, then the post-baseline abnormality will also be considered 
treatment-emergent. The same applies to the post-baseline value being below the lower limits with 
the baseline value being above the upper limits. A listing of subjects meeting any of the criteria 
will also be provided for the double-blind phase.
Table 5:
Criteria for Treatment-emergent Abnormal Vital Signs
Vital Parameter
Lower Range
Upper Range
Systolic BP (mmHg)
<86
>130
Diastolic BP (mmHg)
<50
>89
Pulse (bpm)
<50
>119
Note: The lower and upper range for pulse (bpm) in the 9 -< 12 age cohort are < 60(bpm) and > 
140(bpm), respectively
In addition, descriptive statistics (N, mean, SD, median, minimum and maximum) will be provided 
for the maximum increase from predose at each dosing day. 
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. A seperate lisitng will also be 
provided for the subjects of all ages whose postdose SBP or DBP measures meet withdrawal 
criteria (see Section 10.2. in the protocol).
A listing of subjects with oxygen saturation less than 93% will be provided.
6.4.
Nasal Examination and Nasal Symptom Questionnaire
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 examinations 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. Any treatment emergent change or worsening 
from baseline examination will be recorded as an adverse event.
A shift table for changes in rating for each examination will be presented for the double-blind
phase. Changes in findings from the baseline nasal examination (including the upper respiratory 
tract/throat) will be listed by treatment group.
Data from the nasal symptom questionare with results of mild, modrate and severe will be provided 
in listing.
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6.5.
Electrocardiogram
The ECG variables that will be analyzed include heart rate, RR, PR interval, QRS interval, QT 
interval and QTc intervals. The corrected QT (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.
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 RR, PR, QRS and QTc intervals are given in Table 6.
Table 6:
Limits for RR, PR, QRS and QTc Interval Abnormality
ECG parameter
Abnormally Low
Abnormally High
RR (msec)
< 600
> 1200
PR interval (msec)
--
> 200
QRS interval (msec)
--
> 99
QTc interval (msec)
--
> 449
Note: in the 9-<12 age cohort, the upper range is >180 msec for PR interval, and >89 msec for 
QRS interval. 
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 Guidance4 (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
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>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. A listing of subjects with abnormalities will also be provided.
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. A separate 
listing of subjects with a MOAA/S score of 0 or 1 at any time point during the double-blind phase 
will be presented.
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” 
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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. The CADSS is divided into 3 components using scoring 
method shown in Table 8.
Table 8:
CADSS Scoring Method
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 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-
blinded 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 provided. The highest value and 
greatest change for CADSS total score after dosing across 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 Plus8,9,10. Attachment 4 contains the 
mapping algorithm. Using the C-CASA 2012 Plus, potentially suicide-related events will be 
classified using the following 16 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
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SI-X: Active Suicidal Ideation: other
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/Other/Not enough information, 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.
6.6.4.
Brief Psychiatric Rating Scale, Positive Symptom Subscale (BPRS+)
The Brief Psychiatric Rating Scale (BPRS) is aninstrument that uses a 4-item positive symptom 
subscale to assess psychosis-like side effects. The BPRS+ consists of: suspiciousness, 
hallucinations, unusual thought content and conceptual disorganization. Each symptom is rated 
on a scale of 0 to 6 as follows: 0: not present, not evident or absent; 1: very mild; 2: mild; 3: 
moderate; 4: moderate severe; 5: severe; or 6: extreme. A total score will be derived by summing 
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the individual items, with a range of 0 to 24 with a higher score representing a more severe 
condition.
The BPRS+ is measured prior to each dose, at 40 minutes, and at 1.5 hours post dose during each 
of the dosing phase.
Descriptive statistics (N, median, minimum, and maximum) of the total scores at each time point, 
change from the pre-dose time point within each visit, and the proportion of subjects with an 
increase in total BPRS+ from the pre-dose value at any time during the study will be provided for 
double-blinded treatment phase. The proportion of subjects with a total score of 3 or more at any 
time during the study will also be provided. Mean changes in BPRS+ from pre-dose value will be 
presented graphically for each intranasal dosing day.
6.6.5.
Young Mania Rating Scale (YMRS)
The treatment-emergent occurrence and severity of manic episodes will be assessed by Young 
Mania Rating Scale (YMRS). The YMRS has 11 items and is based on the patient’s subjective 
report of his or her clinical condition. Additional information is based upon clinical observations 
made during the course of the clinical interview. There are four items that are graded on a 0 to 8 
scale (irritability, speech, thought content, and disruptive/aggressive behavior), while the 
remaining seven items are graded on a 0 to 4 scale. These four items are given twice the weight of 
the others to compensate for poor cooperation from severely ill patients.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of YMRS total score ( 0 –
60) will be summarized at designated scheduled visit by treatment group. In addition, the 
proportion of subjects with a YMRS total score >12 at any post-dose time point during the double-
blind phase will be presented.
6.6.6.
Physician Withdrawal Checklist (PWC-20)
The PWC-20 is a 20-item simple and accurate method to assess potential withdrawal symptoms 
following cessation of intranasal esketamine treatment. The PWC-20 will be performed for all 
subjects on Day 25 to establish a baseline prior to discontinuation of esketamine treatment. If 
subjects withdraw early from the study during the DB phase, the PWC-20 will be conducted at the 
Early Withdrawal Visit. For those subjects who enter the post-treatment follow-up phase, the 
PWC-20 will be conducted on Day 28 (F/U), Day 32 (F/U), Day 35 (F/U) and Day 39 (F/U).
The proportion of subjects with withdrawal symptoms at the end of double-blind phase or during 
the follow-up phase will be presented by treatment. In addition, symptoms at follow-up will be 
compared to the end of double-blind phase and will be summarized using the following categories: 
new or worsened symptoms, symptoms present and unchanged, no symptoms, and improved.
6.6.7.
Columbia Suicide Severity Rating Scale (C-SSRS) (9 -< 12 Year Old 
Chort)
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed to assess severity and track suicidal events through any intervention (Posner 2007). It 
is a clinical interview providing a summary of both suicidal ideation and behavior that can be 
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administered during any evaluation or risk assessment to identify the level and type of suicidality 
present. The C-SSRS has been used frequently in clinical studies, and is a validated, standard 
measure for suicidal ideation assessment. Using the C-SSRS, the outcomes will be categorized 
using the scoring for the 11 categories:
Suicidal Ideation (1-5)
1 Wish to be dead
2 Non-specific active suicidal thoughts
3 Active suicidal ideation with any methods (not plan) without intent to act
4 Active suicidal ideation with some intent to act, without specific plan
5 Active suicidal ideation with specific plan and intent
Suicidal Behavior (6-10)
6 Preparatory acts or behavior
7 Aborted attempt
8 Interrupted attempt
9 Actual attempt
10 Suicide
Non-suicidal self-injurious behavior (11)
11 Non-suicidal self-injurious behavior
If no events qualify for a score of 1 to 10, a score of 0 will be assigned (0=“no suicidal ideation or 
behavior that can be assessed on the basis of C-SSRS”). A participant with a score of 11 will be 
considered as not having suicidal ideation or behavior.
A frequency distribution of the scores for the 11 categories will be provided at each time point for 
each phase.
6.6.8.
Cogstate® Computerized Cognitive Battery
Please see the Attachment 5.
6.6.9.
Timeline Follow-Back (TLFB)
The Timeline Follow-Back (TLFB) will be used to assess the potential for ketamine and 
phencyclidine (PCP) abuse during the follow-up phase. Quantitative estimates and drug use-
consumption variables can be used to measure change in drug use levels in outcome monitoring.
The TLFB asks clients to retrospectively estimate their drug use during the double-blink phase and 
capture the frequency of drug use (i.e., used or did not use).
The proportion of subjects with at least 1 yes during follow-up phase will be provided for 
ketamine and PCP.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
Details of the pharmacokinetic and pharmacodynamic analysis is provided in a separate document.
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REFERENCES
1.
Bretz F, Pinheiro JC, Branson M. Combining Multiple Comparisons and Modeling Techniques in Dose-
Response Studies. Biometrics. 2005 Sep 1;61(3):738-48.
2.
CSR ESKETINSUI2001, A Double-blind, Randomized, Placebo Controlled Study to Evaluate the Efficacy and
Safety of Intranasal Esketamine for the Rapid Reduction of the Symptoms of Major Depressive Disorder, 
Including Suicidal Ideation, in Subjects Assessed to be at Imminent Risk for Suicide (20 Jan 2017).
3.
Efron B, Tibshirani R. Bootstrap methods for standard errors, confidence intervals, and other measures of 
statistical accuracy. Statistical science. 1986 Feb 1:54-75.
4.
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.
5.
Murrough, JW, Burdick KE, Levitch CF, et al. Neurocognitive effects of ketamine and association with 
antidepressant response in individuals with treatment-resistant depression: A randomized controlled trial. 
Neuropsychopharmacology. 2015;40:1084–1090.
6.
Papakostas G, Fava M. Does the probability of receiving placebo influence clinical trial outcome? A meta-
regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol. 2008;19(1):34-40.
7.
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.
8.
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. September 2010. 
Available: https://www.federalregister.gov/documents/2010/09/09/2010-22404/draft-guidance-for-industry-on-
suicidality-prospective-assessment-of-occurrence-in-clinical-trials
9.
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.
10.
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
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ATTACHMENTS
Attachment 1: Scoring Guide for CDI 2:SR[S]
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Attachment 2: Criteria of Markedly Abnormal Laboratory Values
Markedly Abnormal Limits
Laboratory Parameter
Low
High
Alanine Aminotransferase (ALT) [U/L]
NA
> 3 x ULN
Albumin [g/L]
< 25
60g/L
Alkaline Phosphatase (ALP) [U/L]
NA
> 400
Aspartate Aminotransferase (AST) [U/L]
NA
> 3 x ULN
Bicarbonate [mmol/L]
< 17
> 35
Bilirubin (Total) [mol/L]
NA
> 2 x ULN
Blood Urea Nitrogen [mmol/L]
NA
12.495
Calcium [mmol/L]
1.743
2.739
Chloride [mmol/L]
< 90
> 120
Creatine Kinase [U/L]
NA
> 3 x ULN
Creatinine [mol/L]
NA
176.8
Gamma Glutamyl Transferase [U/L]
NA
> 3 x ULN
Glucose (Fasting) [mmol/L]
2.775
13.875
Lactate Dehydrogenase [U/L]
NA
> 3 x ULN
Phosphate [mmol/L]
0.646
1.615
Potassium [mmol/L]
< 3
> 5.5
Protein (Total) [g/L]
50 g/L
> 2 x ULN
Sodium [mmol/L]
< 130
> 155
Urate [umol/L]
89.2
594.8
Hemoglobin [g/L]
< 100
> 190
Erythrocytes (RBC) [x1012/L]
< 3
6.6
Leukocytes (WBC) [x109/L]
< 2.5
> 15
Platelets [x109/L]
< 100
> 600
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Attachment 3: SIBAT Module 3 Scoring
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
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
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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 5: SAP for Cognition Tests
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