Clinical trial NCT02782104
Conditions: Depressive Disorder, Treatment-Resistant
Keywords: Depressive Disorder, Treatment-Resistant Esketamine JNJ-54135419
Sponsor: Janssen Research & Development, LLC
Start date: 2016-06-09; Completion date: 2022-12-30
Enrollment: 1148 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the safety and tolerability of esketamine nasal spray in participants with treatment-resistant depression (TRD).

Detailed description:
This is an open-label (the researchers and participants know the treatment the participant is receiving) long-term extension study. The study will consist of 2 open-label Phases: 4-week Induction phase (if applicable) and Open-Label Optimization/Maintenance phase (variable). Participants will enter the study Induction Phase from ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), ESKETINTRD3003 (NCT02493868), ESKETINTRD3005 (NCT02422186) and ESKETINTRD3006 (US sites only). Participants will enter the study Open-Label Optimization/Maintenance phase from ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), ESKETINTRD3003 (NCT02493868) (if appropriate at week 16) or ESKETINTRD3006 (US sites only). In the Open-Label Induction Phase, participants will self-administer flexibly-dosed esketamine nasal spray. During first 4 weeks in Optimization/Maintenance Phase responder participants from the induction phase of study 54135419TRD3008, will continue on the same dose of esketamine nasal spray from the induction phase and have a weekly intranasal treatment session frequency. Participants entering the optimization/maintenance phase from study ESKETINTRD3005 will also have a weekly intranasal treatment session frequency. However, as the ESKETINTRD3005 intranasal study medication is blinded at the time of entry into the current study, the dose of esketamine nasal spray will be administered as outlined in protocol. Participants entering the optimization/maintenance phase from study ESKETINTRD3003 (Direct Entry) or ESKETINTRD3004 who were ongoing in the Optimization, Maintenance, or Optimization/Maintenance phase, respectively, will have the option to have their current intranasal dosing frequency adjusted at the time of entry into 54135419TRD3008 study and should remain on the selected frequency from week 1 to week 4. A one-time dose change will be permitted at study entry. After 4 weeks, esketamine nasal spray treatment sessions will be individualized to either once weekly or once every other week at the fixed 2-week interval (based on clinical global impression - severity \[CGI-S\] performed at that visit), and every 4 weeks for participants dosed at the 4 week interval. Participants safety will be monitored throughout the study.

Arms: arm 1: Open-Label Induction Phase: Participants will self-administer with esketamine nasal spray twice per week for 4 weeks as a flexible dose regimen (56 milligram \[mg\] or 84 mg for those \< 65 years; 28 mg, 56 mg or 84 mg for those \>= 65 years). Participants \>= 65 years old will start at a dose of 28 mg on Day 1. Optimization/Maintenance Phase: Participants entering from studies ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), ESKETINTRD3003 (NCT02493868), ESKETINTRD3004 (NCT02497287), or ESKETINTRD3006 (US sites only) will self-administer esketamine nasal spray (same dose) once weekly. Participants entering from study ESKETINTRD3005 (NCT02422186) will self-administer esketamine nasal spray (28 mg in week 1; 28 or 56 mg in week 2; and 28, 56 or 84 mg in week 3 and 4) once weekly. After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants can be adjusted based upon efficacy and tolerability.
Interventions: intervention 1: Esketamine Nasal Spray
Intervention descriptions: intervention 1: Open-Label Induction Phase: Participants will self-administer with esketamine nasal spray twice per week for 4 weeks as a flexible dose regimen (56 milligram \[mg\] or 84 mg for those \< 65 years; 28 mg, 56 mg or 84 mg for those \>= 65 years). Participants \>= 65 years old will start at a dose of 28 mg on Day 1. Optimization/Maintenance Phase: Participants entering from studies ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585) or ESKETINTRD3006 (US sites only) will self-administer esketamine nasal spray (same dose) once weekly. Participants entering from study ESKETINTRD3005 (NCT02422186) will self-administer esketamine nasal spray (28 mg in week 1; 28 or 56 mg in week 2; and 28, 56 or 84 mg in week 3 and 4) once weekly. After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all participants can be adjusted based upon efficacy and tolerability.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 5 October 2020
Janssen Research & Development *
Clinical Protocol
An Open-label Long-term Extension Safety Study of Esketamine Nasal Spray in 
Treatment-resistant Depression
Safety and Sustenance of Esketamine Treatment Response With Repeated Doses at Intervals 
Determined by Symptom Severity (SUSTAIN-3)
Protocol 54135419TRD3008; Phase 3
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: 2015-003578-34
Status:
Approved
Date:
5 October 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number: EDMS-ERI-109798180, 6.0
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.
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JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 5 October 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 24
TIME AND EVENTS SCHEDULE (Induction Phase) ............................................................................... 33
TIME AND EVENTS SCHEDULE (Optimization/Maintenance Phase) .................................................. 35
ABBREVIATIONS ...................................................................................................................................... 38
DEFINITIONS OF TERMS.......................................................................................................................... 38
1.
INTRODUCTION................................................................................................................................ 39
1.1.
Background .................................................................................................................................... 39
1.1.1.
Summary of Nonclinical Findings ............................................................................................... 39
1.1.2.
Clinical Studies ........................................................................................................................... 42
1.1.2.1.
Pharmacokinetics and Product Metabolism ............................................................................ 42
1.1.2.2.
Pharmacodynamics and Efficacy ............................................................................................ 45
1.1.2.3.
Safety and Tolerability............................................................................................................. 47
1.2.
Overall Rationale for the Study...................................................................................................... 50
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 50
2.1.
Objectives and Endpoints .............................................................................................................. 50
2.1.1.
Objectives ................................................................................................................................... 50
2.1.2.
Endpoints.................................................................................................................................... 51
2.2.
Hypothesis ..................................................................................................................................... 52
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 52
3.1.
Overview of Study Design.............................................................................................................. 52
3.2.
Study Design Rationale.................................................................................................................. 55
3.2.1.
Study Population......................................................................................................................... 55
3.2.2.
Study Phases.............................................................................................................................. 56
3.2.3.
Blinding and Control Group ........................................................................................................ 56
3.2.4.
Intranasal Treatment Group and Dose Selection ....................................................................... 57
3.2.5.
Safety Evaluations...................................................................................................................... 59
3.2.6.
Efficacy Measures ...................................................................................................................... 60
3.2.7.
Medical Resource Utilization ...................................................................................................... 61
3.2.8. 
Patient Stated-choice Preference Survey.................................................................................. 61
4.
SUBJECT POPULATION.................................................................................................................. 61
4.1.
Inclusion Criteria ............................................................................................................................ 62
4.2.
Exclusion Criteria ........................................................................................................................... 65
4.3.
Prohibitions and Restrictions ......................................................................................................... 66
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 67
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 67
6.1.
Intranasal Study Drug .................................................................................................................... 67
6.1.1.
Induction Phase.......................................................................................................................... 69
6.1.2.
Optimization/Maintenance Phase............................................................................................... 70
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CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 5 October 2020
7.
TREATMENT COMPLIANCE............................................................................................................ 72
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 72
9.
STUDY EVALUATIONS .................................................................................................................... 73
9.1.
Study Procedures........................................................................................................................... 73
9.1.1.
Overview..................................................................................................................................... 73
9.1.2.
Induction Phase.......................................................................................................................... 74
9.1.3.
Optimization/Maintenance Phase............................................................................................... 75
9.1.4.
Induction Phase and Optimization/Maintenance Phase - Study Entry....................................... 76
9.1.5.
Early Withdrawal/End of Study Visit ........................................................................................... 76
9.2.
Safety Evaluations ......................................................................................................................... 77
9.3.
Efficacy........................................................................................................................................... 81
9.3.1.
Efficacy Evaluations.................................................................................................................... 81
9.3.1.1.
Montgomery-Asberg Depression Rating Scale (MADRS)....................................................... 81
9.3.1.2.
Clinical Global Impression - Severity (CGI-S) ......................................................................... 82
9.3.1.3.
Patient Health Questionnaire, 9-Item (PHQ-9)........................................................................ 82
9.3.1.4.
Sheehan Disability Scale (SDS).............................................................................................. 82
9.3.1.5.
European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level (EQ 5D-5L) ...................... 83
9.3.1.6.
Subject Treatment Satisfaction Scale ..................................................................................... 83
9.3.1.7.
QLDS....................................................................................................................................... 83
9.4.
Medical Resource Utilization.......................................................................................................... 83
9.5.
Other Evaluations........................................................................................................................... 83
9.5.1.
Patient Stated-choice Preference Survey................................................................................... 83
9.6.
Sample Collection and Handling.................................................................................................... 84
10.
SUBJECT COMPLETION/ DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY................................................................................................. 85
10.1.
Completion ..................................................................................................................................... 85
10.2.
Withdrawal from the Study............................................................................................................. 85
11.
STATISTICAL METHODS................................................................................................................. 86
11.1.
Subject Information ........................................................................................................................ 86
11.2.
Sample Size Determination ........................................................................................................... 86
11.3.
Safety Analyses ............................................................................................................................. 87
11.4.
Efficacy Analyses ........................................................................................................................... 88
11.5.
Medical Resource Utilization Analysis ........................................................................................... 89
11.6.
Patient Stated-choice Preference Survey...................................................................................... 89
11.7.
Independent Data Monitoring Committee ...................................................................................... 89
12.
ADVERSE EVENT REPORTING ...................................................................................................... 89
12.1.
Definitions ...................................................................................................................................... 90
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 90
12.1.2.
Attribution Definitions.................................................................................................................. 91
12.1.3.
Severity Criteria .......................................................................................................................... 91
12.2.
Special Reporting Situations.......................................................................................................... 92
12.3.
Procedures..................................................................................................................................... 92
12.3.1.
All Adverse Events...................................................................................................................... 92
12.3.2.
Serious Adverse Events ............................................................................................................. 93
12.3.3.
Pregnancy................................................................................................................................... 94
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 94
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 94
13.1.
Procedures..................................................................................................................................... 95
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 95
14.
STUDY DRUG INFORMATION......................................................................................................... 95
14.1.
Physical Description of Study Drugs.............................................................................................. 95
14.1.1.
Intranasal Study Drug................................................................................................................. 95
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JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 5 October 2020
14.2.
Packaging ...................................................................................................................................... 96
14.3.
Labeling.......................................................................................................................................... 96
14.4.
Preparation, Handling, and Storage............................................................................................... 96
14.5.
Drug Accountability ........................................................................................................................ 96
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 97
16.
ETHICAL ASPECTS ......................................................................................................................... 97
16.1.
Study-Specific Design Considerations........................................................................................... 97
16.2.
Regulatory Ethics Compliance....................................................................................................... 99
16.2.1.
Investigator Responsibilities ....................................................................................................... 99
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 99
16.2.3.
Informed Consent ..................................................................................................................... 101
16.2.4.
Privacy of Personal Data .......................................................................................................... 101
16.2.5.
Country Selection ..................................................................................................................... 102
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 102
17.1.
Protocol Amendments.................................................................................................................. 102
17.2.
Regulatory Documentation .......................................................................................................... 102
17.2.1.
Regulatory Approval/Notification .............................................................................................. 102
17.2.2.
Required Prestudy Documentation........................................................................................... 102
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 103
17.4.
Source Documentation................................................................................................................. 104
17.5.
Case Report Form Completion .................................................................................................... 104
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 105
17.7.
Record Retention ......................................................................................................................... 105
17.8.
Monitoring .................................................................................................................................... 106
17.9.
Study Completion/Termination..................................................................................................... 106
17.9.1.
Study Completion ..................................................................................................................... 106
17.9.2.
Study Termination..................................................................................................................... 107
17.10.
On-Site Audits .............................................................................................................................. 107
17.11.
Use of Information and Publication.............................................................................................. 108
REFERENCES.......................................................................................................................................... 110
INVESTIGATOR AGREEMENT ............................................................................................................... 117
LIST OF ATTACHMENTS
Attachment 1:
Prohibited Concomitant Medications with Esketamine Nasal Spray Study 
Medication ................................................................................................................ 114
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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: 5 October 2020
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Characterization of Study Population Entering 54135419TRD3008 from Different 
Phase 3 Studies........................................................................................................................ 52
Table 2:
Induction Phase Dose Titration of Esketamine Nasal Spray, Subjects <65 Years .................. 70
Table 3:
Induction Phase Dose Titration of Esketamine Nasal Spray, Subjects ≥65 Years .................. 70
Table 4: 
Optimization/Maintenance Phase Week 1 to 4: Dose Titration of Esketamine Nasal 
Spray for Responder Subjects Entering from ESKETINTRD3005 ........................................... 71
Table 5:
Algorithm for Adjusting Intranasal Treatment Session Frequency (if applicable) 
Starting Week 4 ........................................................................................................................ 72
Table 6:
Volume of Blood to be Collected from Each Subject................................................................ 74
FIGURES
Figure 1: 
Schematic Overview of the 54135419TRD3008 Study ............................................................ 55
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved, Date: 5 October 2020
PROTOCOL AMENDMENTS
Amendments below are listed beginning with the most recent amendment.
Amendment 4 (05 October 2020)
The overall reason for the amendment: Following the conclusion of the post-marketing commitment to FDA 
for 3 years of US data at the end of 2020, the sponsor is extending the study duration to allow for ongoing 
subjects to continue to receive esketamine treatment if clinically warranted and until it is available in the subject’s
respective country, or December 2022, whichever is earlier. The number/frequency of assessments is therefore 
being reduced to mimic clinical practice and reduce burden on sites and subjects while ensuring adequate clinical 
oversight and monitoring of subject safety.
Applicable Section(s)
Description of Change(s)
Rationale: To update subject completion criteria due to extension of study. Updated text in 
Optimization/Maintenance Phase since duration is no longer based on the results of the pivotal Phase 3 trials, 
which have concluded.
Synopsis Overview of 
Study Design; 1.2 Overall 
Rationale for the Study
This study provides an opportunity for subjects who have participated in select 
Phase 3 studies to receive open label esketamine nasal spray until: 

esketamine is approved in the respective country and accessible through the 
local healthcare system funding or until end of December 2022, whichever is 
earlier; or

the subject does not benefit from further treatment (based on the 
investigator’s clinical judgment) or withdraws consent; or 

the company terminates clinical development of esketamine nasal spray for 
TRD in that country/region
3.1. Overview of Study 
Design; 9.1.3. 
Optimization/Maintenance 
Phase
The duration that a subject may participate in the study is variable and is based on 
the subject’s point of entry into the study and the timing of when the predefined 
criteria (below) for ending study participation occurs. 
Study participation will be stopped:

when esketamine is approved in the respective country and accessible through 
the local healthcare system funding or until end of December 2022, 
whichever is earlier; or

the subject no longer benefits from further treatment (based on the 
investigator's clinical judgment), or withdraws consent; or

the company terminates clinical development of esketamine nasal spray for 
TRD in that country/region
3.2.2. Study Phases
Optimization/Maintenance Phase (Variable)
The duration of the optimization/maintenance phase is variable and based on the 
subject’s individual efficacy and tolerability to esketamine nasal spray, or 
when esketamine is approved in the respective country and accessible through the 
local healthcare system funding or until end of December 2022, whichever is 
earlier.
Protocol Version 
Issue Date
Original Protocol
08 February 2016
Amendment 1
14 December 2016
Amendment 2
21 August 2017
Amendment 3
24 April 2019
Amendment 4
05 October 2020
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
7
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
10.1. Completion
A subject will be considered to have completed the study if he/she is actively 
participating in the induction or optimization/maintenance phase when one of the 
following is reached:

esketamine is approved in the respective country and accessible through the 
local healthcare system funding or until end of December 2022, whichever is 
earlier 

the company terminates clinical development of esketamine nasal spray for 
TRD in that country/region
17.9.1. Study Completion
The end of the study will occur based on the subject’s individual efficacy and 
tolerability to esketamine nasal spray, and/or until esketamine is approved in the 
respective country and accessible through the local healthcare system funding or 
until end of December 2022, whichever is earlier.
Study participation will be stopped:

when esketamine is approved in the respective country and accessible through 
the local healthcare system funding or until end of December 2022, 
whichever is earlier; or

the subject no longer benefits from further treatment (based on the 
investigator's clinical judgment), or withdraws consent; or

the company terminates clinical development of esketamine nasal spray for 
TRD in that country/region
Rationale: To update implementation and frequency of subject-completed assessments, safety assessments, and 
clinical laboratory tests in the Optimization/Maintenance Phase to mimic clinical practice and reduce burden on 
sites and subjects while ensuring adequate clinical oversight and monitoring of subject safety.
Time and Events Schedule 
(Optimization/Maintenance 
Phase)
Modified frequency of subject-completed assessments PHQ-9, SDS, 
EQ-5D-5L, TSQM-9, and QLDS from every 4 weeks to every 12 weeks.
Removed MAGDA assessment and related footnote.
MOAA/S assessment will not be required for all visits following Visit 2.4.
Pulse oximetry assessments will not be required for all visits following Visit 
2.4. 
Alcohol breath test will not be required every 8 weeks.
Updated HRUQ footnote for completion until end of December 2020.
Synopsis Medical 
Resource Utilization
Removed requirement to complete the Health Resource Utilization 
Questionnaire (HRUQ) every 4 weeks and at early withdrawal/end of study.
Rationale: To clarify that the choice of oral antidepressant use during the study will be based on the clinical 
judgment of the investigator upon assessment of the benefit risk.
Synopsis Study Phases; Section 
3.1. Overview of Study Design; 
Section 8. Prestudy and 
Concomitant Therapy
All study subjects should be taking a permitted oral antidepressant (per clinical 
judgment) throughout the duration of study participation.
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
8
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
Rationale: To remove Magda Avatar Game Depression Implicit Association (MAGDA) assessment as it was 
never developed or implemented.
Synopsis Objectives, 
Endpoints, and Hypothesis;
Synopsis Efficacy 
Analysis; 2.1.2. Endpoints; 
3.2.6. Efficacy Measures; 
9.5.1. MAGDA; 11.4.
Efficacy Analyses
Removed text regarding MAGDA assessment, which was never used in the study. 
Rationale: To update text regarding the Independent Data Monitoring Committee and clarify that meetings will 
continue through the end of 2020. Additional safety monitoring will continue in-house as this is an open-label, 
single arm study.
Synopsis Overview of 
Study Design; 3.1. 
Overview of Study Design; 
11.7. Independent Data 
Monitoring Committee
The committee will meet approximately every 6 months to review select safety
data through the end of 2020.
Rationale: Remove text related to “anticipated adverse events” to align with current protocol template text for 
open-label studies.
12.3.1. All Adverse Events
12.3.2. Serious Adverse 
Events
Attachment 2: Anticipated 
Events
Deleted text related to anticipated adverse events and updated text to align with 
current protocol template text.
Updated text to align with current protocol template text.
Attachment 2 was removed from the protocol. 
Rationale: To include instructions on handling of missed doses.
6.1.2. 
Optimization/Maintenance 
Phase
Added text regarding missed doses, clarifying that if a subject missed a dose/s and 
the depression symptoms worsened, the investigator can go back to more frequent 
dosing if clinically applicable until the subject is stable.
Rationale: Align with current protocol template text.
13. Product Quality 
Complaint Handling
13.1. Procedures
Update text and add definition for “technical complaints”.
Added text for sample retention of suspected product. 
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 5 October 2020
Amendment 3 (24 April 2019)
The overall reason for the amendment: The protocol was modified to 1) Extend the study to collect data 
characterizing the long-term effects of esketamine on cognitive function and urinary symptoms (cystitis).  2) 
Update categories of treatment emergent adverse events (TEAEs) of special interest. 3) Update Attachment 1 
(Prohibited Concomitant Medications With Esketamine Nasal Spray Study Medication) with new guidelines.
Applicable Section(s)
Description of Change(s)
Rationale: To better characterize the safety risks of long-term use of esketamine, the study was extended to 
collect data on the long-term effects of esketamine on cognitive function and urinary symptoms (cystitis).
Synopsis; 1.2. Overall 
Rationale for the Study
This study provides an opportunity for subjects who have participated in select 
Phase 3 studies to receive open label esketamine nasal spray until:

the end of December 2020 or when it is commercially available in the subject’s 
respective country (whichever is later), in order to have a reasonable number of 
subjects participating for 3 years or longer to collect long term safety data; or 

the subject does not benefit from further treatment (based on the investigator’s 
clinical judgment) or withdraws consent; or 

the company terminates clinical development of esketamine nasal spray for 
TRD in that country/region
Synopsis Overview of 
Study Design; 3.1. 
Overview of Study 
Design; 9.1.3. 
Optimization/Maintenance 
Phase
Study participation will be stopped:

at the end of December 2020 or when esketamine nasal spray is commercially 
available in the subject’s respective country (whichever is later); or

the subject no longer benefits from further treatment (based on the investigator's 
clinical judgment), or withdraws consent; or

the company terminates clinical development of esketamine nasal spray for 
TRD in that country/region
3.2.2. Study Phases
Optimization/Maintenance Phase (Variable)
The duration of the optimization/maintenance phase is variable and based on the 
subject’s individual efficacy and tolerability to esketamine nasal spray, results of 
the pivotal Phase 3 efficacy and safety studies, or when esketamine nasal spray is 
commercially available in the subject’s respective country / the end of December 
2020 (whichever is later).
10.1. Completion
A subject will be considered to have completed the study if he/she is actively 
participating in the induction or optimization/maintenance phase when one of the 
following is reached:

end of December 2020 or when esketamine nasal spray is commercially 
available in the subject’s respective country (whichever is later)

the company terminates clinical development of esketamine nasal spray for 
TRD in that country/region
17.9.1. Study Completion
The end of the study will occur based on the subject’s individual efficacy and 
tolerability to esketamine nasal spray, results of the pivotal Phase 3 efficacy and 
safety studies, and/or until the end of December 2020 or when esketamine nasal 
spray is commercially available in the subject’s respective country (whichever is 
later). 
Study participation will be stopped:

at the end of December 2020 or when esketamine nasal spray is commercially 
available in the subject’s respective country (whichever is later); or

the subject no longer benefits from further treatment (based on the investigator's 
clinical judgment), or withdraws consent; or

the company terminates clinical development of esketamine nasal spray for 
TRD in that country/region
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
10
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
Rationale: To update categories of treatment emergent adverse events (TEAEs) of special interest.
Synopsis Statistical 
Methods; 3.2.5. Safety 
Evaluations; 11.3. Safety 
Analyses
Treatment emergent AEs of special interest will be examined separately grouped in 
the following categories: drug abuse, dependence and withdrawal, increased blood 
pressure, increased heart rate, transient dizziness/vertigo, impaired cognition, 
cystitis, anxiety, events potentially related to suicidality, hepatic adverse events, 
events related to renal disorders, and symptoms of dissociation persisting beyond 
the typical ≤2 hour post esketamine administration, as well as delirium, psychosis or 
mania.
Rationale: Attachment 1 (Prohibited and Permitted Concomitant Medications With Esketamine Nasal Spray 
Study Medication) was modified to clarify the list of prohibited/permitted concomitant medications and the 
guidelines for concomitant medication use.
Attachment 1
The following text for the use of corticosteroids was added to the table since it was 
erroneously omitted in previous versions:
Corticosteroids: Inhaled, intranasal, topical, and ophthalmic steroids are not 
prohibited.
Intermittent IM/IV/PO corticosteroids are permitted with sponsor approval (chronic 
use prohibited).
The following text was added for the use of opioids:
With Sponsor approval, brief treatment with opiates may be allowed for treatment 
of acute injuries etc.
Modafinil and armodafinil were removed from the list of permitted 
psychostimulants.
Rationale: Update for preferred terminology.
Throughout the protocol, 
protocol title
Changed the name of treatment drug from “intranasal esketamine” to “esketamine 
nasal spray”.
4.2. Exclusion Criteria
In Exclusion Criterion 1, the name of the treatment drug was changed:
The evaluation of the benefit versus risk of continued esketamine nasal spray 
treatment is not favorable for the subject in the opinion of the investigator.
9.2. Safety Evaluations
Update for preferred terminology to be consistent with current template language. 
Replaced “endpoint” with “condition”.
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 condition is reached. 
Rationale: Deletion of Section 1.1.3. Marketing Experience since it is not a required section in the protocol and 
is covered in the Investigator’s Brochure.
1.1.3. Marketing 
Experience
Deletion of Section 1.1.3. Marketing Experience including statement below:
No intranasal formulation of esketamine is currently marketed.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
11
Status: Approved, Date: 5 October 2020
Amendment 2 (21 August 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 1) to allow the investigator to adjust the 
frequency of intranasal dosing sessions to every 2 weeks instead of every 4 weeks, depending on the subject’s 
depressive symptomatology, in order to allow greater flexibility with the aim of preventing depression relapse; 2) to 
permit the investigator to review machine read ECG tracing where initiation of treatment or safety follow-up is time-
critical, or if action needs to be taken for safety reasons; 3) to clarify the rationale for removal of the Mini Mental 
State Examination; and 4) to clarify that (i) pulse oximetry is to be performed at all intranasal dosing sessions, and 
(ii) to correct erroneous text relating to the MADRS assessment and permitted benzodiazepine medication.
Applicable Section(s)
Description of Change(s)
Rationale: Changes have been made to allow the investigator to adjust the frequency of intranasal dosing 
sessions during the Maintenance/Optimization Phase at 2 week intervals instead of 4 week intervals, depending
on the subject’s depressive symptomatology, in order to allow greater flexibility with the aim of preventing 
depression relapse.
Synopsis, Dosage and 
Administration, Intranasal 
Study Medication, 
Optimization/Maintenance 
Phase;
Section 6.1.2. 
Optimization/Maintenance 
Phase
Frequency of intranasal treatment sessions reduced from a 4 week interval to a 
2 week interval
The text was revised as follows (bold text added; strikeout text deleted):
Starting at Week 4, the frequency for subsequent intranasal treatment sessions will 
be adjusted (if applicable) based on the algorithm outlined in Table 5 at fixed, 
42-week intervals. 
Table 5. Algorithm for Adjusting Treatment Session Frequency.
Footnote (a): Note: Although tThe CGI-S is administered every 2 weeks from Week 
4 through the end of the Optimization/Maintenance Phase, adjustment of the 
intranasal treatment session frequency is only permitted at the fixed 4 2-week 
interval (based on CGI-S performed at that visit), and every 4 weeks for subjects 
dosed at the 4 week interval.
Time and Events 
Schedule,
Optimization/Maintenance 
Phase
Study Drug: Adjustment of intranasal treatment session frequency (if applicable) 
based on CGI-S
An “X” added to indicate that intranasal treatment session frequency is permitted at 
the fixed 2-week interval
Rationale: Clarification that the investigators review of the machine read ECG tracing (provided by the central 
reader) is considered acceptable in determining if it is appropriate in determining eligibility in cases where 
initiation of treatment or safety follow-up is time-critical and the central cardiology results are not expected to be 
available before the need to begin dosing, or if actions need to be taken for safety reasons.
Section 9.2. Safety 
Evaluations,
Electrocardiogram (ECG) 
Electrocardiogram
The following text was added:
The investigator’s review of the machine read ECG tracing (provided by the central 
reader) is considered acceptable in determining if it is appropriate in determining 
eligibility in cases where initiation of treatment or safety follow-up is time-critical, 
and where the central cardiology results are not expected to be available before the 
need to begin dosing, or if actions need to be taken for safety reasons.
All ECG tracings will be sent to the central ECG vendor, where it will be used to 
determine whether it is appropriate to proceed with dosing.
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
12
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
Rationale: Clarification that if the postmenopausal status of subjects had been previously confirmed in the 
following phase 3 studies: ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004 
and EKETINTRD3006, there is no need to perform the FSH again in this study.
Section 4.1. Inclusion 
Criteria
Criterion 4 was modified as follows (text added in bold):
Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical 
studies.
Not of childbearing potential defined as:
    postmenopausal
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level 
(>40 IU/L or mIU/mL in the postmenopausal range) will be used to 
confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy, however in the absence 
of 12 months of amenorrhea, a single FSH measurement is insufficient. 
Note: FSH not required if post-menopausal status previously confirmed 
in either ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, 
ESKETINTRD3004 or ESKETINTRD3006. FSH is not required if 
subject is ≥65 years.
    permanently sterile 
Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral 
oophorectomy. 
Rationale: Text relating to the MADRS assessment that is no longer relevant following changes made in the 
previous 54135419TRD3008 protocol amendment 1, has now been deleted. 
Section 3.2.6. Efficacy 
Measures 
MADRS
The following text was deleted:
At the end of the induction phase of this study, the MADRS will be used to 
determine response. Subjects who are responders (defined as ≥50% reduction in the 
MADRS total score from baseline [Day 1 prior to the first intranasal dose] to the 
end of the 4-week induction phase) will proceed to the optimization/maintenance 
phase. 
Rationale: Rationale provided for the removal of the Mini Mental State Examination (MMSE) at study entry has 
been revised to more clearly outline the clinical rationale. Revisions as follows (bold text): “Mini Mental State 
Examination (MMSE) was removed from 54135419TRD3008 because the MMSE would already have been 
conducted in the phase 3 ESKETINTRD3001-3005 studies and in addition there are continuous cognitive 
function assessments during the ESKETINTRD3001-3005 studies. Cognition function testing will also be 
assessed in this 54135419TRD3008 study using the Computerized Cognitive Battery and Hopkins Verbal 
Learning Test-Revised (HVLT-R).”
Changes made to the 54135419TRD3008 Protocol Amendment 1 are listed below:
Synopsis, Subject 
Population
Deleted the exclusion of subjects with a MMSE<25.
Time and Events Schedule 
(Induction Phase)
Deleted the row for MMSE.
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
13
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
4.2. Exclusion Criteria
In Exclusion Criteria 3, the following sentence was deleted:
A Mini Mental State Examination (MMSE) <25 (only applicable to subjects 
entering the 54135419TRD3008 study at the Induction Phase).
9.5. Other Evaluations
The subsection (formerly numbered 9.5.1) on MMSE was deleted.
Rationale: Clarification that since this is a safety study rather than an efficacy study, new benzodiazepines or 
dose increases in benzodiazepine medications are permitted during the study provided the dosages remain at or 
below the protocol specified cut-off.
Section 4.3 Prohibitions 
and Restrictions
The following text was revised as follows (bold text added; strike-out text deleted):
Subjects who were taking benzodiazepines at dosages equal to or less than the 
equivalent of 6 mg/day of lorazepam and/or permitted non-benzodiazepine sleep 
medications (eg, zolpidem, zaleplon) can continue these medications. Dose 
increases or new benzodiazepines are permitted during the study as long as 
dosages are equal to or less that the equivalent of 6 mg/day of lorazepam. No 
dose increases or new benzodiazepine medications are permitted during the 
induction phase with the exception of the use of permitted benzodiazepine rescue 
medication.
Rationale: Clarification that pulse oximetry measurements will be performed on all intranasal treatment session 
days during the Optimization/Maintenance Phase.
Time and Events 
Schedule, 
Optimization/Maintenance 
Phase
Safety Assessments (Clinician): Pulse oximetry 
Time and Events Schedule: An “X” was added to the relevant columns for 
clarification purposes that pulse oximetry will be performed on all intranasal 
treatment session days (ie, every week, 2 weeks, 4, 8, 12 and 24 weeks during the 
Optimization/Maintenance Phase).
Footnote d): The following text was added (bold):
Performed predose and at t = 30 minutes and 60 minutes postdose on all intranasal 
treatment session days. 
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
14
Status: Approved, Date: 5 October 2020
Amendment 1 (14 December 2016)
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: To update the entry pathways from other Phase 3 esketamine protocols 
into this protocol, and to make other administrative changes to the protocol. 
Applicable Section(s)
Description of Change(s)
Rationale: Based on feedback from investigators and related design changes affecting the esketamine Phase 3 
parent studies in subjects with treatment resistant depression, the study team has identified the need to provide 
additional subjects access to the 54135419TRD3008 study.
Synopsis Overview 
of Study Design, 
Study Entry Table; 
3.1 Overview of 
Study Design – Table 
1 and Figure 1
The following revisions were made for the entry pathways from each of the other 
esketamine Phase 3 studies to 54135419TRD3008 (strikethrough text deleted; bold text 
added):
Studies ESKETINTRD3001 / ESKETINTRD3002: 
Edited Inclusion requirement: Subject completed induction phase and the 2-week 6 
month follow-up phase visit
Added Inclusion requirement / Point of entry: Subject completed the induction 
phase and was a responder and ESKETINTRD3003 is terminated/ 
Optimization/maintenance phase
Study ESKETINTRD3003:
Added the following Inclusion requirements/Points of entry:
At Week 16 of Optimization, the subject was not eligible to proceed to the 
maintenance phase and sponsor has approved subject’s entry into 
54135419TRD3008/ Induction phase or Optimization/maintenance phase
Subject was in the induction phase and after completion of induction phase, 
was determined to not meet criteria for response, and sponsor has approved 
subject’s entry into 54135419TRD3008 / Induction phase or Optimization/ 
maintenance phase
Study ESKETINTRD3004:
Edited Inclusion requirement: Subject completed the optimization/maintenance 
phase and follow up phase
Added the following Inclusion requirement /Point of entry:
Subject was in the induction phase and did not meet criteria for response, and 
sponsor has approved subject’s entry into 54135419TRD3008/ Induction phase 
or Optimization/ maintenance phase
Added Study ESKTEINTRD3006 United States study sites only and the following 
Inclusion requirements/Points of entry:
Subject completed the induction phase and was a responder/ 
Optimization/maintenance phase
Subject completed induction phase and did not meet the response criteria, and 
sponsor has approved subject’s entry into 54135419TRD3008/ Induction phase 
or Optimization/Maintenance Phase
Figure 1 was revised according to the entry criteria described above.  
Synopsis, Subject 
Population; 
3.2.1. Study 
Population
Added ESKETINTRD3006 (US sites only) as a study from which subjects may enter 
54135419TRD3008.
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
15
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
3.2.2. Study Phases
Clarified entry into the induction phase with the addition of subjects from Study 
ESKETINTRD3006 (US sites only), and with sponsor’s approval, subjects not meeting 
criteria for response from ESKETINTRD3003 and ESKETINTRD3004.
4. Subject Population
The list of studies from which subjects may enter 54135419TRD3008 was revised with 
the addition of ESKETINTRD3006 US Sites only.
4.1. Inclusion Criteria
Inclusion Criterion 1 was modified as follows (strikethrough text deleted; bold text 
added):
Based on the prior study the subject is entering 54135419TRD3008 from:
a. From ESKETINTRD3001 or ESKETINTRD3002 study: 
i.
Subject has completed the induction phase and the 2-week 6 month follow up 
phase visit; or.
i.ii.Subject completed the induction phase and was a responder and study 
ESKETINTRD3003 is terminated.
b. From ESKETINTRD3003 study:
i.
Subject relapsed during the maintenance phase; or 
ii. Subject was in the induction phase of the ESKETINTRD3003 study when the 
study was terminated and, after completion of the induction phase, was determined 
to be a responder; or 
iii. Subject was in the optimization or maintenance phases at the time the study was 
terminated; or
iv. At Week 16 of Optimization, the subject was not eligible to proceed to the 
Maintenance phase and sponsor has approved subject’s entry into 
54135419TRD3008; or
i.v. Subject was in the induction phase and after completion of induction phase 
was determined to not meet response criteria, and sponsor has approved 
subject’s entry into 54135419TRD3008.
c. From ESKETINTRD3004 study:
i.
Subject completed the ESKETINTRD3004 study (ie, Week 52 of the
optimization/maintenance phase and the follow up phase) or
ii
Subject was in the induction phase of the ESKETINTRD3004 study when the 
study was terminated and, after completion of the induction phase, was determined 
to be a responder; or
iii. Subject was in the optimization/maintenance phase at the time the study was 
terminated; or.
ii iv.
Subject was in the induction phase and did not meet criteria for 
response, and sponsor has approved subject’s entry into 54135419TRD3008.
d. From ESKETINTRD3005 study: Subject was in the induction phase of the 
ESKETINTRD3005 study at the time enrollment into the ESKETINTRD3004 study was 
closed and, after completion of the induction phase, was determined to be a responder or 
a non responder did not meet the criteria for response.
e. From ESKETINTRD3006 study (US Study sites only):
i.
Subject completed the induction phase and was a responder, or 
iv.ii.
Subject completed the induction phase and did not meet the response 
criteria and sponsor has approved subject’s entry into 54135419TRD3008. 
9.1.2. Induction 
Phase
The third bullet for subjects who could enter at the Induction Phase was revised as 
follows (strikethrough text deleted; bold text added):

Subjects who completed the induction phase and the 2-week 6 month follow up 
phase visit in ESKETINTRD3001 or ESKETINTRD3002 studies
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
16
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
9.1.3. Optimization/ 
Maintenance Phase
Two new bullets were added for subjects who could enter at the 
Optimization/Maintenance Phase, as follows:

Subjects who completed the induction phase of ESKETINTRD3001 or 
ESKETINTRD3002 and were responders, and study ESKETINTRD3003 is 
terminated.

Subjects (US only) who completed the induction phase of ESKTEINTRD3006 and 
were responders. 
It was clarified that subjects only had to complete the optimization/maintenance phase of 
ESKETINTRD3004 (no longer required to complete the follow-up phase of that study)
9.1.4. Induction 
Phase and 
Optimization/ 
Maintenance Phase –
Study Entry
This section was newly added for subjects who could enter either at the Induction Phase 
or the Optimization/ Maintenance Phase, as follows: 
The following subjects are eligible to enter the study at either the Induction Phase or the 
Optimization/Maintenance Phase:

Subjects in ESKETINTRD3003, who at Week 16 of Optimization were not eligible 
to proceed to the maintenance phase and the sponsor has approved subject’s entry 
into 54135419TRD3008; or 

Subjects in ESKETINTRD3003 and ESKETINTRD3004, who were in the induction 
phase and (for ESKETINTRD 3003, after completion of the induction phase) were 
determined to not meet response criteria, and sponsor has approved subject’s entry 
into 54135419TRD3008; or 

Subjects in ESKETINTRD3006 (US sites only) who completed the induction phase 
but did not meet the response criteria, and sponsor has approved subject’s entry into 
54135419TRD3008.
16.1. Study-Specific 
Design 
Considerations
Revised text in this section (under subheading “Selection of subjects”) as follows 
(strikethrough text deleted; bold text added):
All subjects will be from Phase 3 studies ESKETINTRD3001, ESKETINTRD3002, 
ESKETINTRD3003, ESKETINTRD3004, and ESKETINTRD3005, and 
ESKETINTRD3006 (US Sites only). 
For subjects who have participated in the ESKETINTRD3003, ESKETINTRD3004, and 
ESKETINTRD3005 studies and have responded to intranasal esketamine treatment, or 
did not the meet study criteria for response but per clinical judgment have 
benefitted, it is considered an ethical obligation to provide continued intranasal 
esketamine treatment if the benefit/risk profile is favorable for the subject at the time of 
completion of the previous study. 
For subjects who have completed the induction phase of ESKETINTRD3005 or
ESKETINTRD3006 (US Sites only) and are non responders did not meet the study 
criteria for response, or for subjects who have completed the induction phase and 6
month 2-week follow up phase visit of the ESKETINTRD3001 or ESKETINTRD3002 
study, as the double-blind treatment (intranasal esketamine or placebo) in these studies 
will be blinded, the second induction phase of this study provides the following: 

Subjects who are non-responders to intranasal placebo and oral antidepressant in the 
prior study have the potential of receiving esketamine in this study, and 

Subjects who are non-responders to intranasal esketamine in the prior study who 
decide to participate in this study may not benefit from additional treatment with 
intranasal esketamine. The benefit of additional treatment with esketamine remains 
unknown. In case of no perceived benefit of intranasal esketamine to the subject 
during this study, the subject and/or investigator may choose to discontinue study 
participation.
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
17
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
Rationale: To allow more flexibility when clinically indicated, the sponsor is removing the requirement that a 
subject should rollover from the parent study within a specific period of time. There is now no maximum duration 
between completing the parent study and starting the 54135419TRD3008 study
Time and Events 
Schedule (Induction 
Phase)
Footnote “b” was revised as follows (strikethrough text deleted; bold text added):
Visit 1.1 (Day 1) of 54135419TRD3008 study must occur within 4 weeks of the last 
study visit of the subject’s prior study (ie, ESKETINTRD3001, 3002, 3003, or non
responders from 3005). There is no maximum time limit between completing the 
prior study and enrolling into 54135419TRD3008. If a study procedure from the 
prior study has already been performed on the same day, duplicate predose 
assessments do not need to be repeated on Visit 1.1 (Day 1) of 54135419TRD3008 
study. 
Time and Events 
Schedule 
(Optimization/ 
Maintenance Phase)
Footnote “c” was revised as follows (strikethrough text deleted; bold text added):
For subjects entering the 54135419TRD3008 Optimization/Maintenance Phase after 
completing the induction phase of the ESKETINTRD3003, ESKETINTRD3004, or 
ESKETINTRD3005 studies, the Day 28 visit of the prior study is expected to coincide 
with Visit 2.1 for this study. If so, results for all predose assessments performed on Day 
28 of the induction phase of the prior study will not be repeated as part of Visit 2.1. If 
there is a gap between Day 28 and Visit 2.1, assessments listed for Visit 2.1 should 
be completed. If the MADRS is completed less than 1 week prior to Visit 2.1, it does 
not need to be repeated. Similarly, All other for subjects from the 
ESKETINTRD3003and ESKETINTRD3004 studies entering 54135419TRD3008 at the 
optimization/maintenance phase, Visit 2.1 of the 54135419TRD3008 study must occur 
within 4 weeks of the last study visit of the subject’s prior study (ie, 
ESKETINTRD3003, ESKETINTRD3004); if the visits occur the same day as the last 
visit of the parent study, duplicate predose assessments are not required.
Rationale: Based on feedback from investigators and to mimic clinical practice, rather than using the MADRS 
total score cut-off for responders at the end of the induction phase in this long term open-label safety extension 
study, the sponsor will now allow the investigator to determine whether or not it is clinically appropriate for  the 
subject to proceed to the optimization/maintenance phase.
Synopsis, Study 
Phases; 
3.1. Overview of 
Study Design
The text in the following paragraphs concerning the induction phase was revised 
(strikethrough text deleted; bold text added):
At the end of the induction phase, subjects who are responders (defined as ≥50% 
reduction in the MADRS total score from baseline [prior to the first intranasal dose in 
54135419TRD3008 study] to the end of the 4 week induction phase) may be eligible to 
proceed to the optimization/maintenance phase, according to the investigator’s clinical 
assessment of the benefit versus risk for the subject.
9.1.2. Induction 
Phase
At the end of the induction phase of 54135419TRD3008, responder subjects (defined as 
≥50% reduction in the MADRS total score from baseline [Day 1 prior to the first 
intranasal dose in 54135419TRD3008 study] to the end of the 4 week induction phase) 
may be eligible to proceed to the optimization/maintenance phase, according to the 
investigator’s clinical assessment of the benefit versus risk for the subject.
Rationale: To mimic clinic practice, going from induction to optimization will be determined by the clinician 
instead of an arbitrary cutoff on the MADRS total score; the text was updated accordingly, where relevant
3.2.2. Study Phases
In the subsection concerning the optimization maintenance phase, the following revision 
was made (strikethrough text deleted):
Responder Subjects entering this phase from the induction phase of this study 
(54135419TRD3008) will be able to reduce the frequency of intranasal treatment 
sessions and subsequently individualize and stabilize the treatment session frequency to 
weekly, every other week, or every 4 weeks based on the severity of depression during 
this phase.
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
18
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
3.2.4. Intranasal 
Treatment Group and 
Dose Selection
In the subsection concerning the optimization maintenance phase, the following 
revisions were made (bold text added; strikethrough text deleted):
Responder Subjects entering this phase from the induction phase of 54135419TRD3008, 
who enter the optimization/maintenance phase will continue on the same dose of 
intranasal esketamine from the induction phase and have a weekly intranasal 
treatment session frequency (ie, reduced frequency from the twice-weekly 
frequency in the induction phase).
Subjects who were responders at the end of the induction phase of 
ESKETINTRD3001, ESKETINTRD3002 or ESKETINTRD3006 (US sites only) 
who enter the optimization/maintenance phase will have a weekly intranasal 
treatment session frequency (ie, reduced frequency from the twice-weekly 
frequency in the induction phase). However, as the ESKETINTRD3001, 3002 and 
3006 intranasal study medication is blinded at the time of entry into the current 
study, subjects entering the optimization/maintenance phase should start at 56 mg. 
The dose may remain at 56 mg or be increased to 84 mg, as determined by the 
investigator based on efficacy and tolerability.
With sponsor approval, subjects from ESKETINTRD3003 and (if entering directly 
from ESKETINTRD3003 induction phase), or ESKETINTRD3004 (if entering directly 
from ESKETINTRD3004 the induction phase) who were determined to not meet the 
criteria for response in those studies, will may enter the optimization /maintenance 
phase of 54135419TRD3008 and will have the a weekly intranasal treatment session 
frequency from week 1 to week 4 (ie, reduced from that in the induction phase (twice 
weekly) to weekly for the first 4 weeks of this phase). In addition, a one-time dose 
change will be allowed at study entry.There will be no changes to the intranasal dose 
permitted during the first 4 weeks of this phase (ie, Week 1, 2, 3, and 4) and subjects 
will continue to receive intranasal esketamine treatment at the same dose from the 
induction phase. 
With Sponsor approval subjects from ESKETINTRD3006 (US sites only) entering 
directly from induction phase and determined to not meet criteria for response in 
that study may enter the optimization/maintenance phase. However, as the 
ESKETINTRD3006 intranasal study medication is blinded at the time of entry into 
the current study, subjects entering the optimization/maintenance phase from 
study ESKETINTRD3006 will start at 56 mg. The dose may remain at 56 mg or be 
increased to 84 mg, as determined by the investigator based on efficacy and 
tolerability. Subjects will have a weekly intranasal treatment session frequency 
from week 1 to week 4 (ie, reduced frequency from the twice-weekly frequency in 
the induction phase).
From Week 1 to 4 (inclusive), Subjects entering the optimization/maintenance phase 
from study ESKETINTRD3003 (Direct Entry) or ESKETINTRD3004 who were 
ongoing in the Optimization, Maintenance, or Optimization/Maintenance phase 
respectively, will have the option to have their current intranasal dosing frequency 
adjusted at the time of entry into 54135419TRD3008 study and should remain on 
the selected frequency from week 1 to week 4 (inclusive). continue on the same A 
one-time dose change will be permitted at study entry. and frequency of intranasal 
esketamine from the prior study as they had been receiving at the time of completion of 
those studies.
Subjects entering the optimization/maintenance phase from study 
ESKETINTRD3003 (Transferred Entry) will start at 56 mg. The dose may remain 
at 56 mg or be increased to 84 mg, as determined by the investigator based on 
efficacy and tolerability. In addition, subjects will have the option to have their 
current intranasal dosing frequency adjusted at the time of entry into 
54135419TRD3008 study and should remain on the selected frequency from week 1 
to week 4 (inclusive).
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
19
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
Responder Subjects from the induction phase of ESKETINTRD3005 will have the 
intranasal treatment session frequency reduced to weekly. However, as the 
ESKETINTRD3005 study will be blinded at the time of entry into the current study, these 
subjects will start intranasal esketamine with an initial dose of 28 mg (Week 1; Study 
Day 1) and have their dose adjusted over the following 3 weeks of the 
optimization/maintenance phase as described under the Section 6 Dosage and 
Administration.
Synopsis, Dosage and 
Administration, 
Optimization/ 
Maintenance Phase; 
6.1.2. Optimization/ 
Maintenance Phase
Starting with the first bullet the following revisions were made (bold text added; 
strikethrough text deleted):

Responder  Subjects from the induction phase of studyies 54135419TRD3008, who 
enter the optimization/maintenance phase will continue on the same dose of 
intranasal esketamine from the induction phase and have a weekly intranasal 
treatment session frequency (ie, reduced frequency from the twice-weekly 
frequency in the induction phase).

Subjects who were responders at the end of the induction phase of 
ESKETINTRD3001, ESKETINTRD3002 or ESKETINTRD3006 (US sites only) 
who enter the optimization/maintenance phase will have a weekly intranasal 
treatment session frequency (ie, reduced frequency from the twice-weekly 
frequency in the induction phase). However, as the ESKETINTRD3001, 3002 and
3006 intranasal study medication is blinded at the time of entry into the current 
study, subjects entering the optimization/maintenance phase should start at 
56 mg. The dose may remain at 56 mg or be increased to 84 mg, as determined 
by the investigator based on efficacy and tolerability.

With sponsor approval, subjects from ESKETINTRD3003 and (if entering directly 
from ESKETINTRD3003 induction phase) or ESKETINTRD3004 (if entering directly 
from ESKETINTRD3004 the induction phase) who were determined to not meet the 
criteria for response in those studies may enter the optimization/maintenance 
phase of 54135419TRD3008 continue on the same dose of intranasal esketamine from 
the induction phase and will have a weekly intransal treatment session frequency from 
week 1 to week 4 (ie, reduced frequency from the twice-weekly frequency in the 
induction phase). In addition, a one-time dose change will be allowed at study 
entry.

With sponsor approval, subjects from ESKETINTRD3006 (US sites only) 
entering directly from induction phase and determined to not meet criteria for 
response in that study may enter the optimization/maintenance phase. However, 
as the ESKETINTRD3006 intranasal study medication is blinded at the time of 
entry into the current study, subjects entering the optimization/maintenance 
phase from study ESKETINTRD3006 will start at 56 mg. The dose may remain 
at 56 mg or be increased to 84 mg, as determined by the investigator based on 
efficacy and tolerability. Subjects will have a weekly intranasal treatment 
session frequency from week 1 to week 4 (ie, reduced frequency from the twice-
weekly frequency in the induction phase).

Responder Subjects entering the optimization/maintenance phase from study 
ESKETINTRD3005 will also have a weekly intranasal treatment session frequency. 
However, as the ESKETINTRD3005 intranasal study medication is blinded at the time 
of entry into the current study, the dose of intranasal esketamine will be administered 
as outlined in the table below. (Table 4 in Section 6.1.2)

Subjects entering the optimization/maintenance phase from study ESKETINTRD3003 
(Direct Entry) or ESKETINTRD3004 who were ongoing in the Optimization, 
Maintenance, or Optimization/Maintenance phase, respectively, will have the option 
to have their current intranasal dosing frequency adjusted at the time of entry 
into 54135419TRD3008 study and should remain on the selected frequency from 
week 1 to week 4 (inclusive). continue from week 1 to 4 (inclusive) on the same A 
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
20
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
one-time dose change will be permitted at study entry.  and frequency of intranasal 
esketamine as they had been receiving at the time of completion of those studies

Subjects entering the optimization/maintenance phase from study 
ESKETINTRD3003 (Transferred Entry) will start at 56 mg. The dose may 
remain at 56 mg or be increased to 84 mg, as determined by the investigator 
based on efficacy and tolerability. In addition, subjects will have the option to 
have their current intranasal dosing frequency adjusted at the time of entry into 
54135419TRD3008 study and should remain on the selected frequency from 
week 1 to week 4 (inclusive).
Rationale: To allow appropriate study subjects to enter study 54135419TRD3008 without having to wait for 
laboratory results, as long as the investigator attests that the subject is medically stable per their clinical 
judgment.
4.1 Inclusion Criteria
Inclusion Criterion 3 revised as follows (strikethrough text deleted; bold text added):
Subject must be medically stable according to the investigator’s judgment and 
knowledge of the subject’s medical stability in the parent study. on the basis of 
clinical laboratory tests performed predose on the day of the first intranasal treatment 
session. 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 or to be 
appropriate and reasonable for the population under study. This determination must be 
documented. recorded in the subject's source documents and initialed by the 
investigator.
Rationale: To use the urine pregnancy test in order to allow the results to be available to the site prior to dosing, 
rather than waiting for the results of serum pregnancy test.
4.1 Inclusion Criteria
Inclusion Criterion 5 revised as follows (strikethrough text deleted):
A woman of childbearing potential must have a negative serum (ß human chorionic 
gonadotropin [ß hCG]) urine pregnancy test predose on the day of the first intranasal 
treatment session.
Rationale: To provide consistency with the Phase 3 esketamine studies from which subjects can roll over into 
54135419TRD3008, regarding the use of contraception for male subjects 
4.1 Inclusion Criteria
Inclusion Criterion 6 was revised as follows (strikethrough text deleted; bold text 
added):
During the study (ie, from the first intranasal treatment session) and for a minimum of 1 
spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose 
of intranasal study medication, in addition to the user independent highly effective 
method of contraception, a man who is sexually active with a woman of childbearing 
potential

who is sexually active with a woman of childbearing potential must be practicing a 
highly effective method of contraception with his female partner from those 
listed above (see examples of highly effective methods of contraception provided 
for female subjects). agree to use a double barrier method of contraception (eg, 
diaphragm or cervical/vault caps plus condom with spermicidal 
foam/gel/film/cream/suppository).

who is sexually active with a woman who is pregnant must use a condom if his 
partner is pregnant.

must agree not to donate sperm
Alternatively female partners of childbearing potential may be practicing a highly 
effective method of birth control, eg, established use of oral, injected, or implanted 
hormonal methods of contraception; placement of an intrauterine device (IUD) or 
intrauterine system (IUS); or male partner sterilization. Note: If the childbearing 
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
21
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
potential changes after start of the study, a female partner of a male study subject, must 
begin a highly effective method of birth control, as described above.
Rationale: To decrease the burden on study sites and subjects in this open-label safety extension study, the 
sponsor removed the Mini Mental State Examination (MMSE) at study entry. 
Synopsis, Subject 
Population
Deleted the exclusion of subjects with a MMSE<25.
Time and Events 
Schedule (Induction 
Phase)
Deleted the row for MMSE.
4.2. Exclusion 
Criteria
In Exclusion Criteria 3, the following sentence was deleted:
A Mini Mental State Examination (MMSE) <25 (only applicable to subjects entering the 
54135419TRD3008 study at the Induction Phase).
9.5. Other 
Evaluations
The subsection (formerly numbered 9.5.1) on MMSE was deleted.
Rationale: To decrease the burden on study sites and subjects in this open-label safety extension study. 
9.2. Safety 
Evaluations, Clinical 
Laboratory Tests
Deleted the requirement that the glucose assessment be performed on subjects in a 
fasting state. 
9.2. Safety 
Evaluations, Pulse 
Oximetry
The text in the second paragraph of this section was revised as follows (strikethrough 
text deleted; bold text added):
On intranasal treatment session days, pulse oximetry will be recorded predose and
every 15 minutes from predose to t=1 hours postdose during the induction phase. 
During the optimization/ maintenance phase, pulse oximetry will be recorded 
predose and at 30 minutes and 60 minutes postdose on intranasal treatment session 
days. If oxygen saturation levels are <93% at any time during the 1 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.
Rationale: To remove text that applies to study medication in pill form, which is not applicable for this study.
14.5. Drug 
Accountability
The text in this section was revised as follows (strikethrough text deleted; bold text 
added):
The investigator is responsible for ensuring that all study drug received at the site is 
inventoried and accounted for throughout the study.
The dispensing of study drug to the subject, and the return of study drug from the 
subject (if applicable), must be documented on the drug accountability form. Subjects 
must be instructed to return all original containers, whether empty or containing study 
drug.
The study drug administered to the subject must be documented on the drug 
accountability form. All The study drug will be stored and disposed of according to the 
sponsor's instructions. Study site personnel must not combine contents of the study drug 
containers.
Study drug must be handled in strict accordance with the protocol and the container 
label, and must be stored at the study site in a limited-access area or in a locked cabinet 
under appropriate environmental conditions. Unused study drug, and study drug returned 
by the subject, must be available for verification by the sponsor's study site monitor 
during on-site monitoring visits. The return to the sponsor of unused study drug, or used 
returned study drug for destruction, will be documented on the investigational product 
destruction form. When the study site is an authorized destruction unit and study drug 
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
22
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
supplies are destroyed on-site, this must also be documented on the investigational 
product destruction 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/clinical study site 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. Whenever a subject brings his or 
her study drug to the study site for pill count, this is not seen as a return of supplies. 
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.
Rationale: Clarifications made regarding the usage of certain concomitant medications (ADHD medications, 
anticonvulsants, clonidine, corticosteroids, lithium, and psychostimulants.) 
Attachment 1
For ADHD medications, allowed continuous use (previously prohibited); added that 
these medications can be continued but must not be taken within 12 hours prior to the 
intranasal treatment session or for 2 hours after the intranasal treatment session. 
For anticonvulsants, both episodic and continuous yes now allowed (previously 
prohibited); deleted text prohibiting use of these medications as adjunctive treatment for 
major depressive disorder.
Added rows for clonidine (both episodic and continuous use for blood pressure control 
is allowed) and corticosteroids (systemic; both episodic and continuous use allowed).
Removed lithium as a prohibited medication (ie, now allowed)
For psychostimulants, allowed continuous use (previously prohibited); added that 
prescribed psychostimulants can be continued (or newly initiated) but must not be taken 
within 12 hours prior to the intranasal treatment session or for 2 hours after the 
intranasal treatment session. 
Rationale: Revised the list of anticipated events to remove the terms that are on the adverse drug reactions 
(ADRs) list in the Investigator’s Brochure (anticipated events should be events that are not on the ADR list). 
Attachment 2
Removed the terms “excessive happiness” and “feeling anxious/anxiety”. Deleted one 
instance of the term “abnormal sleep” (was inadvertently listed twice). 
Rationale: Minor changes were made throughout the protocol for compliance with updated protocol template 
text, for clarification, and to correct errors.
Cover page
Deleted Janssen Infections Diseases BVBA from the sponsorship statement. 
Time and Events 
Schedule (Induction 
Phase) 
On Day 28, the visit window was changed to ±1 day (from -1 day) to be consistent with 
other visit windows during the induction phase. 
Footnote “c” was added to the rows “MADRS (7-day recall)”, “computerized test 
battery and HVLT-R”, “Hematology, chemistry”, and “alcohol breath test”. 
Time and Events 
Schedule 
(Optimization/ 
Maintenance Phase)
Footnote “u” was added (to the row “Intranasal esketamine treatment session”). This 
footnote reads as follows: Subjects entering this phase from the induction phase of this 
study (54135419TRD3008) will be able to reduce the frequency of intranasal treatment 
sessions to weekly during Weeks 1 to 4 and subsequently (after Week 4) individualize 
and stabilize the treatment session frequency to weekly, every other week, or every 4 
weeks based on the severity of depression during this phase (see Section 3.2.2).
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
23
Status: Approved, Date: 5 October 2020
Applicable Section(s)
Description of Change(s)
4.1. Inclusion Criteria
Inclusion Criterion 4 was modified to include the following statement:
Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical studies. 
4.3 Prohibitions and 
Restrictions
Revised the first bullet as follows (strikethrough text deleted; bold text added): 

Agree to follow all requirements that must be met during the study as noted in
Refer to Section 4.1 (Inclusion Criteria) and Section 4.2 (Exclusion Criteria) (eg. for 
information regarding contraception requirements).
12.3.1. All Adverse 
Events
Revised the text in the following paragraph (bold text added): 
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).  For anticipated events reported as individual serious adverse 
events the sponsor will make a determination of relatedness in addition to and 
independent of the investigator’s assessment. The sponsor will periodically evaluate 
the accumulating data and, when there is sufficient evidence and the sponsor has 
determined there is a reasonable possibility that the drug caused a serious 
anticipated event, they will submit a safety report in narrative format to the 
investigators (and the head of the investigational institute where required).  The 
investigator (or sponsor where required) must report SUSARs to the appropriate 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the 
protocol unless otherwise required and documented by the IEC/IRB.
17.4. Source 
Documentation
Revised the last paragraph of this section as follows (strikethrough text deleted; bold
text added): 
An electronic source eSource 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 an electronic
source eSource is utilized, references made to the CRF in the protocol include the 
electronic source eSource system but information collected through the electronic 
source eSource may not be limited to that found in the CRF. Data in this system may 
be considered source documentation.
17.5 Case Report 
Form Completion
Deleted text stating “All data relating to the study must be recorded in CRF.”
Attachment 2
Under the subheading Reporting of Adverse Events, revised the following paragraph 
(strikethrough text deleted; bold text added): 
These All adverse events will be captured on the CRF and in the database regardless of 
whether considered to be anticipated events, and will be reported to the sponsor as 
described in Section 12.3.1. 
Investigator 
Agreement Page
Removed the “LAST PAGE” designation.
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
24
Status: Approved, Date: 5 October 2020
SYNOPSIS
An Open-label Long-term Extension Safety Study of Esketamine Nasal Spray in Treatment-resistant 
Depression
Major depressive disorder (MDD), a serious, recurrent, and disabling psychiatric illness, is the second 
leading cause of years lost to disability worldwide. Major depressive disorder is associated with excess 
mortality; and with years of potential life lost. About 30% of patients fail to achieve remission despite 
treatment with multiple antidepressant medications and are considered to have treatment-resistant 
depression (TRD). In patients who respond to antidepressants, the time to onset of effect is typically 4 to 
7 weeks, during which time patients continue to suffer from their symptoms and continue to be at risk of 
self-harm, as well as being impacted by the associated harm to their personal and professional lives. 
Therefore, there is a significant need to develop novel treatments based upon relevant pathophysiologic 
pathways underlying MDD for the rapid relief of symptoms of depression, especially in patients with TRD.
Ketamine and esketamine (S-ketamine, the S enantiomer of ketamine) are approved in many countries and 
widely used for the induction and maintenance of anesthesia via intramuscular (IM) or intravenous (IV) 
administration. The desired analgesic-anesthetic effects of ketamine and esketamine are attributed to the 
blockade of ionotropic N-methyl-D-aspartate (NMDA) glutamate receptors. The mechanism of action of 
ketamine and esketamine is distinct from conventional monoaminergic antidepressant treatments and 
ketamine profoundly affects fast excitatory glutamate transmission, increases brain-derived neurotrophic 
factor (BDNF) release, and stimulates synaptogenesis.
Janssen Research & Development (JRD) is developing esketamine nasal spray as an antidepressant therapy. 
A higher NMDA receptor affinity of esketamine compared to ketamine, allows a lower volume of 
medication to be administered via the non-invasive and rapidly-absorbed intranasal route.
There is an ethical obligation to provide continued esketamine nasal spray treatment to subjects who 
participated in select Phase 3 studies and for whom the benefit versus risk has been favorable. This study 
provides an opportunity for subjects who have participated in select Phase 3 studies to receive open label 
esketamine nasal spray until:

esketamine is approved in the respective country and accessible through the local healthcare system 
funding or until end of December 2022, whichever is earlier; or 

the subject no longer benefits from further treatment (based on the investigator’s clinical judgment) or 
withdraws consent; or 

the company terminates clinical development of esketamine nasal spray for TRD in that country/region
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Primary Objectives
The primary objective of this study is to assess the safety and tolerability of esketamine nasal spray in 
subjects with TRD, with special attention to the following:

Potential long-term effects on cognitive function

Treatment-emergent adverse events (TEAEs), including TEAEs of special interest

Post dose effects on heart rate, blood pressure, respiratory rate and blood oxygen saturation

Potential effects on suicidal ideation/behavior 
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
25
Status: Approved, Date: 5 October 2020
Secondary Objective
The secondary objective is to assess long-term efficacy, including effects on:

Depressive symptoms (clinician and self-reported), 

Overall severity of depressive illness, 

Functioning and associated disability, 

Health-related quality of life and health status,
Exploratory Objectives
The exploratory objectives are to assess:

Medical resource utilization

Response and remission rates to a second induction phase in eligible subjects who had relapsed in 
study ESKETINTRD3003

Subject treatment satisfaction 

Subject tradeoff preferences for key benefit and harm outcomes associated with TRD treatment, using 
a stated-choice preference survey
Endpoints
Safety endpoints are listed below:

Occurrence of TEAEs, including TEAEs of special interest

Potential short-term effects observed on the day of intranasal treatment session with special attention 
to changes from baseline/predose over time for:

Blood pressure (systolic and diastolic) and heart rate

Blood oxygen saturation

12-lead electrocardiogram

Alertness and sedation using Modified Observer’s Assessment of Alertness/Sedation (MOAA/S)

Long-term effects, with special attention to changes from baseline over time for:

Computerized cognitive battery and Hopkins Verbal Learning Test-Revised (HVLT-R), to assess 
potential effects on cognitive function

Columbia-Suicide Severity Rating Scale (C-SSRS), to assess potential effects on suicidal ideation 
and behavior

Changes from baseline over time in clinical laboratory tests, including hematology, serum chemistry, 
and urinalysis

Time to discharge readiness, using the Clinical Global Assessment of Discharge Readiness (CGADR)
Efficacy endpoints include changes from baseline over time for the following:

Depressive symptoms, including response (≥50% improvement from baseline) and remission 
(MADRS total score ≤12, PHQ-9 total score <5); using the Montgomery Asberg Depression Rating 
scale (MADRS) and 9-item self-reported Patient Health Questionnaire (PHQ-9) 

Overall severity of illness, using the Clinical Global Impression Severity (CGI-S)
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
26
Status: Approved, Date: 5 October 2020

Functioning and associated disability, using the Sheehan Disability Scale (SDS)

Health related quality of life and health status, using the European Quality of Life (EuroQol) Group, 
5-Dimension, 5-Level (EQ-5D-5L)

Health related quality of life using the Quality of Life in Depression Scale (QLDS)
Exploratory endpoints include:

Changes from baseline over time for:

Depression response and remission rates (as defined above) to a second induction phase in eligible 
subjects who had relapsed in study ESKETINTRD3003, assessed using the MADRS and PHQ-9 

Subject treatment satisfaction

Subject tradeoff preferences for key benefit and harm outcomes associated with TRD treatment, using 
a stated-choice preference survey
Hypothesis
There is no formal hypothesis for this study.
OVERVIEW OF STUDY DESIGN
This is a multicenter, open-label long term extension study to evaluate the safety, tolerability, and efficacy 
of esketamine nasal spray in subjects with TRD. 
The table below describes the subjects who may be eligible to participate in this study based on the clinical 
judgment of the investigator and their point of entry into 54135419TRD3008:  
Prior Study
Inclusion requirement
Point of entry for 
54135419TRD3008
ESKETINTRD3001
Subject completed induction phase and the 2- week 
follow-up phase visit
Induction phase
Subject completed the induction phase and was a 
responder and ESKETINTRD3003 is terminated.
Optimization/maintenance phase
ESKETINTRD3002
Subject completed induction phase and the 2- week 
follow-up phase visit
Induction phase
Subject completed the induction phase and was a 
responder and ESKETINTRD3003 is terminated.
Optimization/maintenance phase
ESKETINTRD3003
Subject relapsed in maintenance phase
Induction phase
Subject was in the induction phase at the time the study 
was terminated and, and, after completion of the 
induction phase, was determined to be a responder. 
Optimization/maintenance phase
Subject was in the optimization or maintenance phase at 
the time the study was terminated
Optimization/maintenance phase
At Week 16 of Optimization, the subject was not 
eligible to proceed to the maintenance phase and 
sponsor has approved subject’s entry into 
54135419TRD3008
Induction phase or 
Optimization/maintenance phase
Subject was in the induction phase and after completion 
of induction phase, was determined to not meet criteria 
for response and sponsor has approved subject’s entry 
into 54135419TRD3008 
Induction phase or 
Optimization/maintenance phase
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
27
Status: Approved, Date: 5 October 2020
Prior Study
Inclusion requirement
Point of entry for 
54135419TRD3008
ESKETINTRD3004
Subject completed the optimization/maintenance phase 
Optimization/maintenance phase
Subject was in the induction phase at the time the study 
was terminated and, after completion of the induction 
phase, was determined to be a responder. 
Optimization/maintenance phase
Subject was in the optimization/maintenance phase at 
the time the study was terminated
Optimization/maintenance phase
Subject was in the induction phase and did not meet 
criteria for response and sponsor has approved subject’s 
entry into 54135419TRD3008
Induction phase or 
Optimization/maintenance phase
ESKETINTRD3005  Subject was in the induction phase of 
ESKETINTRD3005 study at the time enrollment into 
the ESKETINTRD3004 study was closed and, after 
completion of the induction phase, was determined to be 
a non-responder.  
Induction phase 
Subject was in the induction phase of 
ESKETINTRD3005 study at the time enrollment into the 
ESKETINTRD3004 study was closed and, after 
completion of the induction phase, was determined to be 
a responder
Optimization/maintenance phase
ESKETINTRD3006
United States study 
sites only
Subject completed the induction phase and was a
responder.
Optimization/maintenance phase 
Subject completed induction phase and did not meet the 
response criteria, and sponsor has approved subject’s 
entry into 54135419TRD3008.
Induction phase or 
Optimization/Maintenance Phase 
An Independent Data Monitoring Committee (IDMC) will meet approximately every 6 months to review 
select safety data through the end of 2020. 
This study has 2 open label phases

A 4-week induction phase (if applicable, per table above)

A variable duration optimization/maintenance phase
The duration that a subject may participate in the study is variable and is based on the subject’s point of 
entry into the study and the timing of when the predefined criteria (below) for ending study participation 
occurs.
Study participation will be stopped:

when esketamine is approved in the respective country and accessible through the local healthcare 
system funding or until end of December 2022, whichever is earlier; or

the subject no longer benefits from further treatment (based on the investigator's clinical judgment), 
or withdraws consent; or

the company terminates clinical development of esketamine nasal spray for TRD in that country/region
Study Phases 
All study subjects should be taking a permitted oral antidepressant (per clinical judgment) throughout the
duration of study participation. Changes to the oral antidepressant medication(s) that a subject is taking at 
study entry is permitted per clinical judgment of the investigator. If subject may benefit from an additional 
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
28
Status: Approved, Date: 5 October 2020
antidepressant medication (eg lithium, bupropion, adjunctive antipsychotic, etc.), the investigator should 
discuss with sponsor to determine whether continuing esketamine nasal spray still has a favorable benefit 
versus risk for the subject. 
Induction Phase 
Subjects will self-administer open-label esketamine nasal spray as a flexible dose regimen twice a week for 
4 weeks as outlined in the “Dosage and Administration” section. 
At the end of the induction phase, subjects may be eligible to proceed to the optimization/maintenance 
phase according to the investigator’s clinical assessment of the benefit versus risk for the subject. 
If a subject withdraws from the study before the end of the induction phase for reasons other than 
withdrawal of consent, an Early Withdrawal (EW) visit will be conducted within 1 week of the last 
intranasal dose. 
Subjects who are currently in the induction phase at the time the 54135419TRD3008 study is completed 
will conduct an “End of Study” visit as their final study visit within 1 week of the last intranasal dose.
Optimization/Maintenance Phase: 
During this phase, the dose and intranasal treatment session frequency can be adjusted based on the criteria 
outlined in the “Dosage and Administration” section.
If a subject withdraws from the study before the end of the optimization/maintenance phase for reasons 
other than withdrawal of consent, an EW visit will be conducted within 1 week of the last intranasal dose. 
Subjects who are currently in the optimization/maintenance phase at the time the 54135419TRD3008 study 
is completed will conduct an “End of Study” visit as their final study visit within 1 week of the last intranasal 
dose.
SUBJECT POPULATION
The study population will include adult and elderly men and women who previously participated in studies 
ESKETINTRD3001, 
ESKETINTRD3002, 
ESKETINTRD3003, 
ESKETINTRD3004, 
ESKETINTRD3005 or ESKETINTRD3006 (US sites only) and will have met the inclusion/exclusion 
criteria for entry into those studies.
Potential subjects will be excluded from participating in the study if the evaluation of the risk versus benefit 
of continued esketamine nasal spray treatment is not favorable for the subject in the opinion of the 
investigator. Subjects reporting suicidal ideation with intent to act or suicidal behavior prior to the start of 
the study will be excluded. Subjects with a neurodegenerative disorder or evidence of mild cognitive 
impairment prior to the first intranasal treatment session will be excluded from participating in the study. 
In addition, any subject with uncontrolled hypertension, or a positive test result(s) for drugs of abuse 
(including barbiturates, methadone, opiates, cocaine, phencyclidine, and amphetamine/methamphetamine) 
prior to the first intranasal treatment session will be excluded from participating in the study.
DOSAGE AND ADMINISTRATION
Intranasal Study Medication
Induction Phase:
All eligible subjects will self-administer the intranasal study drug twice a week for 4 weeks at treatment 
sessions at the study site. Intranasal treatment sessions should not take place on consecutive days. 
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JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
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Status: Approved, Date: 5 October 2020
The esketamine nasal spray dose titration in the Induction Phase for subjects <65years of age is described 
in the table below:
Induction Phase Dose Titration of Esketamine nasal spray, Subjects <65 years of age
Day 
Dose
Dose Titration Guidance
Day 1
56 mg
Day 4
56 or 84 mg
The dose may remain at 56 mg or be increased to 84 mg, as 
determined by the investigator based on efficacy and tolerability.
Day 8, 11, 15, 
18, 22, 25
56 or 84 mg
The dose may be increased to 84 mg (if previous dose was 56 mg), 
remain the same, or be reduced to 56 mg (if previous dose was 84 
mg), as determined by the investigator based on efficacy and 
tolerability
The esketamine nasal spray dose titration in the Induction Phase for subjects ≥65years of age is described 
in the table below:
Induction Phase Dose Titration of Esketamine nasal spray, Subjects ≥65 years of age
Day 
Dose
Dose Titration Guidance*
Day 1
28 mg
Day 4
28 or 56 mg
The dose may remain at 28 mg or be increased to 56 mg, as 
determined by the investigator based on efficacy and tolerability
Day 8, 11, 15, 
18, 22, 25
28, 56 or 84 mg
The dose may remain the same, or be increased or reduced by 28 mg 
from the previous dosing session, as determined by the investigator 
based on efficacy and tolerability.
Optimization/Maintenance Phase:
Subjects will self-administer the intranasal study drug at treatment sessions at the study site. Intranasal 
treatment sessions should not take place on consecutive days.
For the first 4 weeks of the optimization/maintenance phase (Week 1 to Week 4):

Subjects 
from 
the 
induction 
phase 
of 
study 
54135419TRD3008, 
who 
enter 
the 
optimization/maintenance phase will continue on the same dose of esketamine nasal spray from the
induction phase and have a weekly intranasal treatment session frequency (ie, reduced frequency from 
the twice-weekly frequency in the induction phase).

Subjects who were responders at the end of the induction phase of ESKETINTRD3001, 
ESKETINTRD3002 or ESKETINTRD3006 (US sites only) who enter the optimization/maintenance 
phase will have a weekly intranasal treatment session frequency (ie, reduced frequency from the twice-
weekly frequency in the induction phase). However, as the ESKETINTRD3001, 3002 and 3006 
intranasal study medication is blinded at the time of entry into the current study, subjects entering the 
optimization/maintenance phase should start at 56 mg. The dose may remain at 56 mg or be increased 
to 84 mg, as determined by the investigator based on efficacy and tolerability.

With sponsor approval, subjects from ESKETINTRD3003 and ESKETINTRD3004 entering directly 
from the induction phase who were determined to not meet the criteria for response in those studies 
may enter the optimization/maintenance phase of 54135419TRD3008 and will have a weekly 
intranasal treatment session frequency from week 1 to week 4 (ie, reduced frequency from the twice-
weekly frequency in the induction phase). In addition, a one-time dose change will be allowed at study 
entry.
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
30
Status: Approved, Date: 5 October 2020

With sponsor approval, subjects from ESKETINTRD3006 (US sites only) entering directly from 
induction phase and determined to not meet criteria for response in that study may enter the 
optimization/maintenance phase. However, as the ESKETINTRD3006 intranasal study medication is 
blinded at the time of entry into the current study, subjects entering the optimization/maintenance 
phase from study ESKETINTRD3006 will start at 56 mg. The dose may remain at 56 mg or be 
increased to 84 mg, as determined by the investigator based on efficacy and tolerability. Subjects will 
have a weekly intranasal treatment session frequency from week 1 to week 4 (ie, reduced frequency 
from the twice-weekly frequency in the induction phase).

Subjects entering the optimization/maintenance phase from study ESKETINTRD3005 will also have 
a weekly intranasal treatment session frequency. However, as the ESKETINTRD3005 intranasal study 
medication is blinded at the time of entry into the current study, the dose of esketamine nasal spray 
will be administered as outlined in the table below.
Optimization/Maintenance Phase Week 1 to 4: Dose Titration of Esketamine nasal spray for Responder 
Subjects Entering from ESKETINTRD3005
Week 
Dose
Dose Titration Guidance
Week 1 
28 mg
Week 2 
28 or 56 mg
The dose may remain at 28mg or be increased to 56mg, as determined by the 
investigator based on efficacy and tolerability
Week 3 
and 4 
28, 56 or 84 mg
The dose may remain the same or be increased or reduced by 28mg from the 
previous dosing session, as determined by the investigator based on efficacy and 
tolerability. For those who have had a prior down titration from a higher dose, a 
dose increase by 28 mg is allowed based on clinical judgment. 

Subjects entering the optimization/maintenance phase from study ESKETINTRD3003 (Direct Entry) 
or 
ESKETINTRD3004 
who 
were 
ongoing 
in 
the 
Optimization, 
Maintenance, 
or 
Optimization/Maintenance phase, respectively, will have the option to have their current intranasal 
dosing frequency adjusted at the time of entry into 54135419TRD3008 study and should remain on 
the selected frequency from week 1 to week 4 (inclusive). A one-time dose change will be permitted 
at study entry. 

Subjects entering the optimization/maintenance phase from study ESKETINTRD3003 (Transferred 
Entry) will start at 56 mg. The dose may remain at 56 mg or be increased to 84 mg, as determined by 
the investigator based on efficacy and tolerability. In addition, subjects will have the option to have 
their current intranasal dosing frequency adjusted at the time of entry into 54135419TRD3008 study 
and should remain on the selected frequency from week 1 to week 4 (inclusive).
After Week 4 (ie, starting at Week 5), based on the investigator’s clinical judgment, the dose of esketamine 
for all subjects can be adjusted based upon efficacy and tolerability. 
Starting at Week 4, the frequency for subsequent intranasal treatment sessions will be adjusted (if 
applicable) based on the algorithm outlined in the table below at fixed, 2-week intervals. 
Current treatment 
session frequency
CGI-S score at current visita
≤ 3
>3
Weekly
Change to every other week frequency
No change in frequency
Every other week
No change in frequency or change to 
every 4 weeks per clinical judgment
Change to weekly frequency
Every 4 weeks
No change in frequency
Change to weekly or every other week 
frequency per clinical judgment
a 
Note: The CGI-S is administered every 2 weeks from Week 4 through the end of the 
Optimization/Maintenance Phase, adjustment of the intranasal treatment session frequency is only permitted 
at the fixed 2-week interval (based on CGI-S performed at that visit), and every 4 weeks for subjects dosed at 
the 4 week interval.
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
31
Status: Approved, Date: 5 October 2020
For example, if at Week 4 a subject is currently at a weekly treatment session frequency and the CGI-S 
score at Week 4 is a 2, the intranasal treatment session frequency will be changed from weekly to every 
other week (ie, the next treatment session for this subject will be at Week 6). 
MEDICAL RESOURCE UTILIZATION
Medical resource utilization data, associated with medical encounters, will be collected using the Healthcare 
Resource Use Questionnaire (HRUQ). The HRUQ includes information regarding utilization of healthcare 
services (including the timing and type of services), enabling changes in level and quantity of services to 
be considered as a variable in economic models.
STATISTICAL METHODS
Analysis Sets
The following analysis sets will be used to summarize efficacy and safety data.

Full Analysis Set for Induction phase: will be defined as all subjects who receive at least one dose of 
esketamine nasal spray during this phase.

Full Analysis Set for Optimization/Maintenance phase: will be defined as all subjects who receive at 
least one dose of esketamine nasal spray during this phase.
Sample Size Determination
No formal sample size calculation was performed as only subjects who have participated in the other 
Phase 3 studies may participate in this study.
Safety Analysis 
Safety data for the induction phase and the optimization/maintenance phase will be analyzed separately for 
each phase as well as for the entire treatment period (induction and optimization/maintenance phase). 
Computerized cognitive test battery and HVLT-R scores and their changes from baseline will be 
summarized at each scheduled time point using descriptive statistics. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). For each 
adverse event, the percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized. Subjects who die, who discontinue treatment due to an adverse event, or who experience a 
severe or a serious adverse event will be summarized separately. 
Treatment emergent AEs of special interest will be examined separately grouped in the following 
categories: drug abuse, dependence and withdrawal, increased blood pressure, increased heart rate, transient 
dizziness/vertigo, impaired cognition, cystitis, anxiety, events potentially related to suicidality, hepatic 
adverse events, events related to renal disorders, and symptoms of dissociation persisting beyond the typical 
≤2 hour post esketamine administration, as well as delirium, psychosis or mania.
Systolic and diastolic blood pressure, pulse/heart rate, respiratory rate, 12-lead electrocardiogram (ECG), 
pulse oximetry, and clinical laboratory test results, and changes from baseline will be tabulated over time, 
using descriptive statistics. Any treatment-emergent abnormalities will be listed. 
Suicide-related thoughts and behaviors based on the C-SSRS will be summarized in incidence and shift 
tables. Separate endpoints for suicidal ideation and suicidal behavior will be defined and summarized 
descriptively.
Descriptive statistics of scores and their changes (and/or percent changes) from predose or baseline will be 
summarized for modified observer's assessment of alertness/sedation (MOAA/S) at each scheduled time 
point. In addition, CGADR responses will be summarized at each scheduled time point. 
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
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Status: Approved, Date: 5 October 2020
Efficacy Analysis

Depression symptoms using the MADRS as well as a patient reported outcome (PHQ-9), global 
change in severity (CGI-S), social, occupational and family functioning related disability (SDS), 
depression specific health related quality of life (QLDS), and health related quality of life and health 
status (EQ-5D-5L) will be summarized descriptively at each scheduled visit for each phase, using both 
last observation carried forward and observed case data. The proportion of subjects who are responders 
(≥50% improvement from baseline) based on the MADRS total score and PHQ-9 total score and the 
proportion of subjects who remitted based on the MADRS total score (MADRS total score ≤12) and 
the PHQ-9 total score (PHQ-9 total score <5) will be provided over time for each phase. 

For subjects who had relapsed in ESKETINTRD3003 and participated in a second induction treatment 
phase, the proportion of responders (≥50% improvement from baseline) and remitters using the 
MADRS total score (MADRS total score ≤12) and PHQ-9 total score (PHQ-9 total score <5) at the 
end of the second induction phase will be provided. 

Subject treatment satisfaction questionnaire for medication (TSQM-9) will be summarized 
descriptively at each scheduled visit for each phase.
Medical Resource Utilization Analysis
Medical resource utilization data (including HRUQ results) will be summarized descriptively.
Patient Stated-choice Preference Analysis
Summary statistics and a regression model will be used to estimate a distribution of preferences weights 
for each level of each benefit and harm in the preference survey (described in a SAP). Maximum acceptable 
risk for harms will be calculated for varying degrees of benefit. Analyses and reporting of these survey 
results may be reported separately.
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
33
Status: Approved, Date: 5 October 2020
TIME AND EVENTS SCHEDULE (Induction Phase)
Phase
Induction Phasea)
Visit number
1.1b)
1.2
1.3
1.4
1.5
1.6
1.7
1.8 
1.9 
Week
1
2
3
4
Study day
1
(baseline)
4
8
11
15
18
22
25
28
Clinical Study Site visit window (in days)
-
±1
±1
±1
±1
±1
±1
±1
±1
Study Procedures
Screening/Administrative
Informed consent (ICF) – performed prior to any study procedure
X
Inclusion/exclusion criteria-
Xc)
Study Drug 
Esketamine nasal sprayg)
X
X
X
X
X
X
X
X
Drug accountability 
(intranasal study medication)
X
X
X
X
X
X
X
X
Safety Assessments (Site-completed)
Physical examination
Xc)
X
Nasal examinationc)
X
X
Vital signs: blood pressure, pulse, respiratory rate, temperature c),g)
X
X
X
X
X
X
X
X
Vital signs (postdose): blood pressure, pulse, respiratory rate d),g)
X
X
X
X
X
X
X
X
Weight
X
X
12-lead ECGe),g)
X
X
X
C-SSRSc),g)
X
X
X
X
X
X
X
X
X
MOAA/S and pulse oximetryf),g)
X
X
X
X
X
X
X
X
CGADRg),h)
X
X
X
X
X
X
X
X
Efficacy Assessments (Clinician)
MADRS (7-day recall)c
X
X
X
X
X
CGI-Sc)
X
X
X
X
X
X
X
Subject-completed Assessments
PHQ-9
X
X
X
SDS
X
X
EQ-5D-5L
X
X
X
TSQM-9
X
X
MAGDAj)
X
X
X
QLDS
X
X
X
Patient Stated-choice Preference Surveyk)
Xl)
Cognition Testing
Computerized test battery and HVLT-Rc
X
X
Clinical Laboratory Assessments
HbA1ci)
X
Hematology, chemistryc
X
X
Urine drug screenc)
X
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
34
Status: Approved, Date: 5 October 2020
Phase
Induction Phasea)
Visit number
1.1b)
1.2
1.3
1.4
1.5
1.6
1.7
1.8 
1.9 
Week
1
2
3
4
Study day
1
(baseline)
4
8
11
15
18
22
25
28
Clinical Study Site visit window (in days)
-
±1
±1
±1
±1
±1
±1
±1
±1
Alcohol breath testc
X
Urinalysisc)
X
X
Urine pregnancy testc) (only for females of child bearing potential)
X
X
X
Ongoing Subject Review
Concomitant Therapy
Ongoing
Adverse Events
Ongoing
Footnotes:
Abbreviations: CGADR = Clinical Global Assessment of Discharge Readiness; CGI-S = Clinical Global Impression – Severity; C-SSRS = Columbia Suicide Severity Rating Scale; 
ECG = electrocardiogram; EQ-5D-5L= EuroQol-5D, 5-level; HbA1C = glycosylated hemoglobin; HVLT-R = Hopkins Verbal Learning Test-Revised; ICF = informed consent form; 
MADRS = Montgomery-Asberg Depression Rating Scale; MAGDA = Magda Avatar Game Depression Implicit Association Scale; 
MOAA/S = Modified Observer's Assessment of Alertness/Sedation; PHQ-9 = Patient Health Questionnaire – 9; SDS = Sheehan Disability Scale; C-SSRS = Columbia Suicide Severity 
Rating Scale; QLDS = Quality of Life in Depression Scale
Note: On intranasal dosing days, time 0 is defined as the time of the first intranasal spray. Therefore, postdose time points are referenced from this.
a)
If a subject withdraws before the end of the induction phase (ie, Visit 1.9, Day 28) for reasons other than withdrawal of consent, an “Early Withdrawal” visit (refer to Time and Events 
Schedule: Optimization/Maintenance Phase) should be conducted within 1 week of the last dose of esketamine nasal spray. If the early withdrawal visit is conducted on the same day 
as a scheduled visit, duplicate assessments are not required. Subjects who are currently in the induction phase at the time the 54135419TRD3008 study is completed will conduct an 
“End of Study” visit as their final study visit within 1 week of the last dose of esketamine nasal spray.
b) There is no maximum time limit between completing the prior study and enrolling into 54135419TRD3008. If a study procedure from the prior study has already been performed on 
the same day, duplicate predose assessments do not need to be repeated on Visit 1.1 (Day 1) of 54135419TRD3008 study. 
c)
Predose (if/when performed on intranasal dosing days).
d) Postdose vital signs will be performed at 40 minutes, 1 hour, and 1.5 hours postdose. Please refer to Section 6.1 for guidance on blood pressure monitoring on intranasal dosing days.
e)
Twelve-lead ECG will be performed predose and t=1 hour postdose at Visit 1.1. Twelve-lead ECG will be performed at t=1 hour postdose only, at Visits 1.5 and 1.8. A time window 
of ±15 minutes will be permitted.
f)
The MOAA/S will be performed every 15 minutes from predose to t=+1 hours postdose (please refer to Section 9.2 for further guidance on MOAA/S assessments). Pulse oximetry will 
be performed every 15 minutes from predose to t=1 hour postdose (please refer to Section 9.2 for further guidance on timing of pulse oximetry assessments).
g) If intranasal dosing is postponed (but occurs within the visit window) due to vital sign results (eg, blood pressure elevation), all assessment time points (including predose) must be 
performed on the actual dosing day.
h) CGADR to be performed at 30 mins; if the response is “No”, the assessment will be repeated every 15 minutes until a “Yes” response is achieved or until the subject is referred for 
appropriate medical care if clinically indicated. On all intranasal treatment session days, subjects must remain at the clinical site until study procedures have been completed and the 
subject is ready for discharge.
i)
HbA1c to be performed only in those subjects with a documented medical history of diabetes. 
j)
In the event the MAGDA assessment is not available for use at the start of this trial, the procedure can be omitted until available for use.
k) Patient Stated-choice Preference Survey to be completed only by English-speaking subjects at United States, Canada, United Kingdom, and Australia sites. The survey will not be 
conducted in any other countries, regardless of whether the subjects in those other countries speak English. The survey is conducted only once per subject.
l)
The survey should be completed during or shortly after Visit 1.9, or if a subject has completed this visit prior to when the survey becomes available, sites should have the subject 
complete the survey at the earliest possible opportunity or at early withdrawal. The survey should be administered predose (if/when performed on intranasal dosing days). See 
Section 9.5.1 in the protocol.
NCT02782104


NCT02782104


NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
37
Status: Approved, Date: 5 October 2020
d) Performed predose and at t = 30 minutes and 60 minutes postdose on all intranasal treatment session days.
e) If a subject withdraws during the induction or optimization/maintenance phase for reasons other than withdrawal of consent, an “Early Withdrawal” visit should be conducted within 
1 week of the last intranasal dose. If the early withdrawal visit is conducted on the same day as a scheduled visit, duplicate assessments are not required. Subjects who are currently in 
the optimization/maintenance phases at the time the 54135419TRD3008 study is completed will conduct an “End of Study” visit as their final study visit within 1 week of the last 
intranasal dose.
f)
If intranasal dosing is postponed (but occurs within the visit window) due to vital sign results (eg, blood pressure elevation), all assessment time points (including predose) must be 
performed on the actual dosing day. 
g) Only applicable to subjects on a weekly intranasal treatment frequency.
h) Esketamine nasal spray frequencies include weekly, once every other week, or once every 4 weeks. 
i)
Only applicable for intranasal treatment session days
j)
Predose (if performed on intranasal treatment session days). HRUQ will be completed until end of December 2020.
k) Patient Stated-choice Preference Survey to be completed only by English-speaking subjects at United States, Canada, United Kingdom, and Australia sites. The survey will not be 
conducted in any other countries, regardless of whether the subjects in those other countries speak English. The survey is conducted only once per subject.
l)
Note for subjects whose point of entry for 54135419TRD3008 is the Optimization/maintenance phase, the survey should be completed during or shortly after Visit 2.4, or if a subject 
completed this visit prior to when the survey becomes available, the subject should complete the survey at the earliest possible opportunity or at early withdrawal. The survey should be 
administered predose (if/when performed on intranasal dosing days). Subjects who completed the Patient Stated-choice Preference survey while enrolled in a prior study 
(ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004, or ESKETINTRD3005) should not be issued the survey. See Section 9.5.1 in the protocol.
m) Postdose vital signs (if/when performed on intranasal dosing days) will be performed at t = +40 minutes, and 1 hours postdose. Please refer to Section 6.1 for guidance for blood 
pressure monitoring on intranasal dosing days.
n) 12-lead electrocardiogram will be performed predose at Visit 2.1 only, and at t= 1 hours postdose only for all other time points. A time window of ±15 minutes is permitted.
o) The MOAA/S will be performed every 15 minutes from predose to t = 1 hours postdose (please refer to Section 9.2 for further guidance on MOAA/S assessments). 
p) CGADR to be performed at 30 mins; if the response is not “Yes”, the assessment will be repeated every 15 minutes until a “Yes” response is achieved or until the subject is referred for 
appropriate medical care if clinically indicated. On all intranasal treatment session days, subjects must remain at the clinical site until study procedures have been completed and the 
subject is ready for discharge. 
q) HbA1c to be performed only in those subjects with a documented medical history of diabetes
r)
Administration of the QLDS will be limited to sites where there are translations available in the local language(s)
s) The study procedures required at a weekly frequency are only associated with an intranasal treatment session day (ie, clinic visit).
t)
Subjects entering this phase from the induction phase of this study (54135419TRD3008) will be able to reduce the frequency of intranasal treatment sessions to weekly during Weeks 1 
to 4 and subsequently (after Week 4) individualize and stabilize the treatment session frequency to weekly, every other week, or every 4 weeks based on the severity of depression 
during this phase (see Section 3.2.2).
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
38
Status: Approved, Date: 5 October 2020
ABBREVIATIONS
ARC
Anticipated Event Review Committee
CGADR
Clinical Global Assessment of Discharge Readiness
CGI-S
C-SSRS
Clinical Global Impression – Severity
Columbia Suicide Severity Rating Scale
CRF
Case report form
CYP
Cytochrome P450
DBP
Diastolic blood pressure
ECG
Electrocardiogram
eDC
Electronic Data Capture
EQ-5D-5L
European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level
EW
Early Withdrawal
GCP
Good Clinical Practice
HbA1c
Glycosylated hemoglobin
HRUQ
Healthcare Resource Use Questionnaire
HVLT-R
Hopkins Verbal Learning Test-Revised
ICF
Informed consent form
ICH
International Conference on Harmonisation 
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IM
Intramuscular
IRB
Institutional Review Board
IV
Intravenous
MADRS
Montgomery-Asberg Depression Rating Scale
MDD
Major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MOAA/S 
Modified Observer's Assessment of Alertness/Sedation
NMDA
N-methyl-D-aspartate
PCP
Primary care physician
PHQ-9
Patient Health Questionnaire, 9-Item
PK
Pharmacokinetics
PQC
Product quality complaint
QLDS
Quality of Life in Depression Scale
SBP
Systolic blood pressure
SDS
Sheehan Disability Scale
TEAE
Treatment emergent adverse events
TRD
Treatment-resistant depression
US
United States
DEFINITIONS OF TERMS
AUC
Area under the concentration-time curve
Cmax
Maximum plasma concentration
Tmax
Median time of Cmax
NCT02782104


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
39
Status: Approved, Date: 5 October 2020
1.
INTRODUCTION
Major depressive disorder (MDD), a serious, recurrent, and disabling psychiatric illness, is the 
second leading cause of years lost to disability worldwide. Major depressive disorder is associated 
with excess mortality; and with years of potential life lost.73,74,78 About 30% of patients fail to 
achieve remission despite treatment with multiple antidepressant medications, and are considered 
to have treatment-resistant depression (TRD).23,61 In patients who respond to antidepressants, the 
time to onset of effect is typically 4 to 7 weeks, during which time patients continue to suffer from 
their symptoms and continue to be at risk of self-harm, as well as being impacted by the associated 
harm to their personal and professional lives.61,66 Therefore, there is a significant need to develop 
novel treatments based upon relevant pathophysiologic pathways underlying MDD for the rapid 
relief of symptoms of depression, especially in patients with TRD.17,18
Ketamine and esketamine (S-ketamine, the S enantiomer of ketamine) are approved and widely 
used for the induction and maintenance of anesthesia via intramuscular (IM) or intravenous (IV) 
administration.35 The desired analgesic-anesthetic effects of ketamine and esketamine are 
attributed to the blockade of ionotropic N-methyl-D-aspartate (NMDA) glutamate receptors.44,55,81
Both ketamine and esketamine profoundly affects fast excitatory glutamate transmission, increases 
brain-derived neurotrophic factor (BDNF) release, and stimulates synaptogenesis.18
Most literature reports of the antidepressant effects of ketamine describe studies using IV 
administration of the racemate, with a few exceptions.38 Janssen Research & Development (JRD) 
is developing esketamine nasal spray as an antidepressant therapy. A higher NMDA receptor 
affinity of esketamine compared to ketamine, allows a lower volume of medication to be 
administered via the non-invasive and rapidly-absorbed intranasal route.42,53,56
For the most comprehensive nonclinical and clinical information regarding esketamine 
(JNJ-54135419), refer to the latest version of the Investigator's Brochure and Addenda for 
esketamine.
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.
Summary of Nonclinical Findings
Safety Pharmacology
The following text is quoted from the United States (US) prescribing information for anesthetic 
Ketalar® (ketamine hydrochloride injection)35 is provided below: Intravenous Ketalar produces a 
fall in arterial blood pressure in the Rhesus monkey and a rise in arterial blood pressure in the dog. 
In this respect the dog mimics the cardiovascular effect observed in man. The pressor response to 
Ketalar injected into intact, unanesthetized dogs is accompanied by a tachycardia, rise in cardiac 
output and a fall in total peripheral resistance. The pressor response to Ketalar is reduced or 
blocked by chlorpromazine (central depressant and peripheral α-adrenergic blockade), by 
β-adrenergic blockade, and by ganglionic blockade.
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Findings from animal studies suggest that the increase in blood pressure produced by 
ketamine/esketamine is due to selective activation of central cardiac stimulating mechanisms 
leading to an increase in cardiac output.
In a 3-month repeat-dose toxicity study with intranasally administered esketamine in dogs, no 
relevant electrocardiogram (ECG) changes were noted up to the highest dose tested, ie, 72 mg/day. 
Heart rate was slightly increased. The cardiovascular safety of racemic ketamine and esketamine 
in humans and animals is summarized in the Investigator’s Brochure.32
Toxicology
Repeat-dose Toxicity Studies
In repeat-dose toxicity studies with intranasally administered esketamine in rats up to 9 mg/day 
for 6 months, and dogs up to 72 mg/day for 3 months of duration, the clinical observations mainly 
related to the central nervous system (eg, changes in activity and gait). No adverse effects were 
noted up to the highest dose tested, ie, 9 mg/day in rats and 72 mg/day in dogs. These observations 
reflected the (exaggerated) pharmacology of the test compound. Minor histologic findings were 
noted in the nasal cavity. These tissue changes were not considered adverse.
In 3- and 9-month repeat-dose toxicity studies with intranasally administered esketamine in dogs, 
no relevant ECG changes were noted up 72 mg/day. Heart rate was slightly increased. 
Further details can be found in the Investigator’s Brochure.32
Genetic Toxicity
A series of in vitro and in vivo genotoxicity studies was conducted with ketamine and esketamine. 
The weight of evidence indicates that esketamine poses no genotoxic risk to humans.32
Neurotoxicity
Racemic ketamine has been reported to induce neurotoxicity in animal fetuses, and in juvenile, 
adolescent, and adult animals, as evidenced by histopathologic brain lesions and functional 
sequelae. The precise thresholds for dose and duration of exposure causing neurotoxicity in 
animals remain to be established. The relevance to humans of ketamine’s neurotoxic action in 
animals is unknown.
In studies exploring neurotoxic effects of ketamine on juvenile and prenatal monkeys, 
neuroapoptosis was observed to be more widespread in fetal brains than in neonatal brains, after 
administration of ketamine anesthesia IV for 5 hours. In fetal brains, the cerebellum, caudate 
nucleus, putamen, and nucleus accumbens were most severely affected. In neonatal brains, the 
cerebellum was not affected; the strongest neuroapoptotic response was noted in the basal ganglia 
and several thalamic areas.
In juvenile rodents, ketamine induced apoptotic neurodegeneration was observed that was more 
widespread than in adult rodents, with the developing brain affected in several major regions. 
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Neuronal cell death was induced in the dorsolateral thalamus at blood levels of ketamine of 
14 µg/mL (7 times the human anesthetic blood level of approximately 2 µg/mL).
No significant neurotoxic effects occurred in juvenile Rhesus monkeys if the anesthesia was 
administered as IM induction followed by IV maintenance duration was 3 hours. Ketamine 
infusion for 9 or 24 hours increased neuronal cell death in the frontal cortex, but no significant 
changes were noted in the hippocampus, thalamus, striatum, or amygdala. Cognitive impairments 
were observed beginning around 10 months of age, and persisted at 3.5 years of age.
The clinical studies will exclude neonates, infants, children, pregnant women, and breastfeeding 
women. Therefore, ketamine’s neurotoxicity in juvenile animals does not represent a safety risk to 
eligible adult subjects. Moreover, the large dosages and prolonged treatment durations associated 
with neurotoxicity in juvenile animals do not suggest a concern.
Chronic treatment with ketamine at high dose levels affected the brain of adolescent monkeys, as 
evidenced by histopathologic lesions and functional impairment. 
The neurotoxicity of ketamine in adult animals is also associated with high dose levels, in contrast 
to the relatively low dose levels of esketamine associated with antidepressant efficacy in humans. 
In single-dose and 14-day repeated-neurotoxicity studies with intranasally administered 
esketamine in rats, no histopathologic brain lesions were noted even upon high exposures, as 
achieved at 54 mg/day in the 14-day study. In the 6-month rat and 9-month dog repeat-dose 
toxicology studies with intranasally administered esketamine, where the animals were of 
adolescent age at initiation of treatment, and in the pre- and post-natal developmental toxicity 
study in rats, no evidence of neurotoxicity was found. Consequently, the risk of neurotoxicity 
associated with intranasal administration of esketamine to adult and adolescent patients is 
considered low.32
Abuse Potential
Animal studies with ketamine suggest that it would have abuse potential in humans. These studies 
included self-administration and withdrawal experiments in several species.32
Reproductive Toxicity
In a rat fertility and early embryonic developmental toxicity study with intranasally administered 
esketamine, no adverse effects on fertility or reproductive capacity or performance were found.
Rat and rabbit embryo-fetal developmental toxicity studies with intranasally administered racemic 
ketamine did not reveal evidence of reproductive toxicity. However, when monkey fetuses were 
exposed in utero to high dose levels of racemic ketamine, neurotoxicity was observed.
Intranasally administered esketamine did not affect pre- and postnatal development in rats. 
However, high dose levels of racemic ketamine induced neurotoxicity in early postnatal rat pups.32
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Considering the neurotoxic potential of ketamine and esketamine, and the fact that no threshold 
for these effects has been demonstrated, female subjects of childbearing potential should be 
adequately protected from becoming pregnant and pregnant women should not be enrolled.
Cardiovascular toxicity
In guinea pig tissues, ketamine-induced negative inotropic effects and shortening of action 
potential duration at the 0-mV level was observed, likely as a result of the suppression of inward 
calcium current, whereas in rat left atria and ketamine-induced positive inotropic effects and 
prolongation of action potential duration at the 0-mV level was observed, likely as a result of a 
decrease in calcium-insensitive transient outward current.20 The inhibitory action on membrane 
currents may partly explain the species and tissue differences in inotropic responses to ketamine.
Blood pressure responses to ketamine also vary with the laboratory species and with experimental 
conditions. Blood pressure is increased in normotensive and renal hypertensive rats with and 
without adrenalectomy and under pentobarbital anesthesia. The US prescribing information for the 
anesthetic Ketalar® (ketamine hydrochloride [HCl] for injection) provides the following guidance. 
Intravenous Ketalar produces a fall in arterial blood pressure in the Rhesus monkey and a rise in 
arterial blood pressure in the dog. In this respect the dog mimics the cardiovascular effect observed 
in man. The pressor response to Ketalar injected into intact, unanesthetized dogs is accompanied 
by a tachycardia, rise in cardiac output and a fall in total peripheral resistance. It causes a fall in 
perfusion pressure following a large dose. The tachycardia and increase in myocardial contractile 
force seen in intact animals does not appear in isolated hearts. These observations support the 
hypothesis that the hypertension produced by Ketalar is due to selective activation of central 
cardiac stimulating mechanisms leading to an increase in cardiac output. 
The dog would be considered the most predictive species in terms of ketamine’s cardiovascular 
effects in humans, but the antidepressant effects of ketamine were studied only in rodent models. 
The myocardial contractility effects and blood pressure responses to ketamine vary between
species.32 Consequently, a margin of safety could not be reliably derived from the available animal 
data.
Overall Conclusion
The currently available nonclinical safety studies support chronic intranasal administration of 
esketamine in human subjects up to a dosage of 84 mg/day.
Further details can be found in the Investigator’s Brochure.32
1.1.2.
Clinical Studies
1.1.2.1.
Pharmacokinetics and Product Metabolism
Metabolism
Ketamine (and esketamine) undergoes extensive metabolism by hepatic cytochrome P450 (CYP). 
In humans, N-demethylation to norketamine is the major route of metabolism, which can undergo 
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further metabolism to form hydroxynorketamine. Ketamine and norketamine are extensively 
hydroxylated to a series of 6 hydroxynorketamine metabolites and 2 hydroxyketamine 
metabolites.77 Like ketamine, norketamine is a noncompetitive antagonist at the NMDA 
receptor.19,29 Norketamine has a half-life in plasma of approximately 5 hours.28 The major human 
hepatic CYPs that catalyze ketamine N-demethylation in vitro are CYP2B6 and CYP3A4.57,80 The 
CYP enzymes responsible for the formation of norketamine metabolites include CYP2A6 and 
CYP2B6.57 Published results of a clinical pharmacokinetics (PK) study indicate that esketamine 
does not invert to the R-enantiomer.25
Excretion
Racemic ketamine and its metabolites have been previously shown to be predominantly excreted 
in the urine. An average of 91% and 3% of a tritium-labeled dose (1 mg/kg) administered to 
6 healthy subjects was recovered in urine and feces, respectively.7 Less than 3% of an administered 
dose was excreted in urine as parent drug.75
A summary of the PK of esketamine administered by the intravenous (IV) and intranasal routes is 
provided below.
Intravenous Esketamine 
Subjects with TRD received 0.2 mg/kg or 0.4 mg/kg esketamine as a 40-minute IV infusion during 
Study ESKETIVTRD2001.13 Maximum concentrations of esketamine were observed at the end of 
the infusion. Mean values for maximum plasma concentration (Cmax) and area under the 
concentration-time curve (AUC) increased with an increase in the esketamine dose administered 
(80.9 and 135 ng/mL, respectively, and 150 and 218 ng*h/mL, respectively, for 0.2 mg/kg and 
0.4 mg/kg esketamine). The mean plasma clearance of esketamine was high (109 L/h and 141 L/h 
for the 0.2 mg/kg and 0.4 mg/kg doses, respectively), as it was similar to or exceeded hepatic blood 
flow in humans.13 The large volume of distribution suggests that esketamine distributes widely 
into tissues (236 L and 303 L, respectively). The half-life of esketamine in plasma was 2.14 and 
2.65 hours, respectively, for the 2 doses.
Esketamine Nasal Spray
Plasma esketamine PK results from Studies ESKETINTRD1001, ESKETINTRD1002, 
ESKETINTRD1003, and the double blind phase of Panel A of the ESKETIVTRD2003 that inform 
dose selection for the Phase 3 program are described below. The results demonstrate that plasma 
esketamine concentrations produced by effective IV regimens (0.2 mg/kg and 0.4 mg/kg as 
40-minute infusions) may be achieved by the intranasal route.
Study ESKETINTRD1001 included 3 cohorts of subjects who were healthy male and female 
subjects.10 The esketamine nasal spray treatments were self-administered under the direct 
supervision of the investigator or designee.
Subjects in Cohorts 1 and 3 received esketamine doses that ranged from 28 to 112 mg. The 
regimens were self-administered in the upright position. No instructions were given with regards 
to sniffing after administration. The reported median time of Cmax (Tmax) of esketamine ranged 
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from 0.37 to 0.83 hours from the time the first spray was administered (ie, 0.33 to 0.5 hours after 
the last spray was administered). The doses of 28 to 112 mg produced mean Cmax values ranging 
from 63.3 to 151 ng/mL, whereas mean AUC∞values ranged from 164 to 565 ng*h/mL. Mean 
Cmax and AUC values of esketamine increased in a less than dose-proportional manner across the 
dose regimens. Furthermore, there was substantial overlap in the range of individual Cmax and AUC 
values among the 3 doses. The mean terminal half-life of esketamine ranged from 5.86 to 
9.83 hours across all treatments.
Subjects in Cohort 2 received 84 mg in a semi-reclined position and were instructed to sniff after 
each spray. Higher mean Cmax and AUCvalues were observed in this cohort (174 ng/mL and 
437 ng*h/mL, respectively) compared with the same esketamine dose self-administered by 
subjects in Cohort 1 (107 ng/mL and 363 ng*h/mL, respectively). The semi-reclined position of 
the head and the instruction to subjects to sniff following intranasal dosing are believed to be the 
cause for the increase in exposure observed in Cohort 2 compared with Cohort 1. As a result, the 
instructions for self-administration of esketamine nasal spray were adapted to include the 
semi-reclined position of the head and sniffing following dosing for all future studies.
During the Phase 1 study ESKETINTRD1002, healthy Japanese and Caucasian subjects received 
single intranasal doses of esketamine 28 mg, 56 mg, and 84 mg in a crossover manner.11 On 
average, plasma esketamine Cmax and AUC values were up to 48% higher in Japanese subjects 
compared with Caucasian subjects. 
Study ESKETINTRD1003 compared the PK, safety, and tolerability of intranasally administered 
esketamine in healthy elderly (65 years of age) and younger adult subjects (18 to 55 years of age, 
inclusive).12 Subjects received a single intranasal treatment of esketamine 28 mg. Median time to 
reach the maximum plasma concentration (tmax) of esketamine was approximately 30 minutes for 
both age groups. The geometric means of Cmax and AUC from time 0 to infinite time, AUC, for 
esketamine were approximately 21% and 17% higher, respectively, in the elderly compared with 
younger adult subjects.
Study ESKETINTRD1012 evaluated the pharmacokinetics and safety of a single intranasal 84-mg 
dose, which was self-administered by 8 healthy subjects who were ≥75 years of age and 8 healthy 
younger adults (18 to 55 years of age).9 Preliminary data showed the median time to reach the 
maximum plasma concentration (tmax) of esketamine was 0.53 hours and 0.83 hours, in healthy 
elderly subjects 75 years of age and younger adults, respectively. The means of the Cmax and area 
under the plasma concentration-time curve from time 0 to infinite time (AUC∞), for esketamine 
were approximately 48% and 31% higher, respectively, in the elderly compared with younger adult 
subjects. Differences were greater based on median Cmax and AUC∞values (97% and 63% higher 
in the elderly, respectively).
Study ESKETINTRD1007 evaluated the effects of daily intranasal administration of mometasone 
on the pharmacokinetics of esketamine nasal spray in healthy subjects and in addition, the effects 
of a single pretreatment with oxymetazoline on the pharmacokinetics of esketamine in subjects 
with allergic rhinitis were assessed. Daily administration of mometasone did not affect the 
pharmacokinetics of esketamine. Pretreatment with oxymetazoline also did not affect the 
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pharmacokinetics of esketamine. These results indicate that subjects using a nasal decongestant or 
corticosteroid for the treatment of allergic rhinitis may receive esketamine nasal spray for the 
treatment of TRD.
Study ESKETINTRD2003 is a 2-panel, doubly randomized, double-blind, placebo-controlled, 
multicenter study.59 Panel A was conducted in the United States and Belgium. Panel A assessed 
the efficacy and safety of 3 dose strengths of esketamine nasal spray (28, 56, and 84 mg) 
administered twice a week in subjects with TRD.8 Results of a preliminary analysis of data from 
the double-blind phase of Panel A indicate mean (standard deviation) esketamine concentrations 
at 40 minutes postdose were 36.4 ng/mL (16.4), 58.1 ng/mL (24.5), and 72.5 ng/mL (34.2), 
respectively, for the 3 doses (data on file). The mean esketamine concentrations in plasma samples 
collected on Days 1 and 11 were similar, suggesting that the PK are consistent after repeated 
administration.
1.1.2.2.
Pharmacodynamics and Efficacy
The efficacy of subanesthetic doses (0.5 mg/kg IV administered over 40 minutes) of IV ketamine 
has been evaluated in approximately 192 subjects with MDD (cases and controls), and 2 studies 
in bipolar depressed subjects (meta-analyses).24 This recent meta-analysis of studies suggests that 
ketamine has a rapid onset (within 1 day) of antidepressant efficacy, including in those who have 
not benefitted from other antidepressants, used as monotherapy or in combination with oral 
antidepressants.
Esketamine (0.2 and 0.4 mg/kg administered over 40 minutes) has similar, rapid, and robust 
antidepressant effect as that seen with IV ketamine. A double-blind, double-randomization, 
placebo-controlled study (ESKETIVTRD2001) enrolled 30 adult subjects with TRD: 10 in the IV 
placebo group, 9 in the IV esketamine 0.20-mg/kg group, and 11 in the IV esketamine 0.40 mg/kg 
group (based on Day 1 randomization).13 The intent-to-treat (ITT) analysis of the primary efficacy 
variable (change in Montgomery-Asberg Depression Rating Scale [MADRS] total score from 
baseline Day 1 to Day 2) indicated that the improvement in both esketamine dose groups was 
statistically significant (1-sided p=0.001 in both dose groups) compared with the placebo group. 
The mean (standard deviation) change from baseline Day 1 to Day 2 in MADRS total score 
was -4.9 (4.72) in the placebo group, -16.8 (10.12) in the esketamine 0.20-mg/kg group, and 
-17.8 (9.45) in the esketamine 0.40-mg/kg group.
The studies listed above assessed the efficacy of ketamine or esketamine after a single dose as the 
primary endpoint. The average duration of response to a single dose of ketamine (0.5 mg/kg) was 
approximately 5 days. An open-label study demonstrated that the response to the first dose could 
be maintained by multiple infusions 3 times a week over 2 weeks. The duration of response lasted 
for approximately 19 days.1
The KETIVTRD2002 study assessed whether multiple doses of ketamine given twice a week 
would also maintain the antidepressant response; the data from this study suggest that ketamine 
(0.50 mg/kg IV over 40 minutes) administered twice a week was sufficient for maintaining the 
initial effect over a 4-week treatment period.14
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As noted above, Study ESKETINTRD2003 is a 2-panel, doubly randomized, double-blind, 
placebo-controlled, multicenter study.8 Panel A was conducted in the United States and Belgium 
and Panel B in Japan. Panel A assessed the efficacy and safety of 3 dose strengths of esketamine 
nasal spray (28, 56, and 84 mg) administered twice a week in subjects with TRD. Panel B 
(ongoing) is designed to assess the efficacy and safety of 14-mg and 56-mg dose strengths. In 
Panel A, subjects in period 1 (1-week duration) were randomly assigned in a 3:1:1:1 ratio to 
placebo (33 subjects), esketamine 28 mg (11 subjects), esketamine 56 mg (11 subjects), or 
esketamine 84 mg (12 subjects). An initial analysis of the data from the double-blind phase of 
Panel A indicates that of the 67 subjects randomized in Period 1, 63 entered Period 2 (1-week 
duration), in which 28 placebo subjects who were eligible for re-randomization at the end of 
Period 1, were randomly assigned in a 1:1:1:1 ratio to placebo (n=6), esketamine 28 mg (n=8), 
esketamine 56 mg (n=9), or esketamine 84 mg (n=5) (data on file). Subjects eligible for re-
randomization had to have a Quick Inventory of Depressive Symptomatology - Self Report (QIDS-
SR16) total score >11 at the end of Period 1.
The improvement (with respect to change in MADRS total score from baseline Day 1 to Day 8) in 
all 3 esketamine dose groups reached statistical significance (p=0.021, p=0.001, and p<0.001 for 
esketamine 28 mg, 56 mg, and 84 mg, respectively) compared with placebo. The results of the 
2 periods were consistent. The mean (SE) differences from placebo on Day 8 (after 1 week of 
treatment), estimated using data from the combined periods, were:

Esketamine 28 mg:
-4.2 (2.09)

Esketamine 56 mg:
-6.3 (2.07)

Esketamine 84 mg:
-9.0 (2.13)
The effect sizes (95% CI) in Period 1 for esketamine, compared with placebo, were:

Esketamine 28 mg:
0.43 (-0.259-1.118) 

Esketamine 56 mg:
0.92 (0.201-1.621)

Esketamine 84 mg:
1.19 (0.473-1.883)
The duration of effect with the 28-mg dose appears to be shorter, with the MADRS total score 
higher on Day 8 than on Day 2. The duration of effect for the 56- and 84-mg doses appears to 
support twice-a-week dosing.
These data with esketamine nasal spray support the hypotheses that esketamine nasal spray is 
effective as a treatment for depression, that it has rapid onset of effect within 2 hours, and that 
multiple repeated sessions dose-dependently show sustained response throughout the study 
duration. A clear dose response was seen in the double-blind data in Panel A, and the point 
estimates and confidence intervals suggest a high effect size (Cohen’s D) with the 56-mg and 
84-mg dose groups, supporting further development.
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1.1.2.3.
Safety and Tolerability
Ketamine is a rapidly acting general anesthetic that is approved and widely used intravenously or 
intramuscularly for the induction and maintenance of anesthesia in children and adults at a dose of 
1 to 3 mg/kg given as a bolus. Ketamine is marketed as a racemic mixture and in Europe also as 
the S-enantiomer, esketamine. Ketamine was first introduced as an anesthetic in 1963 and is 
considered to have an excellent medical safety profile.27,36,60,70
Adverse Events Associated with Short-term Use of Esketamine Nasal Spray in Patients 
with MDD
According to the SmPC for esketamine,36 the following are reported as common adverse effects: 
transient tachycardia, vivid dreams (including nightmares), nausea and vomiting, increased blood 
pressure, increased salivation, blurred vision, dizziness, motor unrest, increase in vascular 
resistance in pulmonary circulation and increase in mucus secretion, increased oxygen 
consumption, laryngospasms, and temporary respiratory depression. It is reported that the risk of 
respiratory depression typically depends on the dosage and injection speed.45
Administration of esketamine is associated with a number of adverse events, which are transient 
in nature and typically resolve in 2 hours or less from the start of drug administration. The Phase 1 
study ESKETINTRD1003 evaluated the pharmacokinetics and safety of a single esketamine nasal 
spray 28 mg in 14 healthy elderly subjects (65 years of age, with 3 subjects 75 years of age) and 
20 healthy younger adult subjects (18 to 55 years of age, inclusive).12 The incidences of the 
treatment emergent adverse events (TEAEs) were slightly higher in young subjects (100% 
[20 subjects]) as compared with elderly subjects (85.7% [12 subjects]). The most commonly 
reported TEAEs by preferred term (>20%) in elderly subjects were dysgeusia and vertigo (9 [64%], 
of 14 subjects each).
In Panel A of the Phase 2 study with esketamine nasal spray (ESKETINTRD2003), the most 
common TEAEs (>10% of subjects in the pooled esketamine treatment groups) during the 
double-blind phase were: dizziness, headache, dissociation, dysgeusia (metallic taste), nausea, 
dissociative disorder, and oral hypoesthesia.64 Dissociative symptoms were the most typical of 
these adverse events observed post dose and were characterized by perceptual changes. Transient 
perceptual changes (dissociation), dizziness, and nausea were typically seen immediately after 
drug administration, resolving by 2 hours. 
No deaths were reported in the double blind or open label phases of ESKETINTRD2003. One 
subject experienced a serious adverse event of esophagitis in Panel A (double-blind phase, 
placebo/placebo treatment group). A total of 3 subjects withdrew during the double-blind phase 
because of adverse events. One subject in esketamine 28-mg group experienced a TEAE of 
syncope of severe intensity on Day 2 of Period 1, 1 day after receiving the first dose of study 
medication. The subject discontinued from the study and the study agent was permanently 
withdrawn due to this event, which resolved on the same day. The investigator considered the 
event to be possibly related to the study agent. Another subject in the placebo/esketamine 56-mg 
group experienced a TEAE of headache of moderate intensity on Day 11 of Period 2 and the study 
agent was permanently withdrawn due to this event, which resolved on the same day. The 
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investigator considered the event to be very likely related to the study agent. A third subject in the 
esketamine group (84 mg/esketamine 84 mg) experienced a TEAE of dissociative disorder 
(verbatim term: Dissociative syndrome) of moderate intensity on Day 8 of Period 2 (day of the 
third esketamine 84 mg dose in the study). The subject discontinued from the study and the study 
agent was permanently withdrawn due to the event of dissociative disorder, which resolved on the 
same day. The investigator considered the event to be very likely related to the study agent.64
Dissociative symptoms measured on the Clinician-Administered Dissociative Symptoms Scale 
(CADSS)6 were dose-dependent and were observed to reduce significantly with multiple doses 
over 2 weeks. No psychotic symptoms were seen. Transient increases in mean blood pressure 
(systolic and diastolic) were observed post dose following the esketamine nasal spray 
administration.
The mean (SD) peak systolic blood pressure (SBP) after the first administration in each dose group 
was:

Placebo: 124.2 (11.51) mm Hg (mean [SD] increase of 5.4 [7.84] mm Hg)

28 mg:
131.8 (15.49) mm Hg (mean [SD] increase of 10.4 [10.44] mm Hg)

56 mg:
130.4 (18.64) mm Hg (mean [SD] increase of 11.2 [15.01] mm Hg)

84 mg:
146.1 (19.9) mm Hg
(mean [SD] increase of 17.1 [15.5] mm Hg)
Mean (SD) peak diastolic blood pressure (DBP) after the first administration in each dose group 
was: 

Placebo: 81.2 (8.36) mm Hg
(mean [SD] increase of 3.8 [7.99] mm Hg)

28 mg:
85.7 (9.16) mm Hg
(mean [SD] increase of 6.5 [7.00] mm Hg)

56 mg:
86.5 (11.34) mm Hg
(mean [SD] increase of 7.2 [9.67] mm Hg)

84 mg:
87.8 (10.62) mm Hg
(mean [SD] increase of 8.1 [9.12] mm Hg)
The blood pressure increase typically resolved within 2 hours. Unlike dissociative symptoms, the 
blood pressure changes observed do not appear to attenuate over time with multiple doses. 
Transient increases in heart rate were also observed in parallel with blood pressure change. There 
was no clinically meaningful change in blood oxygen level.
Adverse Events Associated with Chronic Use of Ketamine
There are no controlled studies of long-term use with esketamine/ketamine in patients with MDD. 
Much of the literature on chronic use of ketamine comes from data gathered from street/illegal use 
of the drug, rather than systematically conducted clinical studies. Data therefore should be 
interpreted with caution, as in many cases, no baseline pre-drug data are available and drug 
exposure is poorly documented.
In a 1-year longitudinal study, 150 subjects were divided into 5 groups of 30 subjects each: 
frequent ketamine users (more than 4 times per week), infrequent ketamine users (at least once a 
month), abstinent users (abstinent for at least 1 month), polydrug controls, and non-users of illicit 
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drugs.50 Eighty percent of the participants were retested at the end of 1 year. Cognitive deficits 
were mainly observed in frequent users and not with the infrequent users. Short-lasting, 
dose-dependent effects of psychosis were associated with ketamine users. There was no increase 
in symptoms over time, and symptoms were completely reversible upon stopping use of ketamine. 
As noted, these data should be interpreted with caution, as baseline data predating drug use were 
not available. Furthermore, in their recent review, Morgan and Curran report that there is little 
evidence of any link between chronic, heavy use of ketamine and diagnosis of a psychotic 
disorder.48
The principal action of ketamine is at the NMDA receptor, and the consequences of ketamine use 
on cognition have been fairly widely investigated. Several studies have examined cognitive 
function in infrequent and frequent ketamine users.16,47,49,52 Overall, infrequent or recreational 
ketamine use does not appear to be associated with long-term cognitive impairment.52 The most 
robust findings are that frequent ketamine users (more than 5 times a week) exhibit impairments 
in both short- and long-term memory.49 Although dosages have varied, 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 TRD. Memory impairments may be reversible when 
individuals stop using the drug, as they were not found in a group of 30 ex-ketamine users who 
had been abstinent for at least a year.50
Ketamine-induced ulcerative cystitis is a recently identified complication.48 The most common 
symptoms are frequency and urgency of urination, dysuria, urge incontinence, and occasionally 
painful hematuria (blood in urine). Computerized tomography scans of these subjects revealed a 
marked thickening of the bladder wall, a small bladder capacity, and perivesicular stranding
consistent with severe inflammation. At cystoscopy, all patients had severe ulcerative cystitis. 
Biopsies in 4 of these cases found denuded urothelial mucosa with thin layers of reactive and 
regenerating epithelial cells, and ulcerations with vascular granulation tissue and scattered 
inflammatory cells. Cessation of ketamine use provided some relief of symptoms. Most of the 
described cases are in near-daily users of ketamine for recreational purposes. The prevalence is 
difficult to determine, as it is seen in recreational users who often do not seek help.
The majority of cases resolve after stopping ketamine use, one-third remaining static.
Abuse Liability, Dependence, and Withdrawal
There are a number of reports of ketamine dependence in the literature31,33,46,54 but no large-scale 
studies, and so the incidence of ketamine dependence is largely unknown.48 An interview study of 
90 ketamine users found that 57% of frequent users, 43% of infrequent users, and 60% of ex-users 
expressed concerns about ketamine addiction.51 The majority of frequent users in that study 
reported using the drug without stopping until supplies ran out, so compulsive patterns of behavior 
are also a concern. Oral ketamine has also been evaluated as a positive control in human abuse 
potential studies, with dosages of 65 mg and 110 mg reported as appropriate for use as positive 
controls for future abuse potential studies of compounds with a similar mechanism of action or 
with possible perception-altering effects.69 There is conflicting evidence of the existence of a 
"withdrawal syndrome" after cessation of ketamine use.48 Cravings seem to be a key problem in 
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frequent users: 28 of the 30 daily users in 1 study reported having tried to stop taking the drug but 
failed; all reported ketamine cravings as the reason for failure.48 The same study found that 12 of 
the 30 daily users reported withdrawal symptoms characterized by anxiety, shaking, sweating, and 
palpitations when they stopped using. A few published case studies also show craving and somatic 
and psychological aspects of anxiety as withdrawal symptoms.15,41 However, a specific ketamine 
withdrawal syndrome has not yet been described.48
Please refer to the Investigator’s Brochure for a summary of the adverse events reported in 
ketamine and esketamine studies.32
1.2.
Overall Rationale for the Study
Options for the treatment of TRD are limited. Esketamine nasal spray is a new medication being 
developed for TRD. There is an ethical obligation to provide continued esketamine nasal spray 
treatment to subjects who participated in select Phase 3 studies especially if the risk versus benefit 
to them has been favorable. This study provides an opportunity for subjects who have participated 
in select Phase 3 studies to receive open label esketamine nasal spray until: 

esketamine is approved in the respective country and accessible through the local healthcare 
system funding or until end of December 2022, whichever is earlier; or

the subject does not benefit from further treatment (based on the investigator’s clinical 
judgment) or withdraws consent; or 

the company terminates clinical development of esketamine nasal spray for TRD in that 
country/region
From a scientific/development perspective, this affords an opportunity to gain additional safety 
and efficacy information that can be helpful to clinicians, patients, and payers regarding 
esketamine’s longer term use.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
The primary objective of this study is to assess the safety and tolerability of esketamine nasal spray 
in subjects with TRD, with special attention to the following: 

Potential long-term effects on cognitive function

Treatment-emergent adverse events (TEAEs), including TEAEs of special interest

Post dose effects on heart rate, blood pressure, respiratory rate and blood oxygen saturation

Potential effects on suicidal ideation/behavior 
Secondary Objective
The secondary objective is to assess long-term efficacy, including effects on:

Depressive symptoms (clinician and self-reported), 
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
Overall severity of depressive illness, 

Functioning and associated disability, 

Health-related quality of life and health status, 
Exploratory Objectives
The exploratory objectives are to assess:

Medical resource utilization

Response remission rates to a second induction phase in eligible subjects who had relapsed in 
study ESKETINTRD3003

Subject treatment satisfaction

Subject tradeoff preferences for key benefit and harm outcomes associated with TRD 
treatment, using a stated-choice preference survey
2.1.2.
Endpoints
Safety endpoints are listed below.

Occurrence of TEAEs, including TEAEs of special interest

Potential short-term effects observed on the day of intranasal treatment session with special 
attention to changes from baseline/predose over time for:

Blood pressure (systolic and diastolic) and heart rate

Blood oxygen saturation

12-lead electrocardiogram

Alertness and sedation using Modified Observer’s Assessment of Alertness/Sedation 
(MOAA/S)

Long-term effects, with special attention to changes from baseline over time for:

Computerized cognitive battery and Hopkins Verbal Learning Test-Revised (HVLT-R), 
to assess potential effects on cognitive function

Columbia-Suicide Severity Rating Scale (C-SSRS), to assess potential effects on suicidal 
ideation and behavior

Changes from baseline over time in clinical laboratory tests, including hematology, serum 
chemistry, and urinalysis

Time to discharge readiness, using the Clinical Global Assessment of Discharge Readiness 
(CGADR)
Efficacy endpoints include changes from baseline over time for the following:

Depressive symptoms, including response (≥50% improvement from baseline) and remission 
(MADRS total score ≤12, PHQ-9 total score <5); using the Montgomery Asberg Depression 
Rating scale (MADRS) and 9-item self-reported Patient Health Questionnaire (PHQ-9) 

Overall severity of illness, using the Clinical Global Impression Severity (CGI-S)
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
Functioning and associated disability, using the Sheehan Disability Scale (SDS)

Health related quality of life and health status, using the European Quality of Life (EuroQol) 
Group, 5-Dimension, 5-Level (EQ-5D-5L)

Health related quality of life using the Quality of Life in Depression Scale (QLDS)
Exploratory endpoints include:

Changes from baseline over time for:

Depression response and remission rates (as defined above) to a second induction phase 
in eligible subjects who had relapsed in study ESKETINTRD3003, assessed using the 
MADRS and PHQ-9 

Subject treatment satisfaction

Subject tradeoff preferences for key benefit and harm outcomes associated with TRD 
treatment, using a stated-choice preference survey
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2.
Hypothesis
There is no formal hypothesis for this study.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design

This is a multicenter, open-label long term extension study to evaluate the safety, tolerability, 
and efficacy of esketamine nasal spray in subjects with TRD. 
The table (Table 1) below describes the subjects who may be eligible to participate in this study 
based on the clinical judgment of the investigator and their point of entry into 54135419TRD3008:
Table 1: 
Characterization of Study Population Entering 54135419TRD3008 from Different Phase 3 
Studies
Prior Study
Inclusion requirement
Point of entry for 
54135419TRD3008
ESKETINTRD3001
Subject completed induction phase and the 2-week 
follow-up phase visit
Induction phase
Subject completed the induction phase and was a 
responder and ESKETINTRD3003 is terminated.
Optimization/maintenance phase 
ESKETINTRD3002
Subject completed induction phase and the 2-week 
follow-up phase visit
Induction phase
Subject completed the induction phase and was a 
responder and ESKETINTRD3003 is terminated.
Optimization/maintenance phase 
ESKETINTRD3003
Subject relapsed in maintenance phase
Induction phase
Subject was in the induction phase at the time the 
study was terminated and, after completion of the 
induction phase, was determined to be a responder. 
Optimization/maintenance phase
Subject was in the optimization or maintenance phase 
at the time the study was terminated
Optimization/maintenance phase
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Table 1: 
Characterization of Study Population Entering 54135419TRD3008 from Different Phase 3 
Studies
Prior Study
Inclusion requirement
Point of entry for 
54135419TRD3008
At Week 16 of Optimization, the subject was not 
eligible to proceed to the maintenance phase and 
sponsor has approved subject’s entry into 
54135419TRD3008
Induction phase or 
Optimization/maintenance phase
Subject was in the induction phase and after 
completion of induction phase, was determined to not 
meet criteria for response, and sponsor has approved 
subject’s entry into 54135419TRD3008 
Induction phase or 
Optimization/maintenance phase
ESKETINTRD3004
Subject completed the optimization/maintenance phase Optimization/maintenance phase
Subject was in the induction phase at the time the 
study was terminated and, after completion of the 
induction phase, was determined to be a responder. 
Optimization/maintenance phase
Subject was in the optimization/maintenance phase at 
the time the study was terminated
Optimization/maintenance phase
Subject was in the induction phase and did not meet 
criteria for response and sponsor has approved 
subject’s entry into 54135419TRD3008
Induction phase or 
Optimization/maintenance phase 
ESKETINTRD3005
Subject was in the induction phase of 
ESKETINTRD3005 study at the time enrollment into 
the ESKETINTRD3004 study was closed and, after 
completion of the induction phase, was determined to 
be a non-responder.
Induction phase 
Subject was in the induction phase of 
ESKETINTRD3005 study at the time enrollment into 
the ESKETINTRD3004 study was closed and, after 
completion of the induction phase, was determined to 
be a responder
Optimization/maintenance phase 
ESKETINTRD3006
United States study 
sites only
Subject completed the induction phase and was a 
responder  
Optimization/maintenance phase 
Subject completed induction phase and did not meet 
the response criteria, and sponsor has approved 
subject’s entry into 54135419TRD3008
Induction phase or 
Optimization/maintenance phase 
An Independent Data Monitoring Committee (IDMC) will meet approximately every 6 months to 
review select safety data through the end of 2020 (see Section 11.7, Independent Data Monitoring
Committee, for details).
This study will have 2 open label phases

A 4-week induction phase (if applicable, per Table 1 above)

A variable duration optimization/maintenance phase
The duration that a subject may participate in the study is variable and is based on the subject’s 
point of entry into the study and the timing of when the predefined criteria (below) for ending 
study participation occurs. 
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Study participation will be stopped:

when esketamine is approved in the respective country and accessible through the local 
healthcare system funding or until end of December 2022, whichever is earlier; or

the subject no longer benefits from further treatment (based on the investigator's clinical 
judgment), or withdraws consent; or

the company terminates clinical development of esketamine nasal spray for TRD in that 
country/region
Subjects will have a final study visit within 1 week of the last dose of esketamine nasal spray. 
All study subjects should be taking a permitted oral antidepressant (per clinical judgment)
throughout the duration of study participation. Changes to the oral antidepressant medication(s)
that a subject is taking at study entry is permitted per clinical judgment of the investigator. If 
subject may benefit from addition of an additional antidepressant medication (eg lithium, 
bupropion, adjunctive antipsychotic, etc.), the investigator should discuss with sponsor to 
determine whether continuing esketamine nasal spray still has a favorable benefit versus risk for 
the subject. 
Induction Phase
Subjects will self-administer open-label esketamine nasal spray as a flexible dose regimen twice a 
week for 4 weeks as outlined in Section 6 (Dosage and Administration). 
At the end of the induction phase, subjects may be eligible to proceed to the 
optimization/maintenance phase, according to the investigator’s clinical assessment of the benefit 
versus risk for the subject. 
If a subject withdraws from the study before the end of the induction phase for reasons other than 
withdrawal of consent, or is not eligible to proceed to the optimization/maintenance phase, an 
Early Withdrawal (EW) visit will be conducted within 1 week of the last intranasal dose. 
Subjects who are currently in the induction phase at the time the 54135419TRD3008 study is 
completed will conduct an “End of Study” visit as their final study visit within 1 week of the last 
intranasal dose.
Optimization/Maintenance Phase: 
During this phase, the dose and intranasal treatment session frequency can be adjusted based on 
the criteria outlined in Section 6.1.2 (Dosage and Administration).
If a subject withdraws from the study before the end of the optimization/maintenance phase for 
reasons other than withdrawal of consent, an EW visit will be conducted within 1 week of the last 
intranasal dose. 
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Subjects who are currently in the optimization/maintenance phase at the time the 
54135419TRD3008 study is completed will conduct an “End of Study” visit as their final study 
visit within 1 week of the last intranasal dose.
A diagram of the study design is provided in Figure 1.
Figure 1: 
Schematic Overview of the 54135419TRD3008 Study
3.2.
Study Design Rationale
3.2.1.
Study Population
The study population will include adult and elderly men and women who previously participated 
in studies ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004, 
or ESKETINTRD3005, or ESKETINTRD3006 (US sites only). 
Options for the treatment of TRD are limited. For subjects who have participated in studies 
ESKETINTRD3003, ESKETINTRD3004, ESKETINTRD3005 or ESKETINTRD3006 (US sites 
only) studies and have responded to esketamine nasal spray treatment, it is considered an ethical 
obligation to provide continued esketamine nasal spray treatment if the benefit/risk profile is 
favorable for the subject at the time of completion of the previous study. Subjects in the placebo-
controlled, double blind ESKETINTRD3005 and who are non-responders at the end of the 
induction phase are eligible to enter the open label induction phase of ESKETINTRD3004, 
therefore if enrollment in the ESKETINTRD3004 is complete these subjects will be given the 
opportunity to enter this study, if clinically appropriate. For subjects who have completed the 
induction phase and 6-month follow up phase of the ESKETINTRD3001 or ESKETINTRD3002 
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study, this study provides an opportunity for subjects to have an induction phase with open-label 
esketamine nasal spray.
3.2.2.
Study Phases
Induction Phase (4 week; if applicable)
The duration of the 4-week open-label phase was selected because this is the duration of the 
induction phase in the prior studies from which these subjects are entering. It is unknown whether 
a second, repeated induction phase may be efficacious in subjects who have relapsed following 
response to esketamine nasal spray treatment (ESKETINTRD3003), have not responded to 
intranasal treatment with esketamine or placebo (ESKETINTRD3001 and ESKETINTRD3002, 
ESKETINTRD3005 and ESKETINTRD3006 [US sites only]), or with sponsor’s approval, 
subjects not meeting criteria for response from ESKETINTRD3003 and ESKETINTRD3004, 
therefore this study will implement the same duration of the subject’s first induction phase.
Optimization/Maintenance Phase (Variable)
The duration of the optimization/maintenance phase is variable and based on the subject’s 
individual efficacy and tolerability to esketamine nasal spray, or when esketamine is approved in 
the respective country and accessible through the local healthcare system funding or until end of 
December 2022, whichever is earlier.
Subjects entering this phase from the induction phase of this study (54135419TRD3008) will
reduce the frequency of intranasal treatment sessions and subsequently individualize and stabilize 
the treatment session frequency to weekly, every other week, or every 4 weeks based on the 
severity of depression during this phase.
All other subjects will enter this phase at the same frequency of intranasal treatment sessions that 
they had in the prior study, and this phase will allow the frequency of intranasal treatment sessions 
to continue to be individualized to once weekly, once every other week, or once every 4 weeks 
based on the severity of depression in order to sustain antidepressant efficacy.
While there is not a separate follow up phase, to ensure subject safety, an End of Study visit will 
be planned to occur within 1 week of the last esketamine nasal spray treatment.
3.2.3.
Blinding and Control Group
Blinding will not be used in this open-label study. 
An open-label design has been selected for this study and is appropriate given the intention to 
provide a continued evaluation of the long term safety, tolerability, and efficacy of esketamine 
nasal spray in a TRD patient population with limited, effective treatment options and who have 
previously participated in a prior Phase 3 studies.
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3.2.4.
Intranasal Treatment Group and Dose Selection
Induction Phase
All subjects will receive open-label esketamine nasal spray during this phase. 
The 56 mg and 84 mg doses and administration interval (2 treatment sessions per week for 
4 weeks) for this phase were based on the sponsor’s previous clinical data, in particular the results 
from Studies ESKETIVTRD2001, KETIVTRD2002, ESKETINTRD1001, and Panel A of Study 
ESKETINTRD2003, described above in Section 1.1.2, and is aligned with the induction phase of 
the prior study the subject is coming from.
The data from Study ESKETINTRD2003 Panel A support the hypotheses that both the 56 mg and 
84 mg doses are effective as a treatment for depression in subjects with TRD; that they have a 
rapid onset of effect; and that 2 treatment sessions per week can sustain the response throughout 
the 4-week duration of the induction phase. In addition, the 56-mg and 84 mg dosages were 
generally well tolerated by subjects.
To potentially improve tolerability, for those subjects that become ≥65 years of age at the time of 
signing the informed consent form (ICF; ie, the study populations in the ESKETINTRD3001, 
ESKETINTRD3002, and ESKETINTRD3003 were <65 years of age), a dose of 28 mg will be 
available. Based on PK data from ESKETINTRD1012 it is also possible that the 28 mg dose in 
the elderly may overlap with the 56 mg dose in younger patients, so addition of the 28 mg dose in 
the elderly may provide an efficacious dose while improving safety.
The use of flexible dosing for esketamine nasal spray may provide improved tolerability by 
gradually increasing to a higher dose and will also inform clinical practice, as many clinicians 
prefer to gradually increase, and then adjust as clinically required, the dose of antidepressant 
medication.
Optimization/Maintenance Phase
Subjects from the induction phase of 54135419TRD3008, who enter the optimization/maintenance 
phase will continue on the same dose of esketamine nasal spray from the induction phase and have 
a weekly intranasal treatment session frequency (ie, reduced frequency from the twice-weekly 
frequency in the induction phase).
Subjects who were responders at the end of the induction phase of ESKETINTRD3001, 
ESKETINTRD3002 
or 
ESKETINTRD3006 
(US 
sites 
only) 
who 
enter 
the 
optimization/maintenance phase will have a weekly intranasal treatment session frequency 
(ie, reduced frequency from the twice-weekly frequency in the induction phase). However, as the 
ESKETINTRD3001, 3002 and 3006 intranasal study medication is blinded at the time of entry 
into the current study, subjects entering the optimization/maintenance phase should start at 56 mg. 
The dose may remain at 56 mg or be increased to 84 mg, as determined by the investigator based 
on efficacy and tolerability.
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With sponsor approval, subjects from ESKETINTRD3003 and ESKETINTRD3004 entering 
directly from the induction phase who were determined to not meet the criteria for response in 
those studies may enter the optimization /maintenance phase of 54135419TRD3008 and will have 
a weekly intranasal treatment session frequency from week 1 to week 4 (ie, reduced from that in 
the induction phase (twice weekly) to weekly). In addition, a one-time dose change will be allowed 
at study entry.
With Sponsor approval subjects from ESKETINTRD3006 (US sites only) entering directly from 
induction phase and determined to not meet criteria for response in that study may enter the 
optimization/maintenance phase. However, as the ESKETINTRD3006 intranasal study 
medication is blinded at the time of entry into the current study, subjects entering the
optimization/maintenance phase from study ESKETINTRD3006 will start at 56 mg. The dose may 
remain at 56 mg or be increased to 84 mg, as determined by the investigator based on efficacy and 
tolerability. Subjects will have a weekly intranasal treatment session frequency from week 1 to 
week 4 (ie, reduced frequency from the twice-weekly frequency in the induction phase).
Subjects entering the optimization/maintenance phase from study ESKETINTRD3003 (Direct 
Entry) or ESKETINTRD3004 who were ongoing in the Optimization, Maintenance, or 
Optimization/Maintenance phase respectively, will have the option to have their current intranasal 
dosing frequency adjusted at the time of entry into 54135419TRD3008 study and should remain 
on the selected frequency from week 1 to week 4 (inclusive). A one-time dose change will be 
permitted at study entry. 
Subjects entering the optimization/maintenance phase from study ESKETINTRD3003 
(Transferred Entry) will start at 56 mg. The dose may remain at 56 mg or be increased to 84 mg, 
as determined by the investigator based on efficacy and tolerability. In addition, subjects will have 
the option to have their current intranasal dosing frequency adjusted at the time of entry into 
54135419TRD3008 study and should remain on the selected frequency from week 1 to week 4 
(inclusive).
Subjects from the induction phase of ESKETINTRD3005 will have the intranasal treatment 
session frequency reduced to weekly. However, as the ESKETINTRD3005 study will be blinded 
at the time of entry into the current study, these subjects will start esketamine nasal spray with an 
initial dose of 28 mg (Week 1; Study Day 1) and have their dose adjusted over the following 
3 weeks of the optimization/maintenance phase as described under the Section 6 Dosage and 
Administration. 
Starting at Week 4, the frequency of intranasal treatment sessions will be individualized and 
subsequent intranasal treatment session frequency will be adjusted (if applicable) based on the 
algorithm below at fixed, 4-week intervals (starting at Week 4,) to once weekly, once every other 
week, or once every 4 weeks based on the severity of depression, as assessed by the CGI-S. This 
continued individualization of treatment session frequency is intended to allow subjects to sustain 
the antidepressant response while minimizing the frequency of intranasal treatment sessions 
required. 
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After Week 4 (ie, starting at Week 5), the dose can be adjusted based upon efficacy and tolerability, 
as determined by clinical judgment.
The rationale for allowing reduction in the frequency of intranasal treatment sessions from twice 
weekly to weekly, once every other week, or once every 4 weeks, is to individualize the treatment 
session frequency (weekly, every other week, or every 4 weeks) for a given subject (based on level 
of depressive symptoms). Open label data from Panel A of a recently completed study 
(ESKETINTRD2003), indicates that even with a reduction in dosing frequency from twice weekly 
to weekly for 3 weeks and then a reduction to every other week for an additional 4 week, the 
majority of patients were able to maintain their treatment response. Additional data from the 
8-week follow up phase of ESKETINTRD2003 indicates that most patients who were responders 
when entering the follow up phase were able to maintain their response for up to 8 weeks after 
cessation of intranasal dosing. Therefor the current study will provide an opportunity to evaluate 
the impact of dosing every 4 weeks, which has not been studied in the other Phase 3 protocols to 
date. Similarly, anecdotal reports from clinical practice with IV ketamine, suggests patient may be 
able to maintain the antidepressant benefits achieved with less frequent dosing.
3.2.5.
Safety Evaluations
Evaluation of TEAEs and concomitant therapies, clinical laboratory tests, vital signs (including 
blood pressure measurements), 12-lead ECG, pulse oximetry, physical examination, and body 
weight, will be performed throughout the study as per the Time and Events Schedule to monitor 
subject safety. 
Treatment emergent AEs of special interest will be analyzed separately grouped in the following 
categories: drug abuse, dependence and withdrawal (standardized Medical Dictionary for 
Regulatory Activities [MedDRA]), increased blood pressure, increased heart rate, transient 
dizziness/vertigo, impaired cognition, cystitis, anxiety, events potentially related to suicidality, 
hepatic adverse events, events related to renal disorders, and symptoms of dissociation persisting 
beyond the typical ≤2 hour post esketamine administration, as well as delirium, psychosis or 
mania.
The effect of esketamine nasal spray on cognition will be assessed as per the Time and Events 
Schedule using the computerized cognitive battery and Hopkins Verbal Learning Test-Revised 
(HVLT-R). The cognitive battery will provide assessment of multiple cognitive domains, 
including attention, visual learning and memory, and executive function. The HVLT-R is a 
measure of verbal learning and memory, and includes assessment of both immediate and delayed 
recall.
Even though it is anticipated that the potential risk for treatment-emergent cystitis is very low 
based upon the doses to be used in this study, subjects will be monitored for adverse events of 
cystitis, bladder pain, and interstitial cystitis during the study. If cystitis is considered to be 
associated with esketamine, subjects will be discontinued from the study and followed up with 
appropriate medical care. 
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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 6.1.
The Columbia Suicide Severity Rating Scale (C-SSRS) will be performed as per the Time and 
Events Schedule to assess suicidal ideation and behavior, the MOAA/S will be used to measure 
treatment-emergent sedation, and the CGADR will be used to measure the subject’s readiness for 
discharge based on parameters including sedation, blood pressure, and adverse events.
On all intranasal dosing days, subjects that self-administer intranasal treatment at the study site 
must remain at the site until study procedures have been completed and the subject is ready for 
discharge and should be accompanied by a responsible adult when released from the clinical site. 
All subjects must not drive a car or work with machines for 24 hours after receiving intranasal 
study drug.
A list of prohibited medications is provided in Attachment 1 for general guidance for the 
investigator (not all-inclusive).
3.2.6.
Efficacy Measures
The efficacy measures were chosen for their reliability, validity, and ability to measure depression 
severity (including changes due to antidepressant treatment). 
MADRS
The 10-item clinician-administered MADRS was designed to be used in subjects with MDD to 
measure the overall severity of depressive symptoms.45 The MADRS scale is a validated, reliable 
scale and acceptable to regulatory health authorities as a primary scale to determine efficacy in 
major depression. 
Efficacy endpoints include assessment of depression symptoms using the MADRS individual 
scores and total score, as well as response and remission rate over time.
CGI-S 
The CGI-S is included to rate the severity of the subject’s illness at the time of assessment, relative 
to the clinician’s past experience with subjects who have the same diagnosis and improvement 
with treatment.26 Refer to Section 9.3.1.2 for additional information regarding CGI-S.
PHQ-9
The PHQ-9 will be used as a patient-reported measure of depressive symptomatology.79 Refer to 
Section 9.3.1.3 for additional information regarding PHQ-9.
During the optimization/maintenance phase, the CGI-S will be used to measure severity of 
depressive symptoms to individualize intranasal treatment session frequency.
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SDS
The Sheehan Disability Scale (SDS) is a patient reported measure included as an assessment of 
functional impairment and associated disability.39,68 Refer to Section 9.3.1.4 for additional 
information regarding SDS.
EQ 5D-5L
The EQ-5D-5L is included as a standardized patient self-completed instrument for use as a measure 
of health-related quality of life and health status.21,22 Refer to Section 9.3.1.5 for additional 
information regarding EQ-5D-5L.
QLDS
The QLDS is a disease specific PRO designed to assess health related quality of life in patients 
with Major Depressive Disorder.30,43,72 The instrument has a recall period of "at the moment", 
contains 34-items with "yes"/"no" response options and takes approximately 5-10 minutes to 
complete. The score range is from 0 (good quality of life) to 34 (very poor quality of life).
3.2.7.
Medical Resource Utilization 
Superior and sustained response and remission rates to the current antidepressant medication(s) 
are expected to result in low utilization of services, (such as outpatient visits, emergency room 
visits, or hospitalization), as assessed using the Healthcare Resource Use Questionnaire (HRUQ). 
The HRUQ includes information regarding utilization of healthcare services, including the timing 
of services, enabling changes in level and quantity of services to be considered as a variable in 
economic models.
3.2.8. 
Patient Stated-choice Preference Survey
Stated-choice conjoint analysis is a method specifically designed to provide information about an 
individual’s willingness to accept tradeoffs between treatments with multiple outcomes. It has been 
used in many therapeutic areas and with many types of patients, including patients with depression. 
The Patient Stated-choice Preference Survey will be used as an exploratory tool to assess the 
manner and degree to which the study subjects value or weigh the clinical outcomes associated 
with esketamine, allowing assessment of the maximum acceptable treatment-related risk that 
subjects would accept for various degrees of benefit.
4.
SUBJECT POPULATION
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues before 
enrolling a subject in the study. Waivers are not allowed.
All the subjects entering 54135419TRD3008 study are coming from 1 of the following esketamine 
Phase 
3 
studies 
(ESKETINTRD3001, 
ESKETINTRD3002, 
ESKETINTRD3003, 
ESKETINTRD3004, ESKETINTRD3005, and ESKETINTRD3006 (US sites only) and will have 
met the inclusion/exclusion criteria for entry into those studies.
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No formal sample size calculation was determined for this study as it is unknown how many 
subjects from the previous studies would participate.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1. Criterion modified per Amendment 1
1.1 Based on the prior study the subject is entering 54135419TRD3008 from:
a.
From ESKETINTRD3001 or ESKETINTRD3002 study: 
i.
Subject has completed the induction phase and the 2-week follow up phase 
visit; or
ii.
Subject completed the induction phase and was a responder and study 
ESKETINTRD3003 is terminated.
b. From ESKETINTRD3003 study:
i.
Subject relapsed during the maintenance phase; or 
ii.
Subject was in the induction phase of the ESKETINTRD3003 study when 
the study was terminated and, after completion of the induction phase, was 
determined to be a responder; or 
iii.
Subject was in the optimization or maintenance phases at the time the study 
was terminated; or
iv.
At Week 16 of Optimization, the subject was not eligible to proceed to the 
Maintenance phase and sponsor has approved subject’s entry into 
54135419TRD3008; or
v.
Subject was in the induction phase and after completion of induction phase 
was determined to not meet response criteria, and sponsor has approved 
subject’s entry into 54135419TRD3008.
c.
From ESKETINTRD3004 study:
i.
Subject completed ESKETINTRD3004 study optimization/maintenance 
phase; or
ii.
Subject was in the induction phase of the ESKETINTRD3004 study when 
the study was terminated and, after completion of the induction phase, was 
determined to be a responder; or
iii.
Subject was in the optimization/maintenance phase at the time the study was 
terminated; or
iv.
Subject was in the induction phase and did not meet criteria for response, and 
sponsor has approved subject’s entry into 54135419TRD3008.
d. From ESKETINTRD3005 study: Subject was in the induction phase of the 
ESKETINTRD3005 study at the time enrollment into the ESKETINTRD3004 study 
was closed and, after completion of the induction phase, was determined to be a 
responder or did not meet the criteria for response.
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e.
From ESKETINTRD3006 study (US Study sites only):
i.
Subject completed the induction phase and was a responder; or 
ii.
Subject completed the induction phase and did not meet the response criteria 
and sponsor has approved subject’s entry into 54135419TRD3008.
2. Subject must be medically stable on the basis of physical examination, vital signs (including 
blood pressure), pulse oximetry, and 12-lead ECG performed predose on the day of the first 
intranasal treatment session. If there are any abnormalities that are not specified in the 
inclusion and exclusion criteria, their clinical significance must be determined by the 
investigator and recorded in the subject's source documents and initialed by the investigator.
3. Criterion modified per Amendment 1
3.1 Subject must be medically stable according to the investigator’s judgment and 
knowledge of the subject’s medical stability in the parent study. This determination must be 
documented. 
4. Criterion modified per Amendment 
4.1 Criterion modified per Amendment 2
4.2 Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical studies.
A woman must be either:
a.
Not of childbearing potential defined as:

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL 
in the postmenopausal range) will be used to confirm a postmenopausal state in women 
not using hormonal contraception or hormonal replacement therapy, however in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Note: 
FSH not required if post-menopausal status previously confirmed in either 
ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004 or 
ESKETINTRD3006. FSH is not required if subject is ≥65 years.

permanently sterile 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, 
bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy.
b.
Of childbearing potential and

practicing a highly effective method of contraception (failure rate of <1% per year 
when used consistently and correctly).
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Examples of highly effective contraceptives include 
-user-independent methods:
implantable progestogen-only hormone contraception associated with inhibition of 
ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); 
vasectomized partner; sexual abstinence (sexual abstinence is considered a highly 
effective method only if defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study drug. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the subject.)
-user-dependent methods:
combined (estrogen-
and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal, and transdermal; 
progestogen-only hormone contraception associated with inhibition of ovulation: 
oral and injectable
Typical use failure rates may differ from those when used consistently and correctly. 
Use should be consistent with local regulations regarding the use of contraceptive 
methods for subjects participating in clinical studies.
Hormonal contraception may be susceptible to interaction with the study drug, which 
may reduce the efficacy of the contraceptive method.

agrees to use a highly effective method throughout the study and for at least 6 weeks 
after the last dose of study drug
Note: If the childbearing potential changes after start of the study or the risk of pregnancy 
changes (eg, a woman who is not heterosexually active becomes active,) a woman must 
begin a highly effective method of contraception, as described throughout the inclusion 
criteria.
5. Criterion modified per Amendment 1
5.1 A woman of childbearing potential must have a negative urine pregnancy test predose 
on the day of the first intranasal treatment session.
6. Criterion modified per Amendment 1
6.1 During the study (ie, from the first intranasal treatment session) and for a minimum of 
1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of 
intranasal study medication, a man who is sexually active with a woman of childbearing 
potential

must be practicing a highly effective method of contraception with his female partner 
from those listed above (see examples of highly effective methods of contraception 
provided for female subjects)

must use a condom if his partner is pregnant.

must agree not to donate sperm
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Note: If the childbearing potential changes after start of the study, a female partner of a male 
study subject, must begin a highly effective method of birth control, as described above.
7. Each subject must sign an informed consent form (ICF) indicating that he or she understands 
the purpose of and procedures required for the study and is willing to participate in the study.
8. Each subject must be willing and able to adhere to the prohibitions and restrictions specified 
in this protocol.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.
1.
Criterion modified per Amendment 3
1.1 The evaluation of the benefit versus risk of continued esketamine nasal spray treatment is 
not favorable for the subject in the opinion of the investigator.
2.
Since the last study visit in the subject’s prior study, subject has suicidal ideation with intent 
to act per the investigator’s clinical judgment or based on the C-SSRS [corresponding to a 
response of “Yes” on Item 4 (active suicidal ideation with some intent to act, without specific 
plan) or Item 5 (active suicidal ideation with specific plan and intent) in the suicidal ideation 
module of the C-SSRS] or suicidal behavior per the investigator’s clinical judgment or based 
on the C-SSRS (corresponding to any score higher than 0 in the suicidal behavior module of 
the C-SSRS).
3.
Criterion modified per Amendment 1
3.1 Subject has:

A neurodegenerative disorder (eg, Alzheimer’s disease, vascular dementia, Parkinson’s 
disease), or evidence of mild cognitive impairment (MCI).
4.
Subject has ongoing evidence of uncontrolled hypertension defined as a supine SBP 
>140 mmHg or DBP >90 mmHg predose on the day of the first intranasal treatment session.
For those ≥65 years uncontrolled hypertension is defined as a supine SBP >150 mm Hg or 
DBP >90 mm Hg.
5.
Subject has positive test result(s) for drugs of abuse (including barbiturates, methadone, 
opiates, cocaine, phencyclidine, and amphetamine/methamphetamine) predose on the day of 
the first intranasal treatment session.
6.
Subject has any anatomical or medical condition that, per the investigator’s clinical judgment 
based on assessment, may impede delivery or absorption of intranasal study drug.
7.
Subject has taken any prohibited therapies that would not permit administration of the first 
intranasal treatment session, as noted in Section 8 (Pre study and Concomitant Therapy) and 
Attachment 1.
8.
Subject is a woman who is pregnant, breast-feeding, or planning to become pregnant while 
enrolled in this study or within 6 weeks after the last dose of intranasal study drug.
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Status: Approved, Date: 5 October 2020
9.
Subject has any condition or situation/circumstance 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.
10. Subject is an employee of the investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study site, as well 
as family members of the employees or the investigator.
NOTE: Investigators should ensure that all study enrollment criteria have been met. If a subject's 
status changes (including laboratory results or receipt of additional medical records) 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.
The sponsor will evaluate and approve/reject requests to rescreen an individual subject on a 
case-by-case basis.
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:

Agree to follow all requirements that must be met during the study as noted in Section 4.1
(Inclusion Criteria) and Section 4.2 (Exclusion Criteria) (eg. for information regarding 
contraception requirements). 

Refer to Section 8 (Prestudy and Concomitant Therapy) and Attachment 1 (Prohibited 
Concomitant Medications for Intranasal Study Medication) for further information on 
prohibited therapies.

Subjects who were taking benzodiazepines at dosages equal to or less than the equivalent of 
6 mg/day of lorazepam and/or permitted non-benzodiazepine sleep medications 
(eg, zolpidem, zaleplon) can continue these medications. Dose increases or new 
benzodiazepines are permitted during the study as long as dosages are equal to or less than the 
equivalent of 6 mg/day of lorazepam 

Benzodiazepines and non-benzodiazepine sleeping medication (eg, zolpidem, zaleplon, 
eszopiclone, and ramelteon) are prohibited within 12 hours prior to the start of each intranasal 
treatment session or cognition testing.

A positive urine drug screen for use of phencyclidine, MDMA, or cocaine will lead to 
discontinuation.

Subjects must abstain from using alcohol within 24 hours before and after each intranasal 
treatment session. If a subject appears intoxicated, dosing should not occur (delayed per the 
permitted visit window; see the Time and Events Schedule).

On all intranasal study drug dosing days, all subjects remain at the clinical study site until 
study procedures have been completed and the subject is ready for discharge and 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.
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
Electroconvulsive therapy, DBS, and vagal nerve stimulation are prohibited during the time 
of study participation.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Randomization will not be used in this study, all subjects will be allocated to open-label esketamine 
treatment. 
Blinding
As this is an open study, blinding procedures are not applicable. 
6.
DOSAGE AND ADMINISTRATION
6.1.
Intranasal Study Drug
On all intranasal treatment session days, a site staff member with training in cardiopulmonary 
resuscitation (eg, Basic Life Support course or equivalent course) that is up to date per local 
regulations must be present with the subject during the intranasal treatment session and the 
postdose observation period.
Instructions for use documents (subject and healthcare provider versions) for intranasal study drug 
administration will be provided as separate documents. Details regarding study drug 
administration will be recorded in the source documents and the case report form (CRF).
All subjects will self-administer the intranasal study drug at treatment sessions at the study site.
Intranasal treatment sessions should not be given on consecutive days.
Food will be restricted for at least 2 hours before each administration of study drug. Drinking of 
any fluids will be restricted for at least 30 minutes before the first nasal spray.
If the subject has nasal congestion on the dosing day, an intranasal decongestant can be used to
reduce congestion or the dosing day be delayed (per the permitted visit window; see the Time and 
Events Schedule). The subjects must wait for at least 1 hour after using an intranasal decongestant 
or corticosteroid before self-administering esketamine.
On all intranasal treatment sessions, subjects must remain at the clinical site until study procedures 
have been completed and the subject is ready for discharge. 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 the intranasal treatment 
session. 
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Guidance for Blood Pressure Monitoring on Intranasal Treatment Session Days 
(Subjects <65 years of age)
Given the potential for treatment emergent transient elevation in systolic and diastolic blood 
pressure, the following guidance should be followed on intranasal dosing days:

Prior to intranasal dosing, subjects must have a blood pressure ≤140/90 mm Hg

If a subject’s predose SBP is >140 mmHg and/or DBP is >90 mm Hg, it is recommended to 
repeat the blood pressure measurement after subject rests in sitting or recumbent position. If 
after rest and repeated measurements, predose SBP is >140 mmHg and/or DBP is >90 mm 
Hg, then dosing should be postponed and the subject scheduled to return on the following day 
or within the given visit window. If the blood pressure elevation still persists on the next visit, 
the subject will be scheduled for a consultation by a cardiologist, other specialist, or primary 
care physician (PCP) prior to further dosing.

If at any post-dose time point on the dosing day the SBP is 180 mmHg but <200 mmHg 
and/or the DBP is 110 mmHg but <120 mmHg, further intranasal dosing should be 
interrupted and the subject should be referred to a cardiologist, other specialist, or primary 
care physician for a follow-up assessment.
After the assessment by a cardiologist, other specialist, or PCP, if recommended by the referring 
doctor and considered appropriate according to the clinical judgment for the subject to continue in 
the study, the subject may continue with intranasal dosing provided the predose blood pressure at 
the next scheduled visit is within the acceptable range (see bullet point above).

If at any post-dose time point on the dosing day the SBP is 200 mmHg and/or the DBP is 
120 mmHg, the subject must discontinue from further dosing and the subject should be 
referred to a cardiologist, other specialist, or PCP for a follow up assessment.

During the induction phase, at 1.5 hours postdose, if the SBP is 160 mm Hg and/or the DBP 
100 mm Hg, blood pressure monitoring should continue every 30 minutes until:

the blood pressure is <160 mm Hg SBP and <100 mm Hg DBP, or 

in the investigator’s clinical judgment, the subject it is clinically stable and can be 
discharged from the study site, or

the subject is referred for appropriate medical care if clinically indicated.

if the blood pressure remains ≥180 mmHg SBP and/or ≥110 mmHg DBP, 2 hours after 
dosing, the subject should be referred for immediate medical treatment.
Guidance for Blood Pressure Monitoring on Intranasal Treatment Session Days 
(Subjects ≥65 years of age)
Given the potential for treatment emergent transient elevation in systolic and diastolic blood 
pressure, the following guidance should be followed on intranasal dosing days:

Prior to any dose escalation, subjects must have had a post-dose blood pressure, on the prior 
intranasal dosing day, of <180 mmHg systolic and <100 mm Hg diastolic blood pressure.
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
If a subjects predose SBP is >150 mmHg and/or DBP is >90 mmHg, it is recommended to 
repeat the blood pressure measurement after subject rests in sitting or recumbent position. If 
after rest and repeated measurements, predose SBP is >150 mmHg and/or DBP is >90 mmHg, 
then dosing should be postponed and the subject scheduled to return on the following day or 
within the given visit window. If the blood pressure elevation still persists on the next visit, 
the subject will be scheduled for a consultation by cardiologist, other specialist, or a primary 
care physician, prior to further dosing.

If at any postdose time point on the dosing day the SBP is 180 mm Hg but <190 mm Hg 
and/or the DBP is 100 mm Hg but <110 mm Hg, further intranasal dosing should be 
interrupted and the subject should be referred to a cardiologist, other specialist, or primary 
care physician for a follow-up assessment.
After the assessment by a cardiologist, other specialist, or primary care physician if recommended 
by the referring doctor and considered appropriate according to the clinical judgment of the 
investigator for the subject to continue in the study, the subject may continue with intranasal dosing 
if the predose blood pressure at the next scheduled visit is within the acceptable range (see bullet 
above).

If at any postdose time point on a dosing day the SBP is 190 mm Hg and/or the DBP is 
110 mm Hg, the subject must instead discontinue from further dosing and be referred to a 
cardiologist, other specialist, or primary care physician for a follow-up assessment.

During the induction phase, at 1.5 hours postdose, if the SBP is 160 mm Hg and/or the DBP 
100 mm Hg, blood pressure monitoring should continue every 30 minutes until: 

the blood pressure is <160 mm Hg SBP and <100 mm Hg DBP, or 

in the investigator’s clinical judgment, the subject is clinically stable and can be 
discharged from the study site, or

the subject is referred for appropriate medical care if clinically indicated.
If the blood pressure remains ≥180 SBP and/or ≥110 mmHg DBP 2 hours after dosing, the subject 
should be referred for immediate medical treatment.
6.1.1.
Induction Phase
All eligible subjects will self-administer the intranasal study drug twice a week for 4 weeks at 
treatment sessions at the study site. Intranasal treatment sessions should not take place on 
consecutive days. 
The esketamine nasal spray dose titration in the Induction Phase for subjects <65years of age is 
described in Table 2:
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Table 2:
Induction Phase Dose Titration of Esketamine Nasal Spray, Subjects <65 Years
Day 
Dose
Dose Titration Guidance
Day 1
56 mg
Day 4
56 or 84 mg
The dose may remain at 56 mg or be increased to 84 mg, as 
determined by the investigator based on efficacy and tolerability.
Day 8, 11, 15, 18, 22, 
25
56 or 84 mg
The dose may be increased to 84 mg (if previous dose was 56 mg), 
remain the same, or be reduced to 56 mg (if previous dose was 84 
mg), as determined by the investigator based on efficacy and 
tolerability
The esketamine nasal spray dose titration in the Induction Phase for subjects ≥65years of age is 
described in Table 3: 
Table 3:
Induction Phase Dose Titration of Esketamine Nasal Spray, Subjects ≥65 Years
Day 
Dose
Dose Titration Guidance*
Day 1
28 mg
Day 4
28 or 56 mg
The dose may remain at 28mg or be increased to 56mg , as 
determined by the investigator based on efficacy and tolerability
Day 8, 11, 15, 18, 22, 
25
28, 56 or 84 mg
The dose may remain the same, or be increased or reduced by 28mg 
from the previous dosing session, as determined by the investigator 
based on efficacy and tolerability.
6.1.2.
Optimization/Maintenance Phase
Subjects will self-administer the intranasal study drug at treatment sessions at the study site. 
Intranasal treatment sessions should not take place on consecutive days.
For the first 4 weeks of the optimization/maintenance phase (Week 1 to Week 4):

Subjects from the induction phase of study 54135419TRD3008, who enter the 
optimization/maintenance phase will continue on the same dose of esketamine nasal spray 
from the induction phase and have a weekly intranasal treatment session frequency 
(ie, reduced frequency from the twice-weekly frequency in the induction phase).

Subjects who were responders at the end of the induction phase of ESKETINTRD3001, 
ESKETINTRD3002 
or 
ESKETINTRD3006 
(US 
sites 
only) 
who 
enter 
the 
optimization/maintenance phase will have a weekly intranasal treatment session frequency 
(ie, reduced frequency from the twice-weekly frequency in the induction phase). However, as 
the ESKETINTRD3001, 3002 and 3006 intranasal study medication is blinded at the time of 
entry into the current study, subjects entering the optimization/maintenance phase should start 
at 56 mg. The dose may remain at 56 mg or be increased to 84 mg, as determined by the 
investigator based on efficacy and tolerability.

With sponsor approval, subjects from ESKETINTRD3003 and ESKETINTRD3004 entering 
directly from the induction phase, who were determined to not meet the criteria for response 
in those studies may enter the optimization/maintenance phase of 54135419TRD3008 and 
will have a weekly intranasal treatment session frequency from week 1 to week 4 (ie, reduced 
frequency from the twice-weekly frequency in the induction phase). In addition, a one-time 
dose change will be allowed at study entry.
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Status: Approved, Date: 5 October 2020

With sponsor approval subjects from ESKETINTRD3006 (US sites only) entering directly 
from induction phase and determined to not meet criteria for response in that study may enter 
the optimization/maintenance phase. However, as the ESKETINTRD3006 intranasal study 
medication is blinded at the time of entry into the current study, subjects entering the 
optimization/maintenance phase from study ESKETINTRD3006 will start at 56 mg. The dose 
may remain at 56 mg or be increased to 84 mg, as determined by the investigator based on 
efficacy and tolerability. Subjects will have a weekly intranasal treatment session frequency 
from week 1 to week 4 (ie, reduced frequency from the twice-weekly frequency in the 
induction phase).

Subjects entering the optimization/maintenance phase from study ESKETINTRD3005 will 
also have a weekly intranasal treatment session frequency. However, as the 
ESKETINTRD3005 intranasal study medication is blinded at the time of entry into the current 
study, the dose of esketamine nasal spray will be administered as outlined in Table 4.
Table 4: 
Optimization/Maintenance Phase Week 1 to 4: Dose Titration of Esketamine Nasal Spray for 
Responder Subjects Entering from ESKETINTRD3005
Week 
Dose
Dose Titration Guidance
Week 1 
28 mg
Week 2 
28 or 56 mg
The dose may remain at 28mg or be increased to 56mg, as determined by the 
investigator based on efficacy and tolerability
Week 3 
and 4 
28, 56 or 84 mg
The dose may remain the same or be increased or reduced by 28mg from the 
previous dosing session, as determined by the investigator based on efficacy and 
tolerability. For those who have had a prior down titration from a higher dose, a 
dose increase by 28 mg is allowed based on clinical judgment. 

Subjects entering the optimization/maintenance phase from study ESKETINTRD3003 (Direct 
Entry) or ESKETINTRD3004 who were ongoing in the Optimization, Maintenance, or 
Optimization/Maintenance phase, respectively, will have the option to have their current 
intranasal dosing frequency adjusted at the time of entry into 54135419TRD3008 study and 
should remain on the selected frequency from week 1 to week 4 (inclusive). A one-time dose 
change will be permitted at study entry. 

Subjects entering the optimization/maintenance phase from study ESKETINTRD3003 
(Transferred Entry) will start at 56 mg. The dose may remain at 56 mg or be increased to 
84 mg, as determined by the investigator based on efficacy and tolerability. In addition, 
subjects will have the option to have their current intranasal dosing frequency adjusted at the 
time of entry into 54135419TRD3008 study and should remain on the selected frequency from 
week 1 to week 4 (inclusive).
After Week 4 (ie, starting at Week 5), based on the investigator’s clinical judgment, the dose of 
esketamine for all subjects can be adjusted based upon efficacy and tolerability. 
Starting at Week 4, the frequency for subsequent intranasal treatment sessions will be adjusted (if 
applicable) based on the algorithm outlined in Table 5 at fixed, 2-week intervals. 
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Table 5:
Algorithm for Adjusting Intranasal Treatment Session Frequency (if applicable) Starting
Week 4
Current treatment 
session frequency
CGI-S score at current visita
≤ 3
>3
Weekly
Change to every other week frequency
No change in frequency
Every other week
No change in frequency or change to 
every 4 weeks per clinical judgment
Change to weekly frequency
Every 4 weeks
No change in frequency
Change to weekly or every other week 
frequency per clinical judgment
a 
Note: The CGI-S is administered every 2 weeks from Week 4 through the end of the 
Optimization/Maintenance Phase, adjustment of the intranasal treatment session frequency is only permitted 
at the fixed, 2-week interval (based on CGI-S performed at that visit), and every 4 weeks for subjects dosed at 
the 4 week interval.
For example, if at Week 4 a subject is currently at a weekly treatment session frequency and the 
CGI-S score at Week 4 is a 2, the intranasal treatment session frequency will be changed from 
weekly to every other week (ie, the next treatment session for this subject will be at Week 6). 
Missed Doses
If a subject missed a dose/s and the depression symptoms worsened, the investigator can go back 
to more frequent dosing if clinically applicable until the subject is stable.
7.
TREATMENT COMPLIANCE
All doses of intranasal study drug will be self-administered by the subjects at the investigative site 
under the direct supervision of the investigator or designee and will be recorded.
The investigator or designated study-site personnel will maintain a log of all intranasal study drug 
dispensed and returned. Drug supplies for each subject will be inventoried and accounted for 
throughout the study (see Section 14.5 Drug Accountability).
8.
PRESTUDY AND CONCOMITANT THERAPY
All study subjects should be taking a permitted oral antidepressant (per clinical judgment)
throughout the duration of study participation. Changes to the oral antidepressant medication(s) 
that a subject is taking at study entry is permitted per clinical judgment of the investigator. If 
subject may benefit from an additional antidepressant medication (eg lithium, bupropion, 
adjunctive antipsychotic, etc.), the investigator should discuss with sponsor to determine whether 
continuing esketamine nasal spray still has a favorable benefit versus risk for the subject.
A list of prohibited medications is provided in Attachment 1 as general guidance for the 
investigator (but is not all inclusive). The sponsor must be notified in advance (or as soon as 
possible thereafter) of any instances in which prohibited therapies are administered.
Concomitant therapies (including psychotherapy) must be recorded throughout the study 
beginning with signing of the informed consent and continuing up to the last visit. Information on 
concomitant therapies should also be obtained beyond this time only in conjunction with new or 
worsening adverse events until resolution of the event. 
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Subjects should continue to take their permitted concomitant medications (eg, antihypertensive 
medications) at their regular schedule; however, restrictions as outlined in Section 4.3 and 
Attachment 1 should be taken into account. Of note, if a subject has routinely taken his/her oral 
antihypertensive medications in the morning, the morning dose should be taken prior to esketamine 
nasal spray on intranasal dosing days.
There is no restriction regarding psychotherapy in this study and subjects may continue or start 
psychotherapy (including cognitive behavioral therapy; CBT) during the study.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as psychotherapy, acupuncture, and special diets) 
different from the study drug must be recorded in the CRF. Modification of an effective preexisting 
therapy should not be made for the explicit purpose of entering a subject into the study, unless 
permitted by protocol (eg, adjustment of blood pressure medications).
Rescue Medications
Rescue medications will not be supplied by the sponsor. In case of treatment-emergent adverse 
events that cannot be resolved by stopping further administration of esketamine nasal spray, the 
following rescue medications may be considered:

For agitation or anxiety: As required, midazolam (maximum dose 2.5 mg orally or IM) or 
short acting benzodiazepine

For nausea: As required, ondansetron 8 mg sublingually, metoclopramide (10 mg orally or IV 
or IM) or dimenhydrinate (25 to 50 mg, IV or IM)

Unless clinically indicated, it is recommended that transient increases in blood pressure not 
be treated, as the blood pressure typically returns to predose values in 2 hours. The effect of 
any treatment may result in hypotension.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedules summarize the frequency and timing of safety, efficacy, and 
medical resource utilization measurements applicable to this study.
Visit-specific predose subject-reported outcomes assessments should be conducted/completed 
before any tests, procedures, or other consultations for that visit to prevent influencing subject 
perceptions. 
A recommended order of study procedures will be provided to sites as a separate document.
Actual dates and times of assessments will be recorded in the source documentation and/or CRF.
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The total blood volume to be drawn from each subject over the first 1 year period will be 
approximately 42 mL (Table 6) and will not exceed the amount of blood donated by a volunteer 
for a single charitable blood donation in 1 day (about 500 mL). The amount of blood volume 
collected during optimization/maintenance phase will be variable due to the nature of the study 
design. Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
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.
Table 6:
Volume of Blood to be Collected from Each Subject 
Phase
Type of Sample
Volume per 
Sample(s), mL
Number of Samples per 
Subject
Total Volume of 
Blood (mL)a
Baseline Tests
HbA1C (if applicable)
2
1
2
Hematology 
2
1
2
Serum chemistryb
5
1
5
Induction Phase
Hematology 
2
1
2
Serum Chemistry
2.5
1
2.5
Optimization/Maintenance Phase
HbA1C (if applicable)
2
3
6
Hematology 
2
5c
10c
Serum Chemistry
2.5
5c
12.5c
Approximate volume of blood collected during the studyd
42 mL
a
Calculated as number of samples multiplied by amount of blood per sample.
b 
Serum chemistry includes serum -hCG pregnancy tests (for women of childbearing potential), and lipid panel.
c 
The number of samples per subject (5) is representative of the samples collected that will be collected in the 
optimization/maintenance phase in an year. The length of the optimization/maintenance phase is variable and 
would decide the total number of samples collected during this phase and in turn the total volume of blood 
collected.
d 
The approximate volume of blood (42 mL) collected during the study will vary as per the total volume of blood 
collected during the variable optimization/maintenance phase. The calculation shown is an estimate for a 1 year 
period.
Note: An indwelling IV cannula may be used for blood sample collection.
Note: Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
9.1.2.
Induction Phase
The following subjects are eligible to enter the study at the induction phase:

Subjects who relapsed during the ESKETINTRD3003 maintenance phase, or

Subjects who were in the induction phase of ESKETINTRD3005 study at the time enrollment 
into the ESKETINTRD3004 study was closed and, after completion of the induction phase, 
were determined to be a non -responder, or 

Subjects who completed the induction phase and the 2 week follow up phase visit in 
ESKETINTRD3001 or ESKETINTRD3002 studies
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Prior to conducting any study procedure for 54135419TRD3008, the investigator (or designated 
study personnel) will review and explain the written ICF to each subject. The ICF will be signed 
at the start of this phase. 
During this phase, all subjects will self-administer open-label treatment with esketamine nasal 
spray treatment twice a week for 4 weeks as a flexible dose regimen. Refer to Section 6, Dosage 
and Administration for details regarding intranasal study medication.
At the end of the induction phase of 54135419TRD3008, subjects may be eligible to proceed to 
the optimization/maintenance phase, according to the investigator’s clinical assessment of the 
benefit versus risk for the subject. 
Refer to Section 9.1.5 for information regarding early withdrawal subjects and subjects that are 
currently in this phase at the time the study is terminated. 
9.1.3.
Optimization/Maintenance Phase
The following subjects are eligible to enter the study at the optimization/maintenance phase: 

Subjects who completed the induction phase of ESKETINTRD3001 or ESKETINTRD3002 
and were responders, and study ESKETINTRD3003 is terminated. 

Subjects who were in the induction phase of ESKETINTRD3003 and ESKETINTRD3004 
studies at the time these studies were terminated and, after completion of the induction phase, 
were determined to be a responder.

Subjects who completed the optimization/maintenance phase of ESKETINTRD3004

Subjects who were in the optimization, maintenance or optimization/maintenance phase of 
ESKETINTRD3003 and ESKETINTRD3004 studies, respectively, at the time these studies 
were terminated

Subjects who were in the induction phase of ESKETINTRD3005 study at the time enrollment 
into the ESKETINTRD3004 study was closed and, after completion of the induction phase, 
were determined to be responders.

Subjects (US only) who completed the induction phase of ESKETINTRD3006 and were 
responders.
The duration that a subject may participate in the study is variable and is based on the subject’s 
point of entry into the study and the timing of when the predefined criteria (below) for ending 
study participation occurs. 
Study participation will be stopped:

when esketamine is approved in the respective country and accessible through the local 
healthcare system funding or until end of December 2022, whichever is earlier; or

the subject no longer benefits from further treatment (based on the investigator's clinical 
judgment), or withdraws consent; or
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
the company terminates clinical development of esketamine nasal spray for TRD in that 
country/region
Refer to Section 6 Dosing and Administration for further details regarding intranasal study 
medication.
Refer to Section 9.1.5 for information regarding early withdrawal subjects and subjects that are 
currently in this phase at the time the study is terminated.
If a subject misses a study visit in the optimization/maintenance phase without notifying the site 
of the reason, the site personnel will attempt to contact the subject to confirm if the subject is still 
interested in participating in the study and if so, to schedule their next visit. During this contact 
the information on adverse events and concomitant medication will be collected. These contacts 
will be repeated weekly until successful scheduling of the next dosing session or otherwise until 
discontinuation from the study (up to 4 contacts will be made).
9.1.4.
Induction Phase and Optimization/Maintenance Phase - Study Entry
The following subjects are eligible to enter the study at either the Induction Phase or the 
Optimization/Maintenance Phase:

Subjects in ESKETINTRD3003, who at Week 16 of Optimization were not eligible to proceed 
to the maintenance phase and the sponsor has
approved subject’s entry into 
54135419TRD3008; or 

Subjects in ESKETINTRD3003 and ESKETINTRD3004, who were in the induction phase 
and (for ESKETINTRD3003, after completion of the induction phase) were determined to not 
meet response criteria, and sponsor has approved subject’s entry into 54135419TRD3008; or 

Subjects in ESKETINTRD3006 (US sites only) who completed the induction phase but did 
not meet the response criteria, and sponsor has approved subject’s entry into 
54135419TRD3008.
9.1.5.
Early Withdrawal/End of Study Visit
Early Withdrawal
If a subject withdraws before the end of the induction or optimization/maintenance phase for 
reasons other than withdrawal of consent, an early withdrawal visit should be conducted within 
1 week of the last intranasal dose.
If the early withdrawal visit occurs on the same day as a scheduled visit, duplicate assessments are 
not required.
End of Study Visit
Subjects in the induction phase or optimization/maintenance phase at the time of study termination 
will have an End of Study visit conducted as the final visit within 1 week of the last intranasal 
dose. 
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If the End of Study visit occurs on the same day as a scheduled visit, duplicate assessments are not 
required.
9.2.
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 CRF.
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 condition is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedules.
There may be instances where a subject has started a scheduled clinic visit in which an intranasal 
treatment session is planned, but due to predose vital sign measurements (eg, blood pressure 
value), a decision has been made to postpone/delay the intranasal treatment session within the visit 
window permitted per protocol. In such cases, all time points (including predose) of the following 
assessments must be repeated on the actual intranasal treatment session day: vital sign (ie, blood 
pressure, pulse, respiratory rate, and temperature), 12-lead ECG, C-SSRS (since last visit), 
MOAA/S, and pulse oximetry.
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or 
the subject's legally acceptable representative) for the duration of the study. Adverse events will 
be followed by the investigator as specified in Section 12, Adverse Event Reporting.
Treatment emergent AEs of special interest will be examined separately (please refer to 
Section 3.2.5 and Section 11.3).
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and urine samples 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 CRF. 
The laboratory reports must be filed with the source documents.
The use of local laboratories is allowed in cases where initiation of treatment or safety follow-up 
is time-critical and the central laboratory results are not expected to be available before the need 
to begin dosing or if actions need to be taken for safety reasons.
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The following tests will be performed by the central laboratory, unless noted otherwise:

Hematology panel:
- hemoglobin
- white blood cell count with differential
- hematocrit
- platelet count
- red blood cell count

Serum chemistry panel:
- sodium
- gamma-glutamyltransferase 
- potassium
- total bilirubin
- chloride
- alkaline phosphatase
- bicarbonate
- creatine phosphokinase 
- blood urea nitrogen 
- calcium
- creatinine
- phosphate
- glucose 
- albumin
- aspartate aminotransferase 
- total protein
- alanine aminotransferase 

Urinalysis:
Dipstick:
Sediment (if dipstick result is abnormal):
- specific gravity
- red blood cells
- pH
- white blood cells
- glucose
- epithelial cells
- protein
- crystals
- blood
- casts
- ketones
- bacteria
- bilirubin
- urobilinogen
- nitrite
- leukocyte esterase
If dipstick result is abnormal, flow cytometry or microscopy 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.
The following tests will be done at time points specified in the Time and Events Schedule or as 
required based on subject status (noted below):

Serum and urine pregnancy testing (for women of childbearing potential only)

Urine drug screen: barbiturates, methadone, opiates, cocaine, phencyclidine, and 
amphetamine/methamphetamine

Alcohol breath test 

Glycosylated hemoglobin (HbA1c) will be monitored only in those subjects with a 
documented medical history of diabetes 

Serum follicle stimulating hormone (FSH) level test if applicable
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Vital Signs (blood pressure, pulse/heart rate, temperature, and respiratory rate)
Blood pressure and pulse/heart rate measurements will be assessed supine with a completely 
automated device or using manual techniques.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest 
in a quiet setting without distractions (eg, television, cell phones).
For further details regarding blood pressure, please see Guidance for Blood Pressure Monitoring 
on Intranasal Dosing Days (Section 6.1).
Tympanic temperature is recommended.
An automated device will be used for measurement of respiratory rate.
Electrocardiogram (ECG)
During the collection of ECGs, subjects should be in a quiet setting without distractions 
(eg, television, cell phones). Subjects should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs. 
All ECG tracings will be sent to a central ECG laboratory. The ECGs will be read at the scheduled 
time points and summarized by a central ECG laboratory. The central ECG laboratory will send 
the sponsor an electronic copy of the data for inclusion in the clinical database. In addition, the 
investigator or sub-investigator is required to review all ECGs at the study visit to assess for any 
potential safety concerns or evidence of exclusionary conditions.
The investigator’s review of the machine read ECG tracing (provided by the central reader) is 
considered acceptable in determining if it is appropriate in determining eligibility in cases where 
initiation of treatment or safety follow-up is time-critical, and where the central cardiology results 
are not expected to be available before the need to begin dosing, or if actions need to be taken for 
safety reasons.
All ECG tracings will be sent to the central ECG vendor, where it will be used to determine 
whether it is appropriate to proceed with dosing.
Pulse Oximetry
Pulse oximetry will be used to measure arterial oxygen saturation. On each dosing day, the device 
will be attached to the finger, toe, or ear before the first nasal spray and then, after the first spray 
it will be monitored and documented. Any arterial oxygen saturation (SpO2) <93% and lasting for 
more than 2 minutes, and confirmed by an additional measurement on another part of the body, 
will be reported as an adverse event.
On intranasal treatment session days, pulse oximetry will be recorded predose and every 
15 minutes to t=1 hour postdose during the induction phase. During the optimization/maintenance 
phase, pulse oximetry will be recorded predose and at 30 minutes and 60 minutes postdose on 
intranasal treatment session days. If oxygen saturation levels are <93% at any time during the 
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1 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.
Physical Examination and Body Weight
Physical examinations and body weight will be performed/measured as per the Time and Events 
Schedule.
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS will be used to assess potential suicidal ideation and behavior. 
The C-SSRS is a measure of the spectrum of suicidal ideation and behavior that was developed in 
the National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to 
assess severity and track suicidal events through any treatment.58 It is a clinical interview providing 
a summary of both suicidal ideation and behavior that can be administered during any evaluation 
or risk assessment to identify the level and type of suicidality present. The C-SSRS can also be 
used during treatment to monitor for clinical worsening.
The C-SSRS assessments in this study will use the Since Last Visit version, which will assess 
suicidal ideation and behavior since the subject’s last visit.
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 specified days in the T&E, the MOAA/S will be performed every 15 minutes from predose to 
t=+1 hours postdose.

If the score is 3 at any time during the 1 hour postdose interval, the MOAA/S will be 
performed every 5 minutes until a score of 4 is reached (at which point a frequency of every 
15 minutes can be resumed until t=+1 hours post dose). 

If a subject does not have a score of at least 5 at t=+1 hours postdose, they 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.
Clinical Global Assessment of Discharge Readiness (CGADR)
The CGADR will be used to measure the subject’s current clinical status and is the clinician’s 
assessment of the readiness to be discharged from the study site. 
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The clinician will answer “Yes” or “No” to the question “Is the subject considered ready to be 
discharged based on their overall clinical status (eg, sedation, blood pressure, and other adverse 
events)?”
On all intranasal treatment session days, subjects must remain at the clinical site until study 
procedures have been completed and the subject is ready for discharge.
Cognition Testing
Computerized Cognitive Battery 
The computerized cognitive battery provides 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 (mean of the 
log 10-transformed reaction times for correct responses)

Visual episodic memory; visual recall test scored using arcsine transformation of the 
proportion of correct responses

Working memory (n back); scored for speed of correct response (mean of the 
log 10-transformed reaction times for correct responses)

Executive function; maze/sequencing test, scored for total number of errors
All measures have been validated against traditional neuropsychological tests and are sensitive to 
the effects of various drugs on cognitive performance, including alcohol and benzodiazepines. 
Completing the cognitive battery requires approximately 25 minutes.
Hopkins Verbal Learning Test-Revised (HVLT-R)
The HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. 
Administration includes 3 learning trials, a delayed recall (20-minute) trial, and a 24-word 
recognition list (including 12 target and 12 foil words).4 The test administrator reads instructions 
and word lists aloud, and records words recalled/recognized by the subject. Scores include 
learning, delayed recall, and recognition. The HVLT-R is a well-validated and widely used 
measure of verbal episodic memory. 
The tests will be administered in the following order: HVLT-R, computerized cognitive test 
battery, and HVLT-R Delayed.
9.3.
Efficacy
9.3.1.
Efficacy Evaluations
9.3.1.1.
Montgomery-Asberg Depression Rating Scale (MADRS)
The MADRS is a clinician-rated scale designed to measure depression severity and detects changes 
due to antidepressant treatment.45 The scale 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 
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possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates 
apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability 
to feel (interest level), pessimistic thoughts, and suicidal thoughts. The test exhibits high inter-rater 
reliability. The structured interview guide for the MADRS (SIGMA) will be used for each 
administration.
The typical recall period for the MADRS is 7 days. 
The MADRS will be used to measure the secondary objectives of effects on depressive symptoms.
9.3.1.2.
Clinical Global Impression - Severity (CGI-S)
The CGI-S provides an overall clinician-determined summary measure of the severity of the 
subject’s illness that takes into account all available information, including knowledge of the 
subject’s history, psychosocial circumstances, symptoms, behavior, and the impact of the 
symptoms on the subject’s ability to function.26 The CGI-S evaluates the severity of 
psychopathology on a scale of 0 to 7. Considering total clinical experience, a subject is assessed 
on severity of mental illness at the time of rating according to: 0=not assessed; 1=normal (not at 
all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 
7=among the most extremely ill patients. The CGI-S permits a global evaluation of the subject’s 
condition at a given time.
The CGI-S will be used to determine intranasal treatment session frequency in the 
optimization/maintenance phase.
9.3.1.3.
Patient Health Questionnaire, 9-Item (PHQ-9)
The PHQ-9 is a 9-item, patient-reported outcome measure to assess depressive symptoms.79 The 
scale scores each of the 9 symptom domains of the DSM-5 MDD criteria and it has been used both 
as a screening tool and a measure of response to treatment for depression. Each item is rated on a
4-point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). 
The subject’s item responses are summed to provide a total score (range of 0 to 27) with higher 
scores indicating greater severity of depressive symptoms. The recall period is 2 weeks.
9.3.1.4.
Sheehan Disability Scale (SDS)
The Sheehan Disability Scale will be used to assess the secondary objective of functional impact 
and associated disability. The SDS, a patient-reported outcome measure, is a 5 item questionnaire 
which has been widely used and accepted for assessment of functional impairment and associated 
disability.39,67 The first three items assess disruption of (1) work/school, (2) social life, and (3) 
family life/home responsibilities using a 0-10 rating scale. The score for the first three items are 
summed to create a total score of 0-30 where a higher score indicates greater impairment. It also 
has one item on days lost from school or work and one item on days when underproductive. The 
recall period for this study is 7 days.
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9.3.1.5.
European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level 
(EQ 5D-5L)
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily 
designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and 
the EQ visual analogue scale (EQ VAS). The EQ-5D-5L descriptive system comprises the 
following 
5 
dimensions: 
mobility, 
self-care, 
usual 
activities, 
pain/discomfort 
and 
anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems 
(Level 1 indicating no problem, Level 2 indicating slight problems, Level 3 indicating moderate 
problems, Level 4 indicating severe problems, and Level 5 indicating extreme problems).21,22
The subject selects an answer for each of the 5 dimensions considering the response that best 
matches his or her health “today.” The descriptive system can be represented as a health state. The 
EQ visual analogue scale self-rating records the respondent’s own assessment of his or her overall 
health status at the time of completion, on a scale of 0 to 100. 
The time taken to complete the questionnaire varies with age, health status, and setting but is likely 
to be around 1 minute.
9.3.1.6.
Subject Treatment Satisfaction Scale
The Treatment Satisfaction Questionnaire for Medication (TSQM-9)2 is a 9-item generic patient 
reported outcome instrument to assess patients’ satisfaction with medication. It is derived from the 
longer TSQM Version 1.45 and covers domains of effectiveness, convenience and global 
satisfaction. The instrument is scored by domain with scores ranging from 0-100 where a lower 
score indicates lower satisfaction. The recall period is “the last 2-3 weeks”.
9.3.1.7.
QLDS
The QLDS is a disease specific PRO designed to assess health related quality of life in patients 
with Major Depressive Disorder.30,43,72 The instrument has a recall period of "at the moment", 
contains 34-items with "yes"/"no" response options and takes approximately 5-10 minutes to 
complete. The score range is from 0 (good quality of life) to 34 (very poor quality of life).
9.4.
Medical Resource Utilization 
Medical resource utilization data, associated with medical encounters, will be collected using the 
Healthcare Resource Use Questionnaire (HRUQ) during the optimization/maintenance phase. The 
HRUQ includes information regarding utilization of healthcare services (including the timing and 
type of services), enabling changes in level and quantity of services to be considered as a variable 
in economic models. 
9.5.
Other Evaluations
9.5.1.
Patient Stated-choice Preference Survey
Stated-choice conjoint analysis is a method specifically designed to provide information about an 
individual’s willingness to accept tradeoffs between treatments with multiple outcomes.34,37,62,63
Preference studies have been performed with patients with depression and other mental 
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illnesses.76,71,40 The Patient Stated-choice Preference survey will be used as an exploratory tool to 
assess the manner and degree to which subjects value or weigh the benefit and harm clinical 
outcomes associated with Esketamine.
The intent is to have subjects complete the survey after having some experience with Esketamine. 
The survey will be administered once and only at sites in the United States, Canada, United 
Kingdom and Australia and only for English speakers. Subjects at any other site, regardless of 
whether they speak English, will not be surveyed. It is expected that subjects will require 20 to 
25 minutes to complete the survey. Since subjects may be in different stages of the trial when the 
survey becomes available, trial sites should have subjects complete the survey as noted in the T&E 
schedule. Specifically, the survey should be completed during or shortly after Visit 1.9, or if 
subjects completed this visit prior to when the survey becomes available, trial sites should have 
the subject complete the survey at the earliest possible opportunity. Note, for subjects whose point 
of entry for 54135419TRD3008 is the Open-label Optimization/maintenance phase, the survey 
should be completed during or shortly after Visit 2.4, or if the subject completed this visit prior to 
when the survey becomes available, the subject should complete the survey at the earliest possible 
opportunity. Subjects who completed the Patient Stated-choice Preference survey while enrolled 
in 
a 
prior 
study 
(ESKETINTRD3001, 
ESKETINTRD3002, 
ESKETINTRD3003, 
ESKETINTRD3004, or ESKETINTRD3005) should not be issued the survey. The survey should 
be performed predose (if/when performed on intranasal dosing days). 
If the subject indicates a desire to discontinue the study, the subject should be asked to complete 
the survey by his or her last visit if, in the study coordinator’s judgment, the subject will give the 
survey the required time and attention.
9.6.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF 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 the study if he/she is actively participating in the 
induction or optimization/maintenance phase when one of the following is reached:

esketamine is approved in the respective country and accessible through the local healthcare 
system funding or until end of December 2022, whichever is earlier 

the company terminates clinical development of esketamine nasal spray for TRD in that 
country/region
10.2.
Withdrawal from the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent (Note: See “Withdrawal of Consent” section below; this should only 
be selected as a reason for withdrawal if the subject does not agree to any further study 
assessments or procedures. If the subject is agreeable to further study assessments or 
procedures, another reason for withdrawal should be selected.) Lack of efficacy

The investigator or sponsor believes (eg, that for safety or tolerability reasons such as an 
adverse event) it is in the best interest of the subject to discontinue the study. The subject does 
not meet criteria for continuing into the optimization/maintenance phase at the end of the 
54135419TRD3008 induction phase.

Violation of protocol procedures (determined on a case-by-case basis)

The subject becomes pregnant

Death 
If a subject discontinues study drug and withdraws from the study before the end of the study, 
assessments should be obtained. Refer to Section 9.1.5 for further information on the EW or End 
of Study Visit.
If a subject misses a study visit in the optimization/maintenance phase without notifying the site 
of the reason, the site personnel will attempt to contact the subject to confirm if the subject is still 
interested in participating in the study and if so, to schedule their next visit. During this contact 
the information on adverse events and concomitant medication will be collected. These contacts 
will be repeated weekly until successful scheduling of the next dosing session or otherwise until 
discontinuation from the study (up to 4 contacts will be made).
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. This should include 
at least 3 telephone calls, certified letters, email requests, etc. To ensure access to follow-up 
subjects, the study sites should attempt to obtain both primary and secondary telephone contact 
numbers (eg, home, work, and mobile phone numbers), as well as other contact information 
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(eg, email addresses) from subjects prior to dosing. In addition, the study site should emphasize 
the importance of follow-up information to the subject prior to dosing. The measures taken to 
follow up must be documented.
When a subject withdraws, the reason for withdrawal is to be documented in the CRF and in the 
source document. Study drug assigned to the withdrawn subject may not be assigned to another 
subject.
Withdrawal of Consent
Every effort will be made in the study to ensure withdrawal of consent is not selected as a reason 
for discontinuation when in fact the subject withdrew for an identifiable reason (eg, due to an 
adverse event or lack of efficacy).
Subjects who wish to withdraw from the study should be asked if they are agreeable to be contacted 
for further follow up (eg, early withdrawal visit, adverse event follow up). Subjects who are not 
agreeable to follow-up contact will be withdrawn from the study as “withdrawal of consent.” 
Subjects who no longer wish to take study drug but are agreeable to be contacted for follow up 
will be withdrawn from the study with the reason noted as “Other” and will specify the reason 
why.
For a subject who “withdraws consent”, it is recommended that the subject withdraw consent in 
writing; if the subject refuses or is physically unavailable, the study site should document and sign 
the reason for the subject’s failure to withdraw consent in writing and maintain it with the subject’s 
source records.
The investigator will be responsible for making all required notifications to the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC).
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 Statistical Analysis Plan (SAP). 
11.1.
Subject Information
The following analysis sets will be used to summarize efficacy and safety data.

Full Analysis Set for Induction phase: will be defined as all subjects who receive at least one 
dose of esketamine nasal spray during this phase.

Full Analysis Set for Optimization/Maintenance phase: will be defined as all subjects who 
receive at least one dose of esketamine nasal spray during this phase. 
11.2.
Sample Size Determination
No formal sample size calculation was performed as only subjects who have participated in the 
other Phase 3 studies may participate in this study.
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11.3.
Safety Analyses
Safety data for the induction phase and the optimization/maintenance phase will be presented 
separately for each phase as well as for the entire treatment period (induction and 
optimization/maintenance phase). The baseline for safety assessments will be defined in the 
Statistical Analysis Plan.
Cognitive Function
Computerized cognitive test battery and HVLT-R: Descriptive statistics of each of the cognitive 
domain scores and changes from baseline will be provided at each scheduled time point.
Adverse Events
The verbatim terms used in the CRF 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 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 
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.
Treatment emergent AEs of special interest will be examined separately grouped in the following 
categories: drug abuse, dependence and withdrawal, increased blood pressure, increased heart rate, 
transient dizziness/vertigo, impaired cognition, cystitis, anxiety, events potentially related to 
suicidality, hepatic adverse events, events related to renal disorders, and symptoms of dissociation 
persisting beyond the typical ≤2 hour post esketamine administration, as well as delirium, 
psychosis or mania.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event.
Vital Signs
Descriptive statistics of body weight, temperature, pulse/heart rate, respiratory rate, pulse oximetry 
and supine blood pressure (systolic and diastolic) values and changes from baseline will be 
provided at each scheduled time point. Any treatment-emergent abnormalities will be listed.
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 provided for each laboratory analyte at baseline and at each scheduled time point in each phase 
of the study. Changes from baseline results will be presented. Frequency tabulations of the 
abnormalities will be provided. Listings of subjects with markedly abnormal laboratory results will 
also be provided.
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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 
QT interval corrected (QTc) according to Bazett's formula (QTcB) and Fridericia's formula 
(QTcF).3,65
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 msec, >480 msec, or 
>500 msec will be summarized, as will the percentage of subjects with QTc interval increases from 
baseline <30 msec, 30 to 60 msec, or >60 msec.
All important 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).
C-SSRS
Suicide-related thoughts and behaviors based on the C-SSRS will be summarized in incidence and 
shift tables. Separate endpoints for suicidal ideation and suicidal behavior will be defined and 
summarized descriptively.
Other Safety and Tolerability Questionnaires and Assessments
CGDAR and MOAA/S: Descriptive statistics of scores and their changes (and/or percent changes) 
from predose or baseline will be summarized at each scheduled time point.
11.4.
Efficacy Analyses
Depression symptoms using the MADRS as well as a patient reported outcome (PHQ-9), global 
change in severity (CGI-S), social, occupational and family functioning related disability (SDS), 
depression specific health related quality of life (QLDS), and health related quality of life and 
health status (EQ-5D-5L) will be summarized descriptively at each scheduled visit for each phase, 
using both last observation carried forward and observed case data. The proportion of subjects who 
are responders (≥50% improvement from baseline) based on the MADRS total score and PHQ-9 
total score and the proportion of subjects who remitted based on the MADRS total score (MADRS 
total score ≤12) and the PHQ-9 total score (PHQ-9 total score <5) will be provided over time for 
each phase. 
For subjects who had relapsed in ESKETINTRD3003 and participated in a second induction 
treatment phase, the proportion of responders (≥50% improvement from baseline) and remitters 
using the MADRS total score (MADRS total score ≤12) and PHQ-9 total score (PHQ-9 total 
score <5) at the end of the second induction phase will be provided. Subject treatment satisfaction 
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questionnaire for medication (TSQM-9) will be summarized descriptively at each scheduled visit 
for each phase. 
11.5.
Medical Resource Utilization Analysis
Medical resource utilization data (including HRUQ results) will be summarized descriptively. 
11.6.
Patient Stated-choice Preference Survey
The stated-choice preference survey will be used as an exploratory tool to assess the manner and 
degree to which esketamine study subjects value or weigh the clinical outcomes associated with 
Esketamine. 
Stated-choice preference surveys generate data that can be used to estimate relative preference 
weight for specified levels of treatment-related benefits and harms. A regression model, described 
in a SAP, will be used to estimate a distribution of preferences around each model parameter. All 
estimates will be reported with 95% confidence intervals. A key result will be the maximum 
acceptable risk for each harm, defined as the largest increase in probability or severity of that harm 
that a patient is willing to accept for a given degree of benefit. Reporting of the survey results may 
be reported separately.
11.7.
Independent Data Monitoring Committee 
An IDMC 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 approximately every 6 months to 
review select safety data through the end of 2020. After the reviews, the IDMC will make
recommendations regarding the continuation of the study. The details will be provided in a separate 
IDMC charter.
The IDMC will consist of at least 1 medical expert in the relevant therapeutic area and at least 
1 statistician. The IDMC responsibilities, authorities, and procedures will be documented in its 
charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
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12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and European Union 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 
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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 nasal spray, expectedness of an adverse 
event will be determined by whether or not it is listed in the Reference Safety Information Section 
of the Investigator’s Brochure. 
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant drug(s), 
concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in 
time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
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Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/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 CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
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.
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. 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 CRF. 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 CRF their opinion concerning the relationship of the adverse event to study therapy. 
All measures required for adverse event management must be recorded in the source document 
and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB.
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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, as well as PQC, 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.
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study drug, 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.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, and 
transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious adverse 
event should be made by facsimile (fax). 
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to study 
conduct

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 
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during the course of a subject's participation in a study must be reported as a serious adverse event,
except hospitalizations for the following:

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 CRF). 
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.

For convenience the investigator may choose to hospitalize the subject for the duration of the 
treatment period.
The cause of death of a subject in a study, 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 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.
13.
PRODUCT QUALITY COMPLAINT HANDLING
Definition
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, reliability, or performance of a distributed product, including its labeling, drug delivery 
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product. 
In addition, it includes any technical complaints, defined as any complaint that indicates a potential 
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product or the drug delivery system. Timely, accurate,
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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.
A sample of the suspected product should be maintained under the correct storage conditions until 
a shipment request is received from the sponsor.
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 Drugs
14.1.1.
Intranasal Study Drug
The esketamine supplied for this study is formulated 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 ethylenediaminetetraacetic 
acid (EDTA) and 1.5 mg/mL citric acid at a pH of 4.5 in water for injection. It is provided in a 
nasal spray pump, which delivers 16.14 mg esketamine hydrochloride (14 mg esketamine base) 
per 100 mcl spray. Each individual nasal spray pump (device) contains a total of 28 mg 
(ie, 2 sprays). 
Esketamine will be manufactured and provided under the responsibility of the sponsor. Please refer 
to the Investigator’s Brochure for a list of excipients.
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14.2.
Packaging
Intranasal Study Drug
Study drug (ie, esketamine nasal spray) will be supplied by the sponsor in a bi-dose nasal spray 
device. The devices will contain 230 µL (of which ~30µL is the residual volume). Each device 
delivers 16.14 mg esketamine hydrochloride (14 mg esketamine base). 
Each nasal spray device will be individually packaged in a blister tray and subsequently put into a 
carton box. Each carton box constitutes one non-child-resistant subject kit, labeled with a unique 
medication kit number. 
14.3.
Labeling
Study drug label will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage 
Study drugs will be stored at the study site in a secure area with restricted access until dispensed to 
the subjects. 
The 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 study drug administered to the subject must be documented on the drug accountability form. 
The study drug will be stored and disposed of according to the sponsor's instructions. 
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study drug, 
or used returned study drug for destruction, will be documented on the investigational product 
destruction 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 investigational product destruction form.
Study drug should be dispensed under the supervision of the investigator or a qualified member of 
the study-site personnel, or by a hospital/clinical study site pharmacist. Study drug will be supplied 
only to subjects participating in the study. 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.
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15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator’s Brochure for esketamine

Investigational Product (IP) Binder, including the IP Procedures investigational product 
procedures manual 

Laboratory manual and materials

Clinician-administered and subject-completed/patient-reported outcomes assessments 
o
Paper versions, as applicable
o
Electronic devices and associated materials

IWRS Manual

ECG equipment and associated materials (eg, manual)

Instructions for Use documents (subject and healthcare provider versions) for intranasal study 
medication

Computerized cognitive battery and HVLT-R, and all associated equipment and materials

Device to measure respiratory rate

Guidance on recommended order of study procedures

Guidance on required equipment for supportive ventilation and resuscitation will be provided 
in a separate document.
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Clinical Study in Treatment-resistant Major Depression
Major depressive disorder is a common, severe, chronic and often life-threatening illness. It is now 
the leading cause of disability worldwide. There is a clear need to develop novel and improved 
therapeutics for treatment-resistant major depression.
Studies with esketamine have shown robust antidepressant effects in several clinical studies and it 
has been well tolerated in these clinical studies.
Selection of Subjects
The primary aim of the study is to evaluate long-term safety and tolerability of esketamine nasal 
spray plus an oral antidepressant in subjects with TRD. Thus, the study cannot be conducted in 
healthy subjects. 
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may 
be withdrawn at any time with no reason given and without penalty or loss of benefits to which 
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they would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, 
and potential adverse events of the study, and provide their consent voluntarily will be enrolled.
All subjects will be from Phase 3 studies
ESKETINTRD3001, ESKETINTRD3002, 
ESKETINTRD3003, ESKETINTRD3004, ESKETINTRD3005, and ESKETINTRD3006 
(US Sites only).
For subjects who have participated in the ESKETINTRD3003, ESKETINTRD3004, and 
ESKETINTRD3005 studies and have responded to esketamine nasal spray treatment or did not 
meet the study criteria for response but per clinical judgment have benefitted, it is considered an 
ethical obligation to provide continued esketamine nasal spray treatment if the benefit/risk profile 
is favorable for the subject at the time of completion of the previous study.
For subjects who have completed the induction phase of ESKETINTRD3005 or 
ESKETINTRD3006 (US sites only) and did not meet the study criteria for response, or for subjects 
who have completed the induction phase and 2-week follow up phase visit of the 
ESKETINTRD3001 or ESKETINTRD3002 study, as the double-blind treatment (esketamine 
nasal spray or placebo) in these studies will be blinded, the second induction phase of this study 
provides the following: 

Subjects who are non-responders to intranasal placebo and oral antidepressant in the prior 
study have the potential of receiving esketamine in this study, and 

Subjects who are non-responders to esketamine nasal spray in the prior study who decide to 
participate in this study may not benefit from additional treatment with esketamine nasal 
spray. The benefit of additional treatment with esketamine remains unknown. In case of no 
perceived benefit of esketamine nasal spray to the subject during this study, the subject and/or 
investigator may choose to discontinue study participation. 
Subjects from ESKETINTRD3001, ESKETINTRD3002, and ESKETINTRD3005 who were 
responders to intranasal placebo and oral antidepressant but did not participate in the subsequent 
available study (eg, ESKETINTRD3003 and ESKETINTRD3004 study, respectively): may or 
may not benefit from additional treatment with esketamine nasal spray. Any additional benefit of 
treatment with esketamine nasal spray remains unknown. In case of no perceived benefit of 
esketamine nasal spray to the subject during this study, the subject and/or investigator may choose 
to discontinue study participation. At any time during the study, subjects may discontinue and 
appropriate follow-up care will be arranged.
Precautions to Ensure Subject Safety in the Study
Subjects may participate in the study only if they have adequate capacity to give consent and after 
fully understanding the potential risks and giving an informed consent. Determination of capacity 
will be made by the study investigator. Subjects may discontinue the study at any time. Potential 
disadvantages and adverse events of participating in the study and alternative treatment options 
will be discussed. For subjects who do not meet predefined response criteria during the study, 
clinical care will be arranged between the subject and the study investigator and/or the subject's 
physician.
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Compensation for any procedure will be fair per local standards and approved by the participating 
site's IRB, in order to avoid offering any undue incentive to participate in the study.
Subjects will be carefully monitored during the study and subjects who are unable to tolerate study 
drugs will be discontinued from the study. If the investigator judges it to be necessary to 
immediately stop study drug, he or she has the option to do so. Specific guidance is provided 
regarding blood pressure monitoring on dosing days (see Section 6.1).
The total blood volume to be collected is considered to be within the normal range allowed for this 
subject population over this time frame. The total blood volume to be collected throughout the study 
participation is variable due to the nature of the study design and will be less than a Red Cross blood 
donation.
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.
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

Sponsor-approved training and informational 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
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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.
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 least once a year, the IEC/IRB will be asked to review and reapprove this study, where required. 
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion.
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16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the study 
has been fully explained. The ICF(s) must be signed before performance of any study-related 
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing 
IEC/IRB and be in a language that the subject can read and understand. The informed consent 
should be in accordance with principles that originated in the Declaration of Helsinki, current ICH 
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw consent 
to participate at any time. They will be informed that choosing not to participate will not affect the 
care the subject will receive for the treatment of his or her disease. Subjects will be told that 
alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow up if needed and that their records may 
be accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject is authorizing such access. It also denotes that the subject agrees to 
allow his or her study physician to recontact the subject for the purpose of obtaining consent for 
additional safety evaluations, if needed.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. After 
this explanation and before entry into the study, consent should be appropriately recorded by means 
of the subject's personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the subject.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be limited 
to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original medical 
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and 
regulatory inspection. This consent also addresses the transfer of the data to other entities and to 
other countries.
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The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps will 
be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
16.2.5.
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, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be 
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involves only logistic or administrative aspects of the study, the IRB/IEC (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 CRF 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
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
A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
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17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care, must be available for the following: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
drug receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).
Some subject-completed and clinician-completed scales and assessments designated by the 
sponsor may be recorded directly into an electronic device and 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

Antidepressant treatment in the current episode of depression
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 an electronic source is utilized, references made to the CRF in 
the protocol include the electronic source system but information collected through the electronic 
source may not be limited to that found in the CRF. Data in this system may be considered source 
documentation.
17.5.
Case Report Form Completion
Case report forms are provided by the sponsor for each subject in electronic format. All CRF 
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 CRF are accurate and correct.
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The study data will be transcribed by study-site personnel from the source documents onto an 
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor. 
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into 
CRFs 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.
If necessary, queries will be generated in the electronic data capture (eDC) tool. If corrections to 
a CRF are needed after the initial entry into the CRF, this can be done 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 uploading 
data transfers from external service providers into the sponsor’s database. Written instructions will 
be provided for collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review CRFs 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 CRFs 
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 
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responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the CRFs with the source documents 
(eg, hospital/clinic/physician’s office medical records); a sample will 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 CRF 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 in the CRF 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, the monitor may contact the site by telephone for an update 
on study progress. It is expected that study -site personnel will be available to provide an update 
on the progress of the study at the site.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The end of the study will occur based on the subject’s individual efficacy and tolerability to 
esketamine nasal spray, and/or until esketamine is approved in the respective country and 
accessible through the local healthcare system funding or until end of December 2022, whichever 
is earlier.
NCT02782104


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Study participation will be stopped:

when esketamine is approved in the respective country and accessible through the local 
healthcare system funding or until end of December 2022, whichever is earlier; or

the subject no longer benefits from further treatment (based on the investigator's clinical 
judgment), or withdraws consent; or

the company terminates clinical development of esketamine nasal spray for TRD in that 
country/region
The study is considered completed with the last study assessment for the last subject participating 
in the study. The final data from the study site will be sent to the sponsor (or designee) after 
completion of the final subject assessment at that study site, in the time frame specified in the 
Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 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.
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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 research data, generated as a result of this study, are
considered confidential and remain the sole property of the sponsor. The investigator agrees to 
maintain this information in confidence and use this information only to accomplish this study, 
and will not use it for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of esketamine, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of 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 
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state that the named authors must have made a significant contribution to the design of the study 
or analysis and interpretation of the data, provided critical review of the paper, and given final 
approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required 
by law.
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Attachment 1: Prohibited Concomitant Medications with Esketamine Nasal Spray Study 
Medication 
This list of medications is not all-inclusive; if necessary, please contact the medical monitor for any 
questions regarding a medication(s).
Please refer to the local prescribing information of the subject’s non-study medications for information 
regarding prohibited concomitant medications. 
Except where specifically noted, the prohibited medications listed in the following table are prohibited from 
1 week (or 5 half-lives, whichever is longer) prior to the first dose of intranasal study medication until after 
the last dose of intranasal study medication.
Note in the following table: N, Prohibited; Y, Permitted, with restrictions (please refer to the column labeled 
“Comments” for additional guidance).
Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for 
Prohibition
ADHD medications 
(eg, atomoxetine, 
guanfacine)
N
Y
Can be continued but must not be 
taken within 12 hours prior to the 
intranasal treatment session or for 
2 hours after the intranasal 
treatment session.
Safety
Amantadine
N
N
PD interaction
Anorexiants 
(eg, phentermine, 
phendimetrazine)
N
N
Safety
Anticholinesterase 
inhibitors
N
N
Subject population is 
excluded
Anticonvulsants  
Y
Y
-
Subjects with seizures are 
excluded. 
Note: Anticonvulsants used 
for indications other than 
seizures may be allowed (eg 
valproate for migraine; 
pregabalin)
Safety and PD 
interaction
MAO-I Antidepressants 
N
N
There must be a minimum 
washout interval of 2 weeks prior 
to the first dose of intranasal 
study medication and MAO-I 
antidepressants are prohibited 
throughout the study.
Safety
Antipsychotics
N
Y
PD interaction
Benzodiazepines (at 
dosages equal to or less 
than the equivalent of 
6 mg/day lorazepam) 
and non-
benzodiazepine 
sleeping medication 
(including: zolpidem, 
zaleplon, eszopiclone, 
and ramelteon)
Y
Y
Prohibited within 12 hours prior 
to the start of each intranasal 
treatment session or cognition 
testing
Safety and PD 
interaction
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Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for 
Prohibition
Benztropine
Y
N
Prohibited if use is continuous 
and prohibited within 12 hours 
prior to the start of cognition 
testing
Safety and PD 
interaction. 
Chloral hydrate, 
melatonin, valerian
N
N
Safety and PD 
interaction
Clonidine
Y
Y
Use for blood pressure control is 
allowed.
Corticosteroids 
(systemic)
Y
N
Inhaled, intranasal, topical, and
ophthalmic steroids are not 
prohibited.
Intermittent IM/IV/PO 
corticosteroids are permitted with 
sponsor approval (chronic use 
prohibited).
PD interaction
Cough/cold 
preparations/nasal 
solutions containing 
vasoconstrictors, 
decongestants
Y
Y
Intranasally-administered 
decongestants (vasoconstrictors) 
should not be used from 1 hour 
prior to each intranasal study 
medication administration.
Pseudoephedrine- containing 
products should not be used 
within 12 hours prior to an 
intranasal treatment session.
Safety and PD 
interaction
CYP3A4 inducers -
Potent
N
N
Subjects may not take a known 
potent inducer of hepatic CYP3A 
activity within 2 weeks of the first 
administration of intranasal study 
medication until at least 24 hours 
after the last intranasal dose of 
study medication.
Examples (not all-inclusive): 
Efavirenz, nevirapine, 
barbiturates, carbamazepine, 
glucocorticoids, modafinil, 
oxcarbazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, 
and St. John's wort
PK
Dextromethorphan
N
N
PD interaction
Diphenhydramine
Y
N
Prohibited within 12 hours prior 
to the start of each intranasal 
treatment session
Safety
Ketanserin
N
N
Safety
Memantine
N
N
PD interaction
Methyldopa
N
N
Safety and PD 
Interaction
Metyrosine
N
N
Safety and PD 
interaction
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JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008 Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
116
Status: Approved, Date: 5 October 2020
Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for 
Prohibition
Non-vitamin K 
antagonist oral 
anticoagulation agents 
(eg, dabigatran, 
rivaroxaban, apixaban)
N
N
Safety
Opioids
N
N
With Sponsor approval, brief 
treatment with opiates may be 
allowed for treatment of acute 
injuries, etc.
PD interaction
Psychostimulants
(eg, amphetamines, 
methylphenidate)
N
Y
Prescribed psychostimulants can 
be continued or newly initiated 
but must not be taken within 12 
hours prior to the intranasal 
treatment session or for 2 hours 
after the intranasal treatment 
session.
Cardiovascular safety
Reserpine
N
N
PD interaction
Thyroid hormone 
supplement for 
treatment of thyroid 
condition only (not for 
depression)
N
Y
Safety
Thyroxine/ 
triiodothyronine (T3), 
thyroid hormone 
prescribed for 
depression
N
N
PD interaction
Warfarin
N
N
Primary condition 
where used is excluded
Abbreviations: ADHD, attention deficit hyperactivity disorder; N, Prohibited; PD, pharmacodynamics; PK, 
pharmacokinetics; Y, Permitted, with restrictions (please refer to the column labeled “Comments” for additional 
guidance).
NCT02782104


NCT02782104


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 19 June 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
Protocol Title
An Open-label Long-term Extension Safety Study of Esketamine Nasal Spray in 
Treatment-resistant Depression
Safety and Sustenance of Esketamine Treatment Response With Repeated Doses at Intervals 
Determined by Symptom Severity
SUSTAIN-3
Protocol 54135419TRD3008; Phase 3
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 Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; 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.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).]
Status:
Approved
Date:
19 June 2020
Prepared by:
Janssen Research & Development, LLC 
EDMS number:
EDMS-RIM-37289, 2.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL 
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.
NCT02782104


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 19 June 2020
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
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 temporary options for 
study-related subject management in the event of disruption to the conduct of the study. This 
guidance does not supersede any local or government requirements or the clinical judgement of 
the investigator to protect the health and well-being of subjects and site staff. If, at any time, a 
subject’s safety is considered by the investigator to be at risk, study treatment may be discontinued
after discussion with the sponsor, and study follow-up will be conducted according to GUIDANCE 
SPECIFIC TO THIS PROTOCOL.
Re-consenting of subjects will be performed (including remote consenting by phone or video 
consultation) as applicable for the measures taken and according to local guidance for informed 
consent applicable during the COVID-19 pandemic.
Every effort should be made to adhere to protocol-specified assessments for subjects on study 
treatment. Modifications to protocol-required assessments may be permitted in accordance with 
this Appendix after consultation with the subject, investigator, and the sponsor. Missed 
assessments/visits will be captured in the clinical trial management system (CTMS) for protocol 
deviations.
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance.
If a subject has tested positive for COVID 19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic will be summarized in the clinical 
study report.
NCT02782104


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved, Date: 19 June 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL
These provisions are meant to minimize the risk of exposure to COVID-19 and to safely maintain 
subjects on study treatment while site capabilities are compromised by COVID-19-related 
restrictions. As restrictions are lifted and the acute phase of the COVID-19 pandemic resolves, 
sites should revert to original protocol conduct as soon as feasible.
At each contact, subjects will be interviewed to collect safety data. Subjects will also be questioned 
regarding general health status to fulfill any physical examination requirement.
Evaluate the subject’s situation on a case by case basis and contact the study responsible physician 
for discussion and decision if necessary. Certain measures, such as those listed below, may be 
necessary and should be instituted in accordance with applicable (including local) laws, regulations, 
guidelines, and procedures.

The safety of study subjects is priority; investigators may make the decision to provide other 
available therapy to patients on the study. Please discuss any decision to provide other therapy 
outside of the protocol with the study responsible physician and ensure that this is recorded in 
the source document and the case report form (CRF) along with reason for administration.

Dosing frequency can change based upon the Clinical Global Impression-Severity (CGI-S)
score, or investigator’s clinical judgement after discussion with the study responsible 
physician. Please refer to the “Regular Dosing Visits” section for additional information.
Reminder: missed esketamine dosing of itself does not result in withdrawal from the study, and 
treatment can resume if considered beneficial per clinical judgement.
Discontinuations of study treatment and withdrawal from the study due to COVID-19 adverse 
events (AEs)/ serious adverse events (SAEs) should be documented as discontinuation due to AE. 
If a subject dies due to COVID-19, “death” should be selected as the reason for treatment 
discontinuation. Discontinuations for other COVID-19 reasons should be documented with the 
prefix “COVID-19-related” in the CRF.
Regular Dosing Visits
In the event that it is not feasible for the subject to be assessed and dosed at the study site (eg, due 
to temporary site closure), the following options may be used on a temporary basis after 
consultation with the sponsor and with the agreement of the subject and investigator:

Administer at an alternative location (to include the equipment/supplies needed for the 
care/treatment of a subject post dose) in the vicinity of the site, with the subject remaining
there during post dose observation period, after consultation with the sponsor and under the 
supervision of site staff;

Continue administering study treatment within the study site, with adjustments for temporary 
changes in dates/hours site is open for study subjects;

Administer at alternative TRD3008 study site (data to stay with primary study site) after 
consultation with the sponsor (at which time specific guidance on the process will be 
provided) and if permitted by local regulations;
NCT02782104


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved, Date: 19 June 2020

Complete clinical and subject rating scales the day prior to dosing via phone or video 
conference.
Missed doses should be documented in the CRF in accordance with the CRF completion 
guidelines.
Non-dosing Days

Rating scales/ safety assessments can be completed remotely (via phone or video conference).

Missed/ out of window assessments should be documented with “COVID-19-related” in the 
comment section of the CRF.

It is recommended that close contact be maintained with study subjects and remote contact 
arranged consistent with the subject’s regularly scheduled visit interval.

If the subject is on weekly dosing, attempt to contact the subject weekly.

If the subject is on dosing every other week or every 4 weeks, attempt to contact the 
subject every other week.
Study subjects who show worsening or who are at high risk for relapse may require more frequent 
monitoring as per investigator discretion.
Laboratory Assessments
If laboratory samples cannot be collected by Covance, sample collection and analysis can be 
performed using the site’s local laboratory at the discretion of the investigator.

Local laboratory results should be reviewed to confirm if any significant changes should be 
added as AEs in the eCRF.

If the investigator does not feel laboratory assessments are required at this time, and subject(s) 
want to avoid any risk to COVID-19 exposure, this rationale should be documented in the 
source documents.
Exposure to COVID-19

If a subject develops COVID-19 infection (or suspected), the PI should contact the sponsor’s 
Medical Monitor to discuss the best course of action based on individual symptoms/ subject 
setting and risk benefit relationship.
NCT02782104


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3008
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved, Date: 19 June 2020
Data Collection

For clinician-completed (MADRS, C-SSRS, CGI-S, PWC-20 [(France only], HRUQ) and 
subject-completed (PHQ-9, SDS, EQ-5D-5L, TSQM-9, QLDS)a scale assessments conducted 
by a telephone contact, the data should be entered directly onto the paper assessment. Ensure 
that the correct date is present on the assessment form in the CRF, or enter remote assessments 
as Unscheduled if the assessments were performed on another day as the visit day.

For missed doses, the dosing form should be inactivated and a “COVID-19 related” comment 
entered on the Comments form.

All COVID-19-related deviations from the main study protocol will be documented according 
to the CRF completion guidelines.
Statistical Analysis
The sponsor will evaluate the totality of the impact of COVID-19 on collection of key study data, 
and additional data analyses will be outlined in the statistical analysis plan.
                                                
a
C-SSRS= Columbia Suicide Severity Rating Scale; CGI-S= Clinical Global Impression – Severity; EQ-5D-5L= European 
Quality of Life (EuroQol) Group, 5-Dimension, 5-Level; HRUQ= Healthcare Resource Use Questionnaire; MADRS= 
Montgomery-Asberg Depression Rating Scale; PHQ-9= Patient Health Questionnaire, 9-Item; PWC= Physician Withdrawal 
Checklist; QLDS= Quality of Life in Depression Scale; SDS= Sheehan Disability Scale; TSQM-9= Treatment Satisfaction 
Questionnaire for Medication, 9-item.
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NCT02782104

SAP_001.pdf: 
1 
Approved, Date: 14 February 2023 
Janssen Research & Development * 
Statistical Analysis Plan 
An Open-label Long-term Extension Safety Study of Intranasal Esketamine in Treatment- 
resistant Depression 
Safety and Sustenance of Esketamine Treatment Response With Repeated Doses at Intervals 
Determined by Symptom Severity (SUSTAIN-3) 
Protocol 54135419TRD3008; Phase 3 
JNJ-54135419 (esketamine)  
Status: 
Approved 
Date: 
14 February 2023 
Prepared by: 
Janssen Research & Development, LLC 
Document No.: EDMS-RIM-103269 3.0 
Compliance:  The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential. 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
2 
Approved, Date: 14 February 2023  
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
LIST OF IN-TEXT TABLES .......................................................................................................................... 4 
LIST OF IN-TEXT FIGURES ........................................................................................................................ 4 
ABBREVIATIONS ........................................................................................................................................ 6 
1. 
INTRODUCTION.................................................................................................................................. 7 
1.1. 
Trial Objectives ................................................................................................................................ 7 
1.2. 
Trial Design ...................................................................................................................................... 7 
1.3. 
Statistical Hypotheses for Trial Objectives ..................................................................................... 11 
1.4. 
Sample Size Justification ............................................................................................................... 11 
1.5. 
Randomization and Blinding .......................................................................................................... 11 
2. 
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 11 
2.1. 
Analysis Phases ............................................................................................................................. 11 
2.1.1. 
Study Reference Start and End Dates ....................................................................................... 12 
2.1.2. 
Analysis Phase Start and End Dates .......................................................................................... 12 
2.1.3. 
Study Day and Relative Day ....................................................................................................... 13 
2.2. 
Baseline and End Point .................................................................................................................. 13 
2.3. 
Visit Windows ................................................................................................................................. 14 
2.4. 
Analysis Sets .................................................................................................................................. 20 
2.4.1. 
All Enrolled Analysis Set ............................................................................................................. 20 
2.4.2. 
Full Analysis Set ......................................................................................................................... 20 
2.4.3. 
Follow-up Analysis Set ............................................................................................................... 20 
2.5. 
Definition of Subgroups .................................................................................................................. 20 
2.6. 
Imputation Rules for Missing Adverse Event (AE) Dates .............................................................. 20 
2.7. 
Imputation Rules for Missing Concomitant Medication Dates ....................................................... 22 
3. 
DATA MONITORING COMMITTEE REVIEW ................................................................................... 23 
4. 
SUBJECT INFORMATION ................................................................................................................ 23 
4.1. 
Demographics and Baseline Characteristics ................................................................................. 23 
4.2. 
Disposition Information................................................................................................................... 25 
4.3. 
Extent of Exposure ......................................................................................................................... 25 
4.4. 
Protocol Deviations ........................................................................................................................ 26 
4.5. 
Concomitant Medications ............................................................................................................... 26 
5. 
EFFICACY ......................................................................................................................................... 26 
5.1. 
Analysis Specifications................................................................................................................... 26 
5.1.1. 
Data Handling Rules ................................................................................................................... 26 
5.1.2. 
Imputation Methods for Missing Items ........................................................................................ 26 
5.2. 
Efficacy Endpoints .......................................................................................................................... 26 
5.2.1. 
Montgomery-Asberg Depression Rating Scale (MADRS) .......................................................... 27 
5.2.1.1. 
Definition .................................................................................................................................. 27 
5.2.1.2. 
Analysis Methods .................................................................................................................... 27 
5.2.2. 
Clinical Global Impression – Severity (CGI-S) ........................................................................... 27 
5.2.2.1. 
Definition .................................................................................................................................. 27 
5.2.2.2. 
Analysis Methods .................................................................................................................... 28 
5.2.3. 
Patient Health Questionnaire – 9 item (PHQ-9) ......................................................................... 28 
5.2.3.1. 
Definition .................................................................................................................................. 28 
5.2.3.2. 
Analysis Methods .................................................................................................................... 28 
5.2.4. 
Sheehan Disability Scale (SDS) ................................................................................................. 28 
5.2.4.1. 
Definition .................................................................................................................................. 28 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
3 
Approved, Date: 14 February 2023  
5.2.4.2. 
Analysis Methods .................................................................................................................... 29 
5.2.5. 
EuroQol Group; 5 Dimension; 5 level (EQ-5D-5L) ..................................................................... 29 
5.2.5.1. 
Definition .................................................................................................................................. 29 
5.2.5.2. 
Analysis Methods .................................................................................................................... 30 
5.2.6. 
Treatment Satisfaction Questionnaire for Medication (TSQM-9) ............................................... 30 
5.2.6.1. 
Definition .................................................................................................................................. 30 
5.2.6.2. 
Analysis Methods .................................................................................................................... 30 
5.2.7. 
Quality of Life in Depression Scale (QLDS) ............................................................................... 31 
5.2.7.1. 
Definition .................................................................................................................................. 31 
5.2.7.2. 
Analysis Methods .................................................................................................................... 31 
6. 
SAFETY ............................................................................................................................................. 31 
6.1. 
Adverse Events .............................................................................................................................. 31 
6.2. 
Clinical Laboratory Tests................................................................................................................ 34 
6.3. 
Vital Signs, Weight, and BMI ......................................................................................................... 34 
6.4. 
Electrocardiogram .......................................................................................................................... 35 
6.5. 
Nasal Examination ......................................................................................................................... 36 
6.6. 
Other Safety Parameters ............................................................................................................... 37 
6.6.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................................... 37 
6.6.2. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) .......................................... 37 
6.6.3. 
Clinical Global Assessment of Discharge Readiness (CGADR) ................................................ 38 
6.6.4. 
Computerized Cognitive Battery and Hopkins Verbal Learning Test-Revised (HVLT-R) .......... 38 
6.6.5. 
Physician’s Withdrawal Checklist, 20-item (PWC-20) ................................................................ 39 
7. 
HEALTH ECONOMICS ..................................................................................................................... 39 
7.1. 
Healthcare Resource Use Questionnaire (HRUQ) ........................................................................ 39 
REFERENCES ............................................................................................................................................ 40 
ATTACHMENTS ......................................................................................................................................... 41 
 
 
 
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
4 
Approved, Date: 14 February 2023  
LIST OF IN-TEXT TABLES 
Table 1:     Analysis Visits ........................................................................................................................... 14 
Table 2: 
Demographic Variables and Baseline Characteristics .............................................................. 24 
Table 3: 
Psychiatric History at Baseline Variables ................................................................................. 24 
Table 4: 
Treatment-Emergent Abnormality Categories for Vital Signs ................................................... 35 
Table 5: 
Limits for HR, PR, QRS and QT Interval Abnormality .............................................................. 36 
Table 6: 
Criteria for Abnormal QTc Values and Changes From Baseline .............................................. 36 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Study Design for 54135419TRD3008 ....................................................................................... 11 
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
5 
Approved, Date: 14 February 2023  
AMENDMENT HISTORY 
SAP Version        Issue Date 
SAP 1.0                  08 March 2019 
Amendment 1        30 June 2020 
Amendment 2        14 February 2023 
 
 
Amendment 1 (SAP 2.0) 
The overall reason for the amendment: few updated are made to be consistent with the MDSI 
program and Amendment 3 of the protocol. 
 
Applicable Section(s)  
Description of Change (s) 
6.1 Adverse Events 
The preferred terms for transient dizziness/vertigo and impaired 
cognition have been updated. 
 
Base on the protocol amendment 3, additional adverse events of 
special interest have been added, including symptoms of 
GLVVRFLDWLRQSHUVLVWLQJEH\RQGWKHW\SLFDOKRXUSRVWHVNHWDPLQH
administration, delirium, psychosis and mania. 
 
 
2.3 Visit Window 
Window for PWC has been added to allow the summarization of 
PWC data for French subjects. 
 
 
 
 
Amendment 2 (SAP 3.0) 
 
Applicable Section(s)  
Description of Change (s) 
5.2.3 PHQ-9 
A subject is defined as a remitter at a given time point if the PHQ-
9 total score is <5 at that time point. The original cut off of <=5 is 
updated to <5 based on clinical comment. 
5.2.6 TSQM-9 
 
Transformed scores are used in analysis. The scoring algorithm is 
added. 
6.6.2 MOAA/S 
Sedation with score less than or equal to 3 is updated to less than or 
equal to 4 based on the comments from CSR interim analysis 3. 
 
 
 
 
 
 
 
 
 
 
 
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NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
6 
Approved, Date: 14 February 2023  
ABBREVIATIONS 
 
 
AE 
Adverse Event 
ASA 
American Society of Anesthesiologists 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CGADR 
Clinical Global Assessment of Discharge Readiness 
CGI-S 
Clinical Global Impression – Severity 
CIOMS 
Council for International Organizations of Medical Sciences 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DBP 
Diastolic Blood Pressure  
DSM 
Diagnostic and Statistical Manual of Mental Disorders  
ECG 
Electrocardiogram 
EQ-5D-5L 
EuroQol Group; 5 Dimension; 5 level 
EQ VAS 
EuroQol Group: Visual Analogue Scale 
EW 
Early Withdrawal  
FDA 
Food and Drug Administration 
HRUQ 
Healthcare Resource Use Questionnaire  
HVLT-R 
Hopkins Verbal Learning Test-Revised 
IDMC 
Independent Data Monitoring Committee 
ICH 
International Conference on Harmonization 
LOCF 
Last Observation Carried Forward 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MDD 
Major Depressive Disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOAA/S 
Modified Observer’s Assessment of Alertness/Sedation 
PHQ-9 
Patient Health Questionnaire – 9 item 
PWC-20 
Physician’s Withdrawal Checklist  
QLDS 
Quality of Life in Depression Scale  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDS 
Sheehan Disability Scale 
SE 
Standard Error 
SBP 
Systolic Blood Pressure 
TEAEs 
Treatment-emergent Adverse Events 
TEMA 
Treatment-emergent Markedly Abnormal 
TRD 
Treatment Resistant Depression 
TSQM-9 
Treatment Satisfaction Questionnaire for Medication  
ULN 
Upper Limit of Normal 
 
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
7 
Approved, Date: 14 February 2023  
1. 
INTRODUCTION 
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analyses for study JNJ-54135419-54135419TRD3008. 
1.1. 
Trial Objectives 
Primary Objectives 
The primary objective of this study is to assess the safety and tolerability of intranasal esketamine 
in subjects with Treatment Resistant Depression (TRD), with special attention to the following: 
x 
Potential long term effects on cognitive function 
x 
Treatment-emergent adverse events (TEAEs), including TEAEs of special interest 
x 
Post dose effects on heart rate, blood pressure, respiratory rate and blood oxygen saturation 
x 
Potential effects on suicidal ideation/behavior 
Secondary Objective 
The secondary objective is to assess long-term efficacy, including effects on: 
x 
Depressive symptoms (clinician and self-reported), 
x 
Overall severity of depressive illness, 
x 
Functioning and associated disability, 
x 
Health-related quality of life and health status, 
Exploratory Objectives 
The exploratory objectives are to assess: 
x 
Medical resource utilization 
x 
Response and remission rates to a second induction phase in eligible subjects who had 
relapsed in study ESKETINTRD3003 
x 
Subject treatment satisfaction 
x 
Subject tradeoff preferences for key benefit and harm outcomes associated with TRD 
treatment, using a stated-choice preference survey 
1.2. 
Trial Design 
This is a multicenter, open-label long term extension study to evaluate the safety, tolerability, and 
efficacy of intranasal esketamine in subjects with TRD. The study population will include adult 
and elderly men and women who previously participated in studies ESKETINTRD3001, 
ESKETINTRD3002, 
ESKETINTRD3003, 
ESKETINTRD3004, 
ESKETINTRD3005, 
or 
ESKETINTRD3006 (US sites only) and will have met the inclusion/exclusion criteria for entry 
into those prior studies. 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
8 
Approved, Date: 14 February 2023  
For 
subjects 
who 
participated 
in 
studies 
ESKETINTRD3003, 
ESKETINTRD3004, 
ESKETINTRD3005 or ESKETINTRD3006 (US sites only) and have responded to intranasal 
esketamine treatment, it is considered an ethical obligation to provide continued intranasal 
esketamine treatment if the benefit/risk profile was  favorable for the subject at the time of 
completion of the previous study. Subjects in the placebo-controlled, double blind 
ESKETINTRD3005 and who are non-responders at the end of the induction phase were eligible 
to enter the open label induction phase of ESKETINTRD3004, therefore if enrollment in the 
ESKETINTRD3004 had completed these subjects were given the opportunity to enter this study, 
if clinically appropriate. For subjects who completed the induction phase and 6-month follow up 
phase of the ESKETINTRD3001 or ESKETINTRD3002 study, this study provided  an opportunity 
for subjects to have an induction phase with open-label intranasal esketamine. 
An Independent Data Monitoring Committee (IDMC) is commissioned for this study to review 
safety data periodically. 
This study (54135419TRD3008) has 2 open label phases: 
x A 4-week induction phase (if applicable) 
x A variable duration optimization/maintenance phase 
The duration that a subject may participate in the study is variable and is based on the subject’s 
point of entry into the study and the timing of when the predefined criteria (below) for ending 
study participation occurs. 
Study participation will be stopped: 
x At the time intranasal esketamine is commercially available or a pre-approval access program 
is available to the subject in the subject’s respective country; or 
x The subject no longer benefits from further treatment (based on the investigator's clinical 
judgment), or withdraws consent; or 
x The company terminates clinical development of intranasal esketamine for TRD. 
Subjects will have a final study visit within 1 week of the last dose of intranasal esketamine. 
A description of the study phases is provided below. 
Induction Phase 
The following subjects are eligible to enter the study at the induction phase: 
x Subjects who relapsed during the ESKETINTRD3003 maintenance phase, or 
x Subjects who were in the induction phase of ESKETINTRD3005 study at the time enrollment 
into the ESKETINTRD3004 study was closed and, after completion of the induction phase, 
were determined to be a non-responder, or 
x Subjects who completed the induction phase and the 2 week follow up phase visit in 
ESKETINTRD3001 or ESKETINTRD3002 studies 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
9 
Approved, Date: 14 February 2023  
Subjects will self-administer open-label intranasal esketamine as a flexible dose regimen twice a 
week for 4 weeks. Subjects who are < 65 years old will start intranasal esketamine with an initial 
dose of 56 mg on Day 1, with the dose adjusted based on efficacy and tolerability in the subsequent 
YLVLWVRIWKHLQGXFWLRQSKDVHIOH[LEOHGRVHRUPJ6XEMHFWVZKRDUH\HDUVROGZLOO
start intranasal esketamine with an initial dose of 28 mg on Day 1, with the dose adjusted based 
on efficacy and tolerability in the subsequent visits of the induction phase (flexible dose: 28, 56 or 
84 mg). 
At the end of the induction phase, subjects may be eligible to proceed to the 
optimization/maintenance phase, according to the investigator’s clinical assessment of the benefit 
versus risk for the subject.  
If a subject withdraws from the study before the end of the induction phase for reasons other than 
withdrawal of consent, or is not eligible to proceed to the optimization/maintenance phase, an 
Early Withdrawal (EW) visit will be conducted within 1 week of the last intranasal dose.  
Subjects who are currently in the induction phase at the time the 54135419TRD3008 study is 
completed will conduct an “End of Study” visit as their final study visit within 1 week of the last 
intranasal dose. 
Optimization/Maintenance Phase 
The following subjects are eligible to enter the study at the optimization/maintenance phase:  
x 
Subjects who completed the induction phase of ESKETINTRD3001 or ESKETINTRD3002 
and were responders, and study ESKETINTRD3003 is terminated.  
x 
Subjects who were in the induction phase of ESKETINTRD3003 and ESKETINTRD3004 
studies at the time these studies were terminated and, after completion of the induction phase, 
were determined to be a responder. 
x 
Subjects who completed the optimization/maintenance phase of ESKETINTRD3004 
x 
Subjects who were in the optimization, maintenance or optimization/maintenance phase of 
ESKETINTRD3003 and ESKETINTRD3004 studies, respectively, at the time these studies 
were terminated 
x 
Subjects who were in the induction phase of ESKETINTRD3005 study at the time enrollment 
into the ESKETINTRD3004 study was closed and, after completion of the induction phase, 
were determined to be responders. 
x 
Subjects (US only) who completed the induction phase of ESKETINTRD3006 and were 
responders. 
Subjects will self-administer the intranasal study drug at treatment sessions at the study site. 
For the first 4 weeks of this phase (Week 1 to Week 4), subject will self-administer the intranasal 
esketamine drug either weekly or have the option to have their current intranasal dosing frequency 
adjusted at the time of entry into 54135419TRD3008, with the dose adjusted based on efficacy 
and tolerability. 
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NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
10 
Approved, Date: 14 February 2023  
After Week 4 (i.e. starting from Week 5), based on the investigator’s clinical judgment, the dose 
of esketamine for all subjects can be adjusted based upon efficacy and tolerability. Starting at 
Week 4, the frequency for subsequent intranasal treatment sessions will be adjusted (if applicable) 
based on the Clinical Global Impression – Severity (CGI-S) score at current visit (weekly, every 
other week or every 4 weeks). For CGI-6WKHLQWUDQDVDOWUHDWPHQWVHVVLRQIUHTXHQF\ZLOOEH
changed from weekly to every other week, or from every other week to every 4 weeks; for CGI-S 
> 3, the intranasal treatment session frequency will be changed from every 4 weeks to weekly or 
every other week, or from every other week to weekly. The adjustment of the intranasal treatment 
session frequency is only permitted at the fixed 2-week interval (based on CGI-S performed at that 
visit), and every 4 weeks for subjects at the 4-week interval. 
If a subject withdraws from the study before the end of the optimization/maintenance phase for 
reasons other than withdrawal of consent, an EW visit will be conducted within 1 week of the last 
intranasal dose.  
Subjects who are currently in the optimization/maintenance phase at the time the 
54135419TRD3008 study is completed will conduct an “End of Study” visit as their final study 
visit within 1 week of the last intranasal dose. 
Induction Phase and Optimization/Maintenance Phase - Study Entry 
The following subjects are eligible to enter the study at either the Induction Phase or the 
Optimization/Maintenance Phase: 
x Subjects in ESKETINTRD3003, who at Week 16 of Optimization were not eligible to proceed 
to the maintenance phase and the sponsor has approved subject’s entry into 
54135419TRD3008; or 
x Subjects in ESKETINTRD3003 and ESKETINTRD3004, who were in the induction phase 
and (for ESKETINTRD3003, after completion of the induction phase) were determined to not 
meet response criteria, and sponsor has approved subject’s entry into 54135419TRD3008; or 
x Subjects in ESKETINTRD3006 (US sites only) who completed the induction phase but did 
not meet the response criteria, and sponsor has approved subject’s entry into 
54135419TRD3008. 
A diagram of the study design is provided in Figure 1.  
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
11
Approved, Date: 14 February 2023  
Figure 1: 
Study Design for 54135419TRD3008 
1.3. 
Statistical Hypotheses for Trial Objectives 
There is no formal hypothesis for this safety study. 
1.4. 
Sample Size Justification 
No formal sample size calculation was performed for the study. All the subjects entering this study 
(54135419TRD3008) are from 1 of the following esketamine Phase 3 studies ESKETINTRD3001, 
ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004, ESKETINTRD3005, and 
ESKETINTRD3006 (US sites only) and will have met the inclusion/exclusion criteria for entry 
into those studies. It is unknown how many subjects from the previous Phase 3 studies would 
participate in this study (54135419TRD3008). 
1.5. 
Randomization and Blinding 
This is an open label study. Randomization and blinding procedures will not be applicable for this 
study. All subjects will be allocated to open-label esketamine treatment. 
2. 
GENERAL ANALYSIS DEFINITIONS 
2.1. 
Analysis Phases 
This study has 2 analysis phases: 
x A 4-week induction phase; 
x A variable duration optimization/maintenance phase. 
For France, there is an additional 4-week follow-up phase.  
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine) 
Statistical Analysis Plan 54135419TRD3008 
12 
Approved, Date: 14 February 2023 
Each analysis phase has its own analysis phase start and end dates. 
2.1.1. 
Study Reference Start and End Dates 
For subjects who enter the study at the induction phase, the reference start date for the study is 
defined as the first dose of intranasal study drug in the induction phase. For subjects who directly 
enter the optimization/maintenance phase of this study, the reference start date is defined as the 
first dose of intranasal study drug in the optimization/maintenance phase. The reference end date 
for subjects who have completed/discontinued from the study is the maximum of the date of last 
visit and trial completion/discontinuation. 
2.1.2. 
Analysis Phase Start and End Dates 
Induction Phase 
The start date of the induction phase (referred to as, ‘IND start date’) is the date of the first dose 
of intranasal study medication in the induction phase. For subjects who continue to the 
optimization/maintenance phase, the induction phase end date (referred to as, ‘IND end date’) is 
the date of first dose of intranasal study medication taken in the optimization/maintenance phase 
or the date of the last visit in the induction phase if date of the first dose is missing. For subjects 
who discontinue in the induction phase, IND end date is the maximum of the date of the last visit 
in the induction phase or the date of early termination from the induction phase. 
The start date/time of the induction phase (referred to as, ‘IND start date/time’) is the IND start 
date and the time of the first dose of intranasal study medication in this phase. If no intranasal 
study medication is administered, the time will be left blank. 
The start and end dates for the induction phase are only defined for subjects who enter the study 
at the induction phase. 
Optimization/Maintenance Phase 
The start date of the optimization/maintenance phase (referred to as, ‘OP/MA start date’) is the 
OP/MA start date of the first dose of intranasal study medication in this phase. For subjects who 
complete/discontinue from the optimization/maintenance phase, the phase end date (referred to as, 
‘OP/MA end date’) is the maximum of the date of the last visit in the optimization/maintenance 
phase or the date of completion/withdrawal from the optimization/maintenance phase.  
The start date/time of the optimization/maintenance phase (referred to as, ‘OP/MA start date/time’) 
is the OP/MA start date and the time of the first dose of intranasal study medication in this phase. 
Follow-Up Phase 
The start date of the follow-up (post-treatment) phase (referred to as, ‘F/U start date’) is the day 
after the end date of the last treatment phase in which the subject participated. For subjects who 
complete/discontinue from the follow-up phase, the follow-up phase end date (referred to as, ‘F/U 
end date’) is the maximum of the last follow-up visit date or end of trial date. 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
13 
Approved, Date: 14 February 2023  
2.1.3. 
Study Day and Relative Day 
Study day is calculated relative to the reference start date for the study. Relative day is calculated 
relative to the analysis phase 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 - reference start date + 1. 
Study day for an event prior to the start of the study is calculated as: 
event date - reference start date.  
Relative day for an event on or after the analysis phase start date is calculated as: 
event date - analysis phase start date + 1. 
Relative day for an event prior to the analysis phase start date is calculated as: 
event date - analysis phase start date. 
There is no study day 0 or relative day 0. 
2.2. 
Baseline and End Point 
Baseline is defined for each parameter/assessment. 
x Study Baseline: For subjects who enter the study at the induction phase, the last observation 
prior to or on the start date of induction phase is denoted as ‘Baseline’; for subjects who directly 
enter the study at the optimization/maintenance phase, the last observation prior to or on the 
start date of optimization/maintenance phase is denoted as ‘Baseline’. 
x Baseline (OP/MA): The last observation prior to or on the start date of the 
optimization/maintenance phase is denoted as ‘Baseline (OP/MA)’.  
Note: 
 
o The ‘Study Baseline’ value is used to describe the change from baseline in the safety 
analysis unless otherwise specified. 
o For subjects who enter the study at the induction phase, the ‘Baseline (IND)’ value is used 
for the efficacy analysis for the induction phase.; for subjects who enter the 
optimization/maintenance phase, the ‘Baseline (OP/MA)’ is used for the efficacy analysis 
for the optimization/maintenance phase. 
For each variable measured over time, the ‘End Point (IND)’ value is defined as the last 
postbaseline assessment value during the induction phase for subjects who enter the study at the 
induction phase.  
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
14 
Approved, Date: 14 February 2023  
The ‘End Point (OP/MA)’ value is defined as the last postbaseline assessment value during the 
optimization/maintenance phase.  
2.3. 
Visit Windows 
As subjects do not always adhere to the protocol visit schedule, the following rules are applied to 
assign actual visits to protocol visits. Listed below are the visit windows 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 induction phase for subjects who enter the study at the induction phase, and the first day any 
study drug was taken in the optimization/maintenance phase for responders from induction phase 
and subjects directly entering the optimization/maintenance phase of this study). 
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 
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 
Daya 
Time Interval 
(label on output) 
Time Intervala 
(Day) 
Target Time 
Pointa 
(Day) 
Montgomery-
Asberg 
Depression 
Rating Scale 
(MADRS) 
IND 
1 
Baseline 
 
1 
8 
Day 8 (IND) 
2 - 11 
8 
15 
Day 15 (IND) 
12 - 18 
15 
22 
Day 22 (IND) 
19 - 24 
22 
28 
Day 28 (IND) 
25 to end of IND 
28 
IND final visit 
End Point (IND) 
2 to end of IND 
  
OP/MA 
i=1,2,3,... 
1 
Baseline (OP/MA) 
 
1 
15 
Week 3 (OP/MA) 
2 - 32 
15 
50 
Week 8 (OP/MA) 
33 - 64 
50 
50 + i*28 
Week (8 + i*4) 
(OP/MA) 
37 + i*28 to 64 + 
i*28 
50 + i*28 
OP/MA final 
visit 
End Point (OP/MA) 
2 to end of OP/MA 
  
CGI-S 
IND 
1 
Baseline 
 
1 
4 
Day 4 (IND) 
2 - 6 
4 
8 
Day 8 (IND) 
7 - 9 
8 
11 
Day 11 (IND) 
10 - 13 
11 
15 
Day 15 (IND) 
14 - 18 
15 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
15 
Approved, Date: 14 February 2023  
Table 1:     Analysis Visits 
Parameter 
Analysis 
Phase 
Scheduled 
Daya 
Time Interval 
(label on output) 
Time Intervala 
(Day) 
Target Time 
Pointa 
(Day) 
22 
Day 22 (IND) 
19 - 24 
22 
28 
Day 28 (IND) 
25 to end of IND 
28 
IND final visit 
End Point (IND) 
2 to end of IND 
  
OP/MA 
i=1,2,3,... 
1 
Baseline (OP/MA) 
 
1 
8 
Week 2 (OP/MA) 
2 - 11 
8 
15 
Week 3 (OP/MA) 
12 - 18 
15 
22 
Week 4 (OP/MA) 
19 - 29 
22 
22 + i*14 
Week (4 + i*2) 
(OP/MA) 
16 + i*14 to 29 + 
i*14 
22 + i*14 
OP/MA final 
visit 
End Point (OP/MA) 
2 to end of OP/MA 
  
Patient Health 
Questionnaire – 
9 item (PHQ-9), 
EuroQol Group; 
5 dimension; 5 
level (EQ-5D-
5L), 
Quality of Life 
in Depression 
Scale (QLDS) 
IND 
1 
Baseline 
 
1 
15 
Day 15 (IND) 
2 - 21 
15 
28 
Day 28 (IND) 
22 to end of IND 
28 
IND final visit 
End Point (IND) 
2 to end of IND 
  
OP/MA 
i=1,2,3,... 
1 
Baseline (OP/MA) 
 
1 
15 
Week 3 (OP/MA) 
2 - 32 
15 
50 
Week 8 (OP/MA) 
33 - 64 
50 
50 + i*28 
Week (8 + i*4) 
(OP/MA) 
37 + i*28 to 64 + 
i*28 
50 + i*28 
OP/MA final 
visit 
End Point (OP/MA) 
2 to end of OP/MA 
  
Sheehan 
Disability Scale 
(SDS) 
IND 
1 
Baseline 
 
1 
28 
Day 28 (IND) 
2 to end of IND 
28 
IND final visit 
End Point (IND) 
2 to end of IND 
  
OP/MA 
i=1,2,3,... 
1 
Baseline (OP/MA) 
 
1 
15 
Week 3 (OP/MA) 
2 - 32 
15 
50 
Week 8 (OP/MA) 
33 - 64 
50 
50 + i*28 
Week (8 + i*4) 
(OP/MA) 
37 + i*28 to 64 + 
i*28 
50 + i*28 
OP/MA final 
visit 
End Point (OP/MA) 
2 to end of OP/MA 
  
Treatment 
Satisfaction 
Questionnaire 
for Medication 
(TSQM-9) 
IND 
1 
Baseline 
 
1 
28 
Day 28 (IND) 
2 to end of IND 
28 
IND final visit 
End Point (IND) 
2 to end of IND 
  
OP/MA 
i=1,2,3,... 
1 
Baseline (OP/MA) 
 
1 
50 
Week 8 (OP/MA) 
2 - 64 
50 
50 + i*28 
Week (8 + i*4) 
(OP/MA) 
37 + i*28 to 64 + 
i*28 
50 + i*28 
OP/MA final 
visit 
End Point (OP/MA) 
2 to end of OP/MA 
  
IND 
28 
Day 28 (IND) 
1 to end of IND 
28 
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NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
16 
Approved, Date: 14 February 2023  
Table 1:     Analysis Visits 
Parameter 
Analysis 
Phase 
Scheduled 
Daya 
Time Interval 
(label on output) 
Time Intervala 
(Day) 
Target Time 
Pointa 
(Day) 
Patient Stated-
choice 
Preference 
OP/MA 
22 
Week 4 (OP/MA) 
1 to end of OP/MA 
22 
Nasal exam 
IND 
1 
Baseline 
 
1 
28 
Day 28 (IND) 
2 to end of IND 
28 
IND final visit 
End Point (IND) 
2 to end of IND 
  
Vital Signs: 
Temperature 
(TEMP) (IND 
[predose], 
OP/MA 
[predose]), 
Blood Pressure 
(BP)b,  
Hear Rate (HR), 
Respiratory 
(RESP) (IND 
[predose, 40M, 
1H, 1H30M], 
OP/MA 
[predose, 40M, 
1H]) 
IND 
1 
Baseline 
SUHGRVH 
1 
Day 1 (IND): 40M 
Day 1 (IND): 1H 
Day 1 (IND): 1H30M 
4 
Day 4 (IND): Predose 
2 - 6 
4 
Day 4 (IND): 40M 
Day 4 (IND): 1H 
Day 4 (IND): 1H30M 
8 
Day 8 (IND): Predose 
7 - 9 
8 
Day 8 (IND): 40M 
Day 8 (IND): 1H 
Day 8 (IND): 1H30M 
11 
Day 11 (IND): Predose 
10 - 13 
11 
Day 11 (IND): 40M 
Day 11 (IND): 1H 
Day 11 (IND): 1H30M 
15 
Day 15 (IND): Predose 
14 - 16 
15 
Day 15 (IND): 40M 
Day 15 (IND): 1H 
Day 15 (IND): 1H30M 
18 
Day 18 (IND): Predose 
17 - 20 
18 
Day 18 (IND): 40M 
Day 18 (IND): 1H 
Day 18 (IND): 1H30M 
22 
Day 22 (IND): Predose 
21 - 23 
22 
Day 22 (IND): 40M 
Day 22 (IND): 1H 
Day 22 (IND): 1H30M 
25 
Day 25 (IND): Predose 
24 to end of IND 
25 
Day 25 (IND): 40M 
Day 25 (IND): 1H 
Day 25 (IND): 1H30M 
IND final visit 
End Point (IND) 
Day 1 (IND): 40M 
to end of IND 
  
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
17 
Approved, Date: 14 February 2023  
Table 1:     Analysis Visits 
Parameter 
Analysis 
Phase 
Scheduled 
Daya 
Time Interval 
(label on output) 
Time Intervala 
(Day) 
Target Time 
Pointa 
(Day) 
OP/MA 
i=1,2,3,... 
1 
Baseline (OP/MA) 
 
1 
Week 1 (OP/MA): 40M 
Week 1 (OP/MA): 1H 
8 
Week 2 (OP/MA): 
Predose 
2 - 11 
8 
Week 2 (OP/MA): 40M 
Week 2 (OP/MA): 1H 
15 
Week 3 (OP/MA): 
Predose 
12 - 18 
15 
Week 3 (OP/MA): 40M 
Week 3 (OP/MA): 1H 
22 
Week 4 (OP/MA): 
Predose 
19 - 25 
22 
Week 4 (OP/MA): 40M 
Week 4 (OP/MA): 1H 
22 + i*7 
Week (4 + i*1) 
(OP/MA): Predose 
19 + i*7 to 25 + i*7 
22 + i*7 
Week (4 + i*1) 
(OP/MA): 40M 
Week (4 + i*1) 
(OP/MA): 1H 
OP/MA final 
visit 
End Point (OP/MA) 
Week 1: 40M to end 
of OP/MA 
  
Weight and body 
mass index 
(BMI), 
Hematology and 
Chemistry, 
Urinalysis 
IND 
1 
Baseline 
 
1 
28 
Day 28 (IND) 
2 to end of IND 
28 
IND final visit 
End Point (IND) 
2 to end of IND 
  
OP/MA 
i=1,2,3,... 
1 
Baseline (OP/MA) 
 
1 
106 
Week 16 (OP/MA) 
2 - 148 
106 
106 + i*84 
Week (16 + i*12) 
(OP/MA) 
65 + i*84 to 148 + 
i*84 
106 + i*84 
OP/MA final 
visit 
End Point (OP/MA) 
2 to end of OP/MA 
  
Electrocardiogra
m (ECG) 
IND 
1  
Baseline 
SUHGRVH 
 
1  
Day 1 (IND): 1H 
15 
Day 15 (IND): 1H 
2 - 20 
15 
25 
Day 25 (IND): 1H 
21 to end of IND 
25 
IND final visit 
End Point (IND) 
Day 1 (IND): 1H to 
end of IND 
  
OP/MA 
i=1,2,3,... 
1 
Baseline (OP/MA) 
 
1 
Week 1 (OP/MA): 1H 
50 
Week 8 (OP/MA): 1H 
2 - 64 
50 
50 + i*28 
Week (8 + i*4) 
(OP/MA): 1H 
37 + i*28 to 64 + 
i*28 
50 + i*28 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
18 
Approved, Date: 14 February 2023  
Table 1:     Analysis Visits 
Parameter 
Analysis 
Phase 
Scheduled 
Daya 
Time Interval 
(label on output) 
Time Intervala 
(Day) 
Target Time 
Pointa 
(Day) 
OP/MA final 
visit 
End Point (OP/MA) 
Week 1: 1H to end 
of OP/MA 
  
Columbia-
Suicide Severity 
Rating Scale(C-
SSRS) 
IND 
1 
Baseline 
 
1 
4 
Day 4 (IND) 
2 - 6 
4 
8 
Day 8 (IND) 
7 - 9 
8 
11 
Day 11 (IND) 
10 - 13 
11 
15 
Day 15 (IND) 
14 - 16 
15 
18 
Day 18 (IND) 
17 - 20 
18 
22 
Day 22 (IND) 
21 - 23 
22 
25 
Day 25 (IND) 
24 - 26 
25 
28 
Day 28 (IND) 
27 to end of IND 
28 
IND final visit 
End Point (IND) 
2 to end of IND 
  
OP/MA 
i=1,2,3,... 
1 
Baseline (OP/MA) 
 
1 
8 
Week 2 (OP/MA) 
2 - 11 
8 
15 
Week 3 (OP/MA) 
12 - 18 
15 
22 
Week 4 (OP/MA) 
19 - 29 
22 
22 + i*14 
Week (4 + i*2) 
(OP/MA) 
16 + i*14 to 29 + 
i*14 
22 + i*14 
OP/MA final 
visit 
End Point (OP/MA) 
2 to end of OP/MA 
  
MOAA/Sc (IND 
and OP/MA 
[predose and 
every 15 minutes 
to 1H]), 
CGADRd (IND 
and OP/MA 
[30M; if not 
“Yes”, repeat 
every 15 minutes 
until “Yes”] 
 
 
 
 
 
 
 
 
 
 
 
 
IND 
1 
Day 1 (IND) 
 
1 
4 
Day 4 (IND) 
2 - 6 
4 
8 
Day 8 (IND) 
7 - 9 
8 
11 
Day 11 (IND) 
10 - 13 
11 
15 
Day 15 (IND) 
14 - 16 
15 
18 
Day 18 (IND) 
17 - 20 
18 
22 
Day 22 (IND) 
21 - 23 
22 
25 
Day 25 (IND) 
24 to end of IND 
25 
IND final visit 
End Point (IND) 
2 to end of IND 
  
OP/MA 
i=1,2,3,... 
1 
Week 1 (OP/MA) 
 
1 
8 
Week 2 (OP/MA) 
2 - 11 
8 
15 
Week 3 (OP/MA) 
12 - 18 
15 
22 
Week 4 (OP/MA) 
19 - 25 
22 
22 + i*7 
Week (4 + i*1) 
(OP/MA) 
19 + i*7 to 25 + i*7 
22 + i*7 
OP/MA final 
visit 
End Point (OP/MA) 
2 to end of OP/MA 
  
Pulse Oximetrye 
(IND [predose 
and every 15 
minutes to 1H], 
IND 
1 
Baseline 
 
1 
4 
Day 4 (IND) 
2 - 6 
4 
8 
Day 8 (IND) 
7 - 9 
8 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT02782104


JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
19 
Approved, Date: 14 February 2023  
Table 1:     Analysis Visits 
Parameter 
Analysis 
Phase 
Scheduled 
Daya 
Time Interval 
(label on output) 
Time Intervala 
(Day) 
Target Time 
Pointa 
(Day) 
OP/MA 
[predose, 30M, 
1H]) 
11 
Day 11 (IND) 
10 - 13 
11 
15 
Day 15 (IND) 
14 - 16 
15 
18 
Day 18 (IND) 
17 - 20 
18 
22 
Day 22 (IND) 
21 - 23 
22 
25 
Day 25 (IND) 
24 to end of IND 
25 
IND final visit 
End Point (IND) 
2 to end of IND 
  
OP/MA 
i=1,2,3,... 
1 
Week 1 (OP/MA) 
 
1 
8 
Week 2 (OP/MA) 
2 - 11 
8 
15 
Week 3 (OP/MA) 
12 - 18 
15 
22 
Week 4 (OP/MA) 
19 - 25 
22 
22 + i*7 
Week (4 + i*1) 
(OP/MA) 
19 + i*7 to 25 + i*7 
22 + i*7 
OP/MA final 
visit 
End Point (OP/MA) 
2 to end of OP/MA 
  
Healthcare 
Resource Use 
Questionnaire 
(HRUQ) 
OP/MA 
i=1,2,3,... 
1 
Week 1 (OP/MA) 
 
1 
22 
Week 4 (OP/MA) 
2 - 36 
22 
22 + i*28 
Week (4 + i*4) 
(OP/MA) 
9 + i*28 to 36 + i*28 
22 + i*28 
OP/MA final 
visit 
End Point (OP/MA) 
2 to end of OP/MA 
  
PWC 
OP/MA 
End Point 
(OP/MA) 
End Point (OP/MA) 
1 to end of OP/MA 
 
FU 
7 
Week 1 (F/U) 
1 to 10 
7 
14 
Week 2 (F/U) 
11 to 17 
14 
21 
Week 3 (F/U) 
18 to 24 
21 
28 
Week 4 (F/U) 
25 to end of F/U 
28 
F/U final visit 
End Point (F/U) 
1 to end of F/U 
 
a For IND phase, time interval is relative to the first day of the induction phase. 
  For OP/MA phase, time interval is relative to the first day of the optimization/maintenance phase. 
b During the IND and OP/MA phase, at 1.5 hours postdose if the systolic blood pressure (SBP) LVDQGRUWKH
diastolic blood pressure (DBP) LVEORRGSUHVVXUHPRQLWRULQJVKRXOGFRQWLQXHHYHU\PLQXWHVXQWLOWKH
blood pressure if SBP < 160 and DBP < 100, or investigator's clinical judgment the subject it is clinically stable 
and can be discharged from the study site or the subject is referred for appropriate medical care if clinically 
indicated. LIWKHEORRGSUHVVXUHUHPDLQV PP+J6%3DQGRU mmHg DBP, 2 hours after dosing, the 
subject should be referred for immediate medical treatment. 
c If the MOAA/S score is <= 3 at any time during the 1 hour postdose interval, the MOAA/S will be performed every 
5 minutes until a score of 4 is reached (at which point a frequency of every 15 minutes can be resumed until t=+1 
hours post dose) 
d If the response is “No”, the assessment will be repeated every 15 minutes until a “Yes” response is achieved or until 
the subject is referred for appropriate medical care if clinically indicated. On all intranasal treatment session days, 
subjects must remain at the clinical site until study procedures have been completed and the subject is ready for 
discharge. 
e If pulse oximetry is < 93% at any time during the 1 hour postdose interval, pulse oximetry will be recorded every 5 
PLQXWHVXQWLOOHYHOVUHWXUQWRRUXQWLOWKHVXEMHFWLVUHIHUUHGIRUDSSURpriate medical care, if clinically 
indicated 
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Statistical Analysis Plan 54135419TRD3008  
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2.4. 
Analysis Sets 
Subjects will be classified into the following analysis sets: all enrolled and full analysis sets. 
Analyses of change from baseline will include only those subjects who have both baseline and at 
least 1 post-baseline observation in that phase.  
2.4.1. 
All Enrolled Analysis Set 
This analysis set will include all subjects who are eligible to enter this study and received at least 
1 dose of intranasal study medication. 
2.4.2. 
Full Analysis Set 
The following analysis sets will be used to summarize efficacy and safety data and are defined for 
each phase. Analyses of change from baseline will include only those subjects who have both 
baseline and at least 1 post-baseline observation in that phase. 
Full (IND) analysis set: All subjects who receive at least 1 dose of intranasal study medication in 
the induction phase. 
Full (OP/MA) analysis set: All subjects who receive at least 1 dose of intranasal study medication 
in the optimization/maintenance phase. 
2.4.3. 
Follow-up Analysis Set 
The Follow-up analysis set includes all subjects who enter the follow-up phase. This analysis set 
will be used to summarize all safety evaluations during the follow-up phase. 
2.5. 
Definition of Subgroups 
Descriptive statistics will be provided for the response and remission rates to a second induction 
phase in the subgroup of subjects who had relapsed in study ESKETINTRD3003. 
2.6. 
Imputation Rules for Missing Adverse Event (AE) Dates  
Treatment-emergent adverse events (TEAEs)  
x For subjects who enter the study at the induction phase, treatment-emergent AEs are those 
events with an onset date/time on or after the start of IND phase study medication, and 
occurred on or before the end of the optimization/maintenance phase.  A conservative 
approach will be used to handle the missing dates for AEs 
x For subjects who directly enter the optimization/maintenance phase of this study, 
treatment-emergent AEs are those events with an onset date/time on or after the start of 
OP/MA phase study medication, and occurred on or before the end of the 
optimization/maintenance phase.  A conservative approach will be used to handle the 
missing dates for AEs 
Onset Date 
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Statistical Analysis Plan 54135419TRD3008  
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AEs for each phase are those events with an onset date/time on or after the start of that particular 
phase and occurred on or before the end of that phase. The rules for estimating incomplete AE 
onset dates will be as follows: 
Subject Entry into 54135419TRD3008 at the IND Phase: 
If the onset date of an adverse event is missing the 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 IND start date 
ii) The day of IND start date, if the month/year of the onset of AE is the same as month/year 
of the IND start date and month/year of the AE resolution date is different 
iii) The day of IND start date or day of AE resolution date, whichever is earliest, if 
month/year of the onset of AE and month/year of the IND 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 IND start date 
ii) One day after the IND 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 IND start date.  
Subject Entry into 54135419TRD3008 at the OP/MA Phase: 
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 OP/MA start date 
ii) The day of OP/MA start date, if the month/year of the onset of AE is the same as 
month/year of the OP/MA start date and month/year of the AE resolution date is different 
iii) The day of OP/MA start date or day of AE resolution date, whichever is earliest, if 
month/year of the onset of AE and month/year of the OP/MA 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 OP/MA start date 
ii) One day after the OP/MA 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 OP/MA 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. 
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Statistical Analysis Plan 54135419TRD3008  
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If the resolution date of an adverse event is missing both day and month, it will be set to 
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. 
Subject Entered into 54135419TRD3008 at the IND Phase: 
If the time of onset is missing, it will be imputed as follows: 
i) 
00:00 if the date of onset is after IND start date 
ii) The time of intranasal medication start in the IND phase if the date of onset is the same as 
IND start date 
Subject Entered into 54135419TRD3008 at the OP/MA Phase: 
If the time of onset is missing, it will be imputed as follows: 
i) 
00:00 if the date of onset is after OP/MA start date 
ii) The time of intranasal medication start in the OP/MA phase if the date of onset is the 
same as OP/MA start date 
If a missing time is associated with a partial or missing date, the date will be imputed first prior to 
imputing the time. 
2.7. 
Imputation Rules for Missing Concomitant Medication Dates  
If a partial date is reported, it is assumed the medication (or therapy) was taken in all phases that 
overlap with the partial date. If both start and end dates are missing but this concomitant 
medication was taken both prior to the study entry and still ongoing at study end, it is assumed 
medication was taken in all phases. 
The rules for estimating an incomplete concomitant medication start date are as follows: 
Subject Entered into 54135419TRD3008 at the IND Phase:  
If the month of the concomitant medication start date is equal to the month of the start of the 
induction phase, then the estimated start date is the IND start date;  
If the month of the concomitant medication start date is greater than the month of the start of 
the induction phase and earlier than the study end date, then the estimated start date of the 
concomitant medication is the first day of the month; 
If the month of the concomitant medication start date is greater than the month of the study end 
date, then no imputation will be done; 
If the month and year of the concomitant medication start date are known and the IND start date 
is after the month of the concomitant medication start date, then no imputation will be done; 
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Statistical Analysis Plan 54135419TRD3008  
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Approved, Date: 14 February 2023  
If either the month or year of the concomitant medication start date is missing, no imputation 
is to be performed. 
Subject Entered into 54135419TRD3008 at the OP/MA Phase: 
If the month of the concomitant medication start date is equal to the month of the start of the 
optimization phase, then the estimated start date is the OP/MA start date;  
If the month of the concomitant medication start date is greater than the month of the start of 
the OP/MA phase and earlier than the study end date, then the estimated start date of the 
concomitant medication is the first day of the month;  
If the month of the concomitant medication start date is greater than the month of the study end 
date, then no imputation will be done; 
If the month and year of the concomitant medication start date are known and the OP/MA start 
date is after the month of the concomitant medication start date, then no imputation will be 
done; 
If either the month or year of the concomitant medication start date is missing, no imputation 
is to be performed. 
3. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW 
An IDMC will be established to monitor data on an ongoing basis to ensure the continuing safety 
of the subjects enrolled in this study. The committee will meet every 6 months to review safety 
data. After the reviews, the IDMC will make recommendations regarding the continuation of the 
study.  
The IDMC will review CIOMS (Council for International Organizations of Medical Sciences) 
reports  and summaries of AEs including AEs by preferred term, serious adverse events (SAE), 
and discontinuations due to AEs. Details about the review to be performed and the roles and 
responsibilities of the IDMC are presented in a separate IDMC charter. 
Interim analyses will be performed on as needed basis (e.g. request from health 
authorities).  Details of statistical output required for the interim analyses will be defined in the 
Data Presentation Specifications. 
Sensitivity/exploratory analyses may be conducted for efficacy and safety variables of interest to 
evaluate the impact missed doses and/or remote visits which occurred due to COVID-19. 
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 for the All Enrolled analysis set (described in Section 2.4.1). Continuous 
variables will be summarized using descriptive statistics (N, mean, standard deviation [SD], 
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Statistical Analysis Plan 54135419TRD3008  
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median, minimum, and maximum). Categorical variables will be summarized using a frequency 
distribution with the number and percentage of subjects in each category. Baseline values 
(described in Section 2.2) will be used for these summaries. 
Table 2: 
Demographic Variables and Baseline Characteristics 
Continuous Variables: 
x Age (years) 
x Baseline weight (kg) 
x Baseline height (cm) 
x Baseline BMI (kg/m2) calculated as Weight (kg)/[Height (m)]2 
 
Categorical Variables: 
x Age in years (18 - 44, 45 - 64, 65 – 74, 75) 
x Sex (male, female) 
x Racea (White, Black or African American, Asian, American Indian or Alaskan 
native, Native Hawaiian or other Pacific islander, other) 
x Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
x Baseline BMI (underweight: < 18.5 kg/m2, normal: 18.5 to < 25 kg/m2, 
overweight: 25 kg/m2 to < 30 kg/m2, obese: 30 to < 40 kg/m2, morbidly obese:t 
40 kg/m2) 
x Employment Status 
x Hypertension Status 
x Country 
x Region 
a If multiple race categories are indicated, then Race is recorded as “Multiple”. 
 
Table 3: 
Psychiatric History at Baseline Variables 
Continuous Variables: 
x Baseline MADRS total score 
x Baseline PHQ-9 total score 
x Baseline CGI-S score 
x Age (years) when diagnosed with major depressive disorder (MDD) 
x Duration of current episode 
 
Categorical Variables: 
x Baseline CGI-S score 
x Baseline C-SSRS category (no event, suicidal ideation, suicidal behavior) 
x Family history of 
- 
Depression 
- 
Anxiety Disorder 
- 
Bipolar Disorder 
- 
Schizophrenia 
- 
Alcohol Abuse 
- 
Substance Abuse 
 
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Statistical Analysis Plan 54135419TRD3008  
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Note: The psychiatric history is derived from the first study subjects participated in. For example, 
if a subject first participated in ESKETINTRD3001, then went on to ESKETINTRD3003 and 
continued to participate in 54195413TRD3008, the psychiatric history is obtained from the 
ESKETINTRD3001 database and will be copied to the 54195413TRD3008 database. 
4.2. 
Disposition Information 
The number of subjects who enrolled from studies ESKETINTRD3001, ESKETINTRD3002, 
ESKETINTRD3003, ESKETINTRD3004, ESKETINTRD3005, or ESKETINTRD3006 (US sites 
only) will be provided. 
The following disposition summaries will be provided for IND and OP/MA phases separately. 
These summaries will be provided for each of the Full analysis sets described in Section 2.4.2.  
– The number of subjects who entered a specific treatment phase 
– The number of subjects who discontinued a specific treatment phase prematurely and their 
reasons for discontinuation 
– The number of subjects who are ongoing in each phase at the time the sponsor terminated 
the study. 
The number of subjects who terminated the trial and the reasons for ending study participation 
throughout the study will also be summarized. This will be summarized for All Enrolled analysis 
set described in Section 2.4.1. 
4.3. 
Extent of Exposure 
Extent of exposure in terms of total duration of exposure and number of dosing sessions of 
intranasal study medication will be summarized by phase for the Full analysis sets and across both 
phases for the All Enrolled analysis set described in Section 2.4.2. 
– The total duration of exposure for the intranasal study drug for each phase is defined as the time 
between the first and the last dose of study medication in that specific phase (last day of study 
medication - first day of study medication + 1). If a subject only receives a partial dose it is 
considered as a day of dosing.  
Descriptive statistics (N, mean, SD, median, minimum and maximum) and frequency 
distribution of total duration of exposure of intranasal study drug will be presented. A frequency 
distribution of the total number of dosing sessions of intranasal study medication will be 
presented.  
Starting at Week 4, during the optimization/maintenance phase, the number and percentage of 
subjects at each dosing frequency (weekly, every other week and every 4 weeks) and the 
number of subjects who changed their frequency will be summarized every 4 weeks.  
– Modal dose for a subject is defined as the most frequently taken dose by a subject. Mean dose 
of a subject is calculated as the sum of doses during the phase divided by the total number of 
days exposed in the phase. The final dose is the last non-zero dose received during the phase. 
The calculation of mean, modal and final dose will exclude days off study drug.  
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Statistical Analysis Plan 54135419TRD3008  
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Descriptive statistics (N, mean, SD, median, minimum and maximum) of modal dose, mean 
and final dose of intranasal study drug will be presented by phase. A frequency distribution of 
dose level (28, 56 and 84 mg) will be presented at each dosing session. In addition, at end of 
each phase the number and percentage of  subjects  at each dose (28, 56 and 84 mg) of intranasal 
study medication will be provided. 
4.4. 
Protocol Deviations 
Deviations that occurred during the study will be tabulated for the All Enrolled analysis set. Major 
deviations will be tabulated for the following categories: subject not withdrawn as per protocol, 
selection criteria not met, excluded concomitant treatment, treatment deviation, non-compliance, 
regulatory requirement. More categories may be included depending on the nature of the protocol 
deviation. 
4.5. 
Concomitant Medications 
The number and percent of subjects who receive concomitant therapies will be summarized by 
phase using the generic term of the medication for the Full (IND, OP/MA) analysis sets described 
in Section 2.4.2. 
5. 
EFFICACY 
5.1. 
Analysis Specifications 
5.1.1. 
Data Handling Rules 
For the efficacy scales MADRS, CGI-S, PHQ-9, and SDS both observed case and last observation 
carried forward (LOCF) values will be determined for the induction, optimization/maintenance 
phases. For analysis performed by phase, LOCF will be performed within the respective phase. 
For analysis performed for entire treatment phase, induction data will be carried forward to 
optimization/maintenance.  Besides the observed cases and the end point assessment, the LOCF 
values will be created for intermediate postbaseline time points as well. These imputed time points 
will be labeled as ‘Day X LOCF’ or ‘Week X LOCF’ 
5.1.2. 
Imputation Methods for Missing Items 
Imputation of the MADRS total score is described in Section 5.2.1.1. For all other scales where 
multiple items are summed to create a total, if any item of the scale is missing at a visit, the total 
score for that scale at that visit will be considered missing. 
5.2. 
Efficacy Endpoints 
Efficacy analyses during the induction phase and the optimization/maintenance phase will be 
provided for the Full analysis sets defined in Section 2.4.2. 
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Statistical Analysis Plan 54135419TRD3008  
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5.2.1. 
Montgomery-Asberg Depression Rating Scale (MADRS) 
5.2.1.1. 
Definition 
The MADRS is a clinician-rated scale designed to measure depression severity and to detect 
changes due to antidepressant treatment5. The scale consists of 10 items, each of which is scored 
from 0 (item is not present or is 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. 
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 sum of the non-missing items multiplied 
by the ratio of the maximum number of items (i.e., 10) to the number of non-missing items. 
A subject is defined a responder at a given time point if the percent improvement in MADRS total 
VFRUHLV 
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time point. 
5.2.1.2. 
Analysis Methods 
Descriptive statistics of the total score and change from baseline (of the respective phase) will be 
provided for each visit during both IND and OP/MA phases. Graphical presentations will be 
provided. In addition, the proportion of subjects who responded and remitted based on the MADRS 
total score will be provided over time for each phase. Summaries of both observed and LOCF data 
will be presented. 
For subjects who had relapsed in ESKETINTRD3003 and participated in a second induction 
treatment phase, the proportion of responders and remitters using the MADRS total score at the 
end of the second induction phase will be provided. 
5.2.2. 
Clinical Global Impression – Severity (CGI-S) 
5.2.2.1. 
Definition 
The CGI-S provides an overall clinician-determined summary measure of the severity of the 
subject’s illness that takes into account all available information, including knowledge of the 
subject’s history, psychosocial circumstances, symptoms, behavior, and the impact of the 
symptoms on the subject’s ability to function3. The CGI-S evaluates the severity of 
psychopathology on a scale of 0 to 7. Considering total clinical experience, a subject is assessed 
on severity of mental illness at the time of rating according to: 0 = not assessed; 1 = normal (not 
at all ill); 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = 
severely ill; 7 = among the most extremely ill patients. The CGI-S permits a global evaluation of 
the subject’s condition at a given time. 
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Statistical Analysis Plan 54135419TRD3008  
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5.2.2.2. 
Analysis Methods 
Descriptive statistics of the medians and median change from baseline (of the respective phase) 
will be provided for each visit during both IND and OP/MA phases. In addition, a frequency 
distribution will be provided for each visit for both phases. Summaries of both observed and LOCF 
data will be presented. 
5.2.3. 
Patient Health Questionnaire – 9 item (PHQ-9) 
5.2.3.1. 
Definition 
The PHQ-9 is a 9-item, self-report scale assessing depressive symptoms8. Each item is rated on a 
4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every 
day), with a total score range of 0-27. A higher score indicates greater severity of depression. The 
recall period is 2 weeks. The scale scores each of the nine symptom domains of the Diagnostic and 
Statistical Manual of Mental Disorders (DSM) Major Depressive Disorder criteria and it has been 
used both as a screening tool and a measure of response to treatment for depression. The severity 
of the PHQ-9 is categorized as follows: None-minimal (0 - 4), Mild (5 - 9), Moderate (10 - 14), 
Moderately Severe (15 - 19) and Severe (20 - 27).  A subject is defined as a responder at a given 
time point if the percent improvement from baseline in PHQ-WRWDOVFRUHLV$VXEMHFWLV
defined as a remitter at a given time point if the PHQ-9 total score is <5 at that time point. 
5.2.3.2. 
Analysis Methods 
Descriptive statistics of the total score and change from baseline (of the respective phase) will be 
provided for each visit during both IND and OP/MA phases. The frequency of severity categories 
will be summarized over time during each phase. Graphical presentations will be provided. In 
addition, the proportion of subjects who achieve response and remission based on the PHQ-9 total 
score will be summarized for each visit during both phases. Summaries of both observed and 
LOCF data will be presented.  
For subjects who had relapsed in ESKETINTRD3003 and participated in a second induction 
treatment phase, the proportion of subjects who achieve response and remission at the end of the 
second induction phase will be provided. 
5.2.4. 
Sheehan Disability Scale (SDS) 
5.2.4.1. 
Definition 
The SDS is a subject-reported outcome measure and is a 5-item questionnaire which has been 
widely used and accepted for assessment of functional impairment and associated disability. The 
first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home 
responsibilities using a 0-10 rating scale. The score for the first three items are summed to create 
a total score of 0-30 where a higher score indicates greater impairment. It also has one item on 
days lost from school or work and one item on days when underproductive. The recall period for 
this study is 7 days. 6FRUHV IRUHDFKLWHPDQGIRUWKHWRWDOVFRUHDUHFRQVLGHUHGUHVSRQVH
Scores  2 for HDFKLWHPDQGIRUWKHWRWDOVFRUHDUHFRQVLGHUHGUHPLVVLRQ,IDQ\RIWKHILUVW
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JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
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three items are missing, the total score will be set to missing as well as response and remission 
status. 
5.2.4.2. 
Analysis Methods 
Descriptive statistics of the total score and change from baseline (of the respective phase) will be 
provided for each visit during both IND and OP/MA phases. Graphical presentations will be 
provided. Summaries of both observed and LOCF data will be presented. The total score as well 
as the individual item scores will be summarized.  In addition, the proportion of subjects who 
achieve response and remission will be summarized at each time point. 
5.2.5. 
EuroQol Group; 5 Dimension; 5 level (EQ-5D-5L) 
5.2.5.1. 
Definition 
The EQ-5D-5L1,2 is a standardized 2-part instrument for use as a measure of health outcome, 
primarily designed for self-completion by respondents. It essentially consists of the EQ-5D-5L 
descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-5L descriptive system 
comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems (Level 
1 indicating no problem, Level 2 indicating slight problems, Level 3 indicating moderate problems, 
Level 4 indicating severe problems, and Level 5 indicating extreme problems). 
The subject selects an answer for each of the 5 dimensions considering the response that best 
matches his or her health “today.” The descriptive system can be represented as a health state. The 
EQ VAS self-rating records the respondent’s own assessment of his or her overall health status at 
the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the best health 
you can imagine).  
The time taken to complete the questionnaire varies with age, health status, and setting but is likely 
to be around 1 minute. 
Individual scores from the 5 dimensions will be used to obtain a weighted health status index as 
shown below:  
i) 
Scores from each dimension will be combined to obtain a 5L profile score or health 
state: e.g., a score of 1 for each dimension will give a 5L profile score of 11111. 
Dimension scores will be combined in the following order: Mobility, Self-Care, Usual 
Activities, Pain/Discomfort, Anxiety/Depression 
ii) 
The value set of the Health Status Index for various values of 5L profile scores is 
published for Canada in the following website:  
https://www.ncbi.nlm.nih.gov/pubmed/26492214 
iii) 
The Canadian value set will be used to get the HSI values for all the countries 
participating in the study 
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Statistical Analysis Plan 54135419TRD3008  
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In addition, a sum score will be derived as follows: The scores of the five dimensions (values 1-5) 
will be added (sums between 5 and 25). From this score, subtract 5 (range 0-20) and multiply by 
5 (range 0-100). 
5.2.5.2. 
Analysis Methods 
Descriptive statistics of actual values and changes from baseline for the weighted EQ-5D health 
status index, the EQ VAS, and the sum score will be summarized for each visit for both IND and 
OP/MA phases. In addition, a frequency distribution will be provided for each individual 
dimension at each visit for both phases. Summaries of observed data will be presented. 
5.2.6. 
Treatment Satisfaction Questionnaire for Medication (TSQM-9) 
5.2.6.1. 
Definition 
The TSQM-9 is a 9-item generic patient reported outcome instrument to assess patients’ 
satisfaction with medication. It is derived from the longer TSQM Version 1.4 and covers domains 
of effectiveness (item 1-Satisfied, Ability to Treat; item 2-Satisfied, Relieves Symptoms; item 3-
Satisfied, Time It Takes to Work), convenience (item 4-Easy/Difficult to Use the Med; item 5-
Easy/Difficult to Plan the Use; item 6 -Convenient, Take Med as Instructed) and global satisfaction 
(item 7-Confident Taking This Med Is Good; item 8-Certain, Good Things Outweigh Bad; item 9-
How Satisfied, Overall). The instrument is scored by domain with a transformed scores ranging 
from 0-100 where a lower score indicates lower satisfaction. The recall period is “the last 2-3 
weeks”. 
Scoring algorithm 
Effectiveness:  
>,WHP,WHP,WHPí@GLYLGHGE\î 
,IRQHLWHPLVPLVVLQJ>6XPRIWZRFRPSOHWHGLWHPVí@GLYLGHGE\î 
 
Convenience:  
>6XPRI,WHPWR,WHPí@GLYLGHGE\î 
,IRQHLWHPLVPLVVLQJ>6XPRIWZRFRPSOHWHGLWHPVí@GLYLGHGE\î 
 
Overall satisfaction: 
([Sum(Item 7 to Item 9) – 3] divided by 14) * 100  
If either Item 7 or 8 is missing  
([(Sum(the two completed items)) – 2] divided by 10) * 100  
If Item 9 is missing  
([(Sum(Item 7 and Item 8)) – 2] divided by 8) * 100 
5.2.6.2. 
Analysis Methods 
Descriptive statistics of the transformed score and change from baseline (of the respective phase) 
will be provided for each domain by visit during both IND and OP/MA phases. Summaries of 
observed data will be presented. 
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JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
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5.2.7. 
Quality of Life in Depression Scale (QLDS) 
5.2.7.1. 
Definition 
The QLDS is a disease specific PRO designed to assess health related quality of life in patients 
with Major Depressive Disorder. The instrument has a recall period of “at the moment", contains 
34-items with “yes” / “no” response options and takes approximately 5-10 minutes to complete. 
The score range is from 0 (good quality of life) to 34 (very poor quality of life). 
5.2.7.2. 
Analysis Methods 
Descriptive statistics of the total score and change from baseline (of the respective phase) will be 
provided for each visit during both IND and OP/MA phases. Summaries of observed data will be 
presented. 
6. 
SAFETY 
Safety data for the induction and optimization/maintenance phases will be presented separately for 
each phase. Summaries for each phase will be based on the Full analysis sets described in Section 
2.4.2. In addition, adverse event and cognition data will be summarized for the entire treatment 
period combining the induction and optimization/maintenance phases. Summaries for the entire 
treatment period will be based on the All Enrolled analysis set described in Section 2.4.1. 
6.1. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) (version 18.1 or above) will be used 
to classify AEs by system organ class and preferred term. TEAEs that occurred in each study phase 
will be summarized by system organ class and preferred term.  
The number (%) of subjects with TEAEs, serious TEAEs (SAEs), and TEAEs that led to study 
drug discontinuation will be summarized by system organ class and preferred term. Data listings 
will be generated for deaths, other SAEs, and discontinuations due to AEs.   
In addition, data listing and summary will be provided for subjects with AEs ongoing at the time 
of entry into this study.    
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.  
Treatment-emergent adverse events (TEAEs) are defined as follows for each study phase: 
x 
TEAEs in the induction phase:  
a. If AE onset time is not missing: 
i)   If subjects continue to OP/MA phase: IND phase start date/time  AE onset date and 
time < IND phase end date 
ii)   If subjects discontinue in the IND phase: IND phase start date/time  AE onset date 
and time  IND phase end date 
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Statistical Analysis Plan 54135419TRD3008  
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b. If AE onset time is missing: 
i)   If subjects continue to OP/MA phase: IND phase start date/time  AE onset date < IND 
phase end date 
ii)   If subjects discontinue in the IND phase: IND phase start date/time  AE onset date  
IND phase end date 
x 
TEAEs in the optimization/maintenance phase:  
a. 
If AE onset time is not missing: OP/MA phase start date/time $(RQVHWGDWH and time 
 OP/MA phase end date  
b. ,I$(RQVHWWLPHLVPLVVLQJ230$SKDVHVWDUWGDWH$(RQVHWGDWH230$SKDVH 
end date  
x 
For the AEs that have both day and month missing, treatment-emergent flag is assigned based 
on the rules presented in Section 2.6. 
In addition, TEAEs will be summarized by severity and relationship to study medication using the 
preferred term. For the summaries of TEAEs by severity/relationship to study medication, the 
observation with the most severe occurrence/closest relationship to study medication will be 
chosen if there is more than one incident of an AE reported during the analysis phase by the subject. 
AE duration for transient dizziness/vertigo and anxiety will also be summarized.  
Adverse Events of Special Interest 
Clinically relevant TEAEs of special interest will be examined separately grouped in the following 
categories: 
x 
drug abuse, dependence and withdrawal (Aggression, Confusional state, Decreased activity, 
Dependence, Disorientation, Dissociation, Dissociative disorder, Dizziness, Drug use 
disorder, Drug abuse, Drug abuser, Drug dependence, Drug detoxification, Drug diversion, 
Drug rehabilitation, Drug tolerance, Drug tolerance increased, Drug withdrawal convulsions, 
Drug withdrawal headache, Drug withdrawal syndrome, Euphoric mood, Feeling abnormal, 
Feeling drunk, Feeling of relaxation, Hallucination, Hallucination auditory, Hallucination 
gustatory, Hallucination olfactory, Hallucination synaesthetic, Hallucination tactile, 
Hallucination visual, Hallucinations mixed, Inappropriate affect, Mental impairment, Product 
tampering, Psychomotor hyperactivity, Psychotic disorder, Rebound effect, Somatic 
Hallucination, Somnolence, Substance abuser, Substance dependence, Substance use, 
Substance use disorder, Substance-induced mood disorder, Substance-induced psychotic 
disorder, Thinking abnormal, Withdrawal arrhythmia, Withdrawal syndrome);  
x 
increased blood pressure (Blood pressure increased, Blood pressure diastolic increased, Blood 
pressure systolic increased, Hypertensive crisis, Hypertensive emergency, Hypertension); 
x 
increased heart rate (Heart rate increased, Tachycardia, Extrasystoles); 
x 
transient dizziness/vertigo (Dizziness, Dizziness exertional, Dizziness postural, Procedural 
dizziness, Vertigo, Vertigo labyrinthine, Vertigo positional, Vertigo CNS origin);  
x 
impaired cognition (Cognitive disorder);  
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Statistical Analysis Plan 54135419TRD3008  
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x 
cystitis (Allergic cystitis, Chemical cystitis, Cystitis, Cystitis erosive, Cystitis haemorrhagic, 
Cystitis interstitial, Cystitis noninfective, Cystitis ulcerative, Cystitis-like symptom, 
Pollakiuria, Dysuria, Micturition urgency, Nocturia); 
x 
anxiety (Anticipatory anxiety, Anxiety, Anxiety disorder, Agitation, Fear, Feeling jittery, 
Irritability, Nervousness, Panic attack, Tension);  
x 
events potentially related to 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)  
x 
hepatic adverse events (Cholecystitis, Cholelithiasis, Hepatic steatosis, Hepatitis, Non-
alcoholic steatohepatitis, Primary biliary cholangitis, Alanine aminotransferase increased, 
Aspartate aminotransferase increased, Blood bilirubin increased, Gamma-glutamyl 
transferase increased, Hepatic enzyme increased, Liver function test abnormal, Liver function 
test increased, Transaminases increased, Urine bilirubin increased, Urobilinogen urine 
increased) 
x 
events related to renal disorders (Cystitis, Pyelonephritis, Urethritis, Urinary tract infection, 
Blood creatinine increased, Blood urea increased, Blood urine present, Creatinine renal 
clearance increased, Protein urine present, Urine analysis abnormal, Urine leukocyte esterase 
positive, Bladder discomfort, Bladder irritation, Bladder outlet obstruction, Cystitis 
noninfective, Dysuria, Haematuria, Hypertonic bladder, Lower urinary tract symptoms, 
Micturition urgency, Nephrolithiasis, Nocturia, Pollakiuria, Polyuria, Proteinuria, Renal colic, 
Renal failure, Semenuria, Stress urinary incontinence, Ureterolithiasis, Urge incontinence, 
Urinary bladder polyp, Urinary hesitation, Urinary incontinence, Urinary retention) 
x 
V\PSWRPV RI GLVVRFLDWLRQ SHUVLVWLQJ EH\RQG WKH W\SLFDO  KRXU SRVW HVNHWDPLQH
administration (dissociation) 
x 
delirium (Post-injection delirium sedation syndrome, Postoperative delirium, Delirium, 
Intensive care unit delirium) 
x 
psychosis (Acute psychosis, Affective disorder, Alcoholic psychosis, Bipolar I disorder, 
Epileptic psychosis, Hysterical psychosis, Mania, Parkinson's disease psychosis, Postictal 
psychosis, Psychosis postoperative, Psychotic disorder, Psychotic disorder due to a general 
medical condition, Reactive psychosis, Rebound psychosis, Schizoaffective disorder, 
Substance-induced psychotic disorder, Transient psychosis)  
x 
mania (Hypomania, Mania) 
The number and percentage of subjects taking concomitant medication for dissociation events 
(preferred term of Dissociation) at any time during each treatment phase will be provided. 
Summary statistics for the duration of all episodes of TEAEs associated with discharge readiness 
(Dissociation, Dizziness, Feeling abnormal, Feeling drunk, Nausea, Somnolence, Vertigo, and 
Vomiting) with an onset on the day of intranasal study drug administration will be provided for 
each treatment phase. During the induction phase the summaries are presented for each dosing 
session and during the optimization/maintenance phase the summaries are presented for the first 
four dosing sessions and at the Month 3, Month 6 and Month 9 dosing sessions.  In addition, the 
number of occurrences of TEAEs associated with discharge readiness and the number of 
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occurrences of TEAEs associated with substance dependence is presented by dosing sessions for 
each treatment phase. 
AEs collected at Follow-up phase for France subjects will be provided in a listing. 
6.2. 
Clinical Laboratory Tests 
Descriptive statistics (N, mean, median, minimum, and maximum) for values and changes from 
baseline will be provided for clinical laboratory tests (hematology, chemistry and urinalysis) at 
each scheduled time point in the IND and OP/MA phases. Baseline values (as described in Section 
2.2) will be used for change summaries and to determine abnormal values during all treatment 
phases. 
Clinical laboratory tests that meet the criteria for markedly abnormal will be listed by subject for 
each phase. The incidence of treatment-emergent markedly abnormal (TEMA) laboratory values 
that occurred at any time during each treatment phase will be presented. Clinical laboratory test 
values will be considered ĀTEMA using the criteria defined by the Sponsor (Janssen Research & 
Development, LLC)” listed in Attachment 1. The identification of TEMA laboratory values is 
based on the postbaseline value being out of range while the baseline value (defined above) is 
either missing or within the range given in Attachment 1. If postbaseline 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 postbaseline value being 
below the lower limit with the baseline value being above the upper limit. Baseline values are 
defined in Section 2.2. 
The incidence of subjects with ALT values > 3*upper normal limit (ULN) will be presented for 
each study phase. Additionally, incidence of hepatic toxicity (Hy’s Law)9 defined as ALT values 
> 3*ULN and total bilirubin values > 2*ULN will be presented for each study phase. Similar to 
the markedly abnormal analysis, only subjects with Baseline ALT values 3*ULN (and Baseline 
total bilirubin values 2*ULN for hepatic toxicity) (or if the 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 values (described in Section 2.2) at 
each scheduled time-point during the induction and optimization/maintenance phases will be 
presented for temperature, systolic blood pressure, diastolic blood pressure, pulse rate, respiratory 
rate, oxygen saturation, weight, and BMI. Baseline will be used for change summaries and to 
determine abnormal values during all treatment phases (IND and OP/MA). Graphical presentations 
will be provided.  
In addition, descriptive statistics of pulse rate and blood pressure (systolic and diastolic) values 
and changes and percent changes from predose will be provided for each intranasal dosing day. 
The proportion of subjects who have a treatment-emergent abnormality, as defined in Table 4 
below, during each treatment phase will be presented. A listing of subjects meeting any of the 
following criteria during each treatment phase will also be provided. 
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Statistical Analysis Plan 54135419TRD3008  
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Table 4: 
Treatment-Emergent Abnormality Categories for Vital Signs 
 
Vital Parameter 
Post-baseline value outside of normal limit if: 
Abnormally low 
Abnormally high 
Pulse (bpm) 
A decrease from Baseline of t 15 to a 
value d 50 
An increase from Baseline of t 15 to a 
value t 100 
Systolic BP (mmHg) 
A decrease from Baseline of t 20 to a 
value d 90 
An increase from Baseline of t 20 to a 
value t 180 
Diastolic BP (mmHg) 
A decrease from Baseline of t 15 to a 
value d 50 
An increase from Baseline of t 15 to a 
value t 105 
BP = blood pressure; Baseline is defined in Section 2.2. 
 
The proportion of subjects who experienced treatment-emergent acute hypertension (systolic BP 
 180 or diastolic BP  110) at any time during each treatment phase will be summarized by 
hypertension status. 
Mean (+/-SE) values for systolic BP, diastolic BP and heart rate will be summarized by 
hypertension status and presented graphically for each treatment phase.  In addition, for subjects 
with hypertension who receive antihypertensive medication, the same tables and graphs will be 
summarized by medication type (beta-blockers, all other agents).  
A listing of subjects with oxygen saturation less than 93% will be provided. 
6.4. 
Electrocardiogram 
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 QTcB (Bazett) and QTcF 
(Fridericia). Baseline values are defined in Section 2.2. 
The 
maximum 
postbaseline 
value 
during 
each 
treatment 
phase 
(induction 
and 
optimization/maintenance phase) will be presented separately and will be computed for each ECG 
parameter using data from both scheduled and unscheduled visits. 
Summary tables for observed values and changes from baseline will be presented at each scheduled 
time point during both treatment phases (induction and optimization/maintenance phases). 
The frequency of treatment-emergent abnormalities will be tabulated and presented for all 
treatment phases. The identification of treatment-emergent abnormal ECG values is based on the 
post-baseline value (a value occurring after the start of the phase) being out of range while the 
Baseline value (described in Section 2.2) is either missing or within the limits given in Table 5. If 
postbaseline ECG results are above the upper limits (abnormally high) and the Baseline value is 
below the lower limits (abnormally low) or missing, then the postbaseline abnormality will also 
be considered treatment-emergent. The same applies to the postbaseline value being below the 
lower limits (abnormally low) with the Baseline value being above the upper limits (abnormally 
high) or missing. Abnormal ranges for the HR, PR, QRS and QT intervals are given in Table 5. 
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JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
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Table 5: 
Limits for HR, PR, QRS and QT Interval Abnormality 
ECG parameter 
Abnormally Low 
Abnormally High 
HR (bpm) 
d 50 
t 100 
PR interval (msec) 
-- 
t 210 
QRS interval (msec) 
d 50 
t 120 
QT interval (msec) 
d 200 
t 500 
 
Based on the maximum QTc value for each subject during a given phase (separate for each QTc 
correction, QTcB and QTcF) the incidence of abnormal QTc values and changes from Baseline 
will be summarized. Criteria for abnormal corrected QT intervals and changes from Baseline are 
given in Table 6 and are derived from the International Conference on Harmonization (ICH) E14 
Guidance4 (the same criteria apply to all QT corrections). 
Table 6: 
Criteria for Abnormal QTc Values and Changes From Baseline 
Parameter 
Classification 
Criteria 
Clinically Significant QTc Value 
No 
d 500 
Yes 
> 500 
QTc change from Baselinea 
No concern 
d 30 
Concern 
> 30 – 60 
Clear concern 
> 60 
QTc value 
Normal 
d 450 
> 450 - 480 
> 450 - d 480 
> 480 - 500 
> 480 - d 500 
> 500 
> 500 
These criteria are based on ICH E14 Guideline 
a Baseline is defined in Section 2.2. 
 
The proportion of subjects with treatment emergent abnormalities will be presented for the IND 
and OP/MA phases. A listing of subjects with abnormalities will also be provided. 
6.5. 
Nasal Examination 
Targeted nasal examinations (including the upper respiratory tract/throat) will be conducted by a 
qualified healthcare practitioner. The objective of the examination at Screening is to rule out any 
subjects with anatomical or medical conditions that may impede drug delivery or absorption. 
Subsequent 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.  
Changes in findings from Baseline (described in Section 2.2) for each examination (including the 
upper respiratory tract/throat) will be listed for each treatment phase. 
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Statistical Analysis Plan 54135419TRD3008  
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6.6. 
Other Safety Parameters 
6.6.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS7 is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters 
Study to assess severity and track suicidal events through any treatment. It is a semi structured 
clinician-administered questionnaire designed to solicit the occurrence, severity, and frequency of 
suicide-related ideation and behaviors during the assessment period. Using the C-SSRS, 
potentially suicide-related events will be categorized using the following scores: 
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 (non-fatal) 
10: Completed Suicide 
If no events qualify for a score of 1 to 10, a score of 0 will be assigned (0 = “no event that can be 
assessed on the basis of C-SSRS”). Higher scores indicate greater severity. 
The summaries of the C-SSRS outcomes will be based on the Full analysis set for subjects who 
have at least 1 post-baseline C-SSRS measurement and a pre-treatment C-SSRS assessment. 
A frequency distribution at each scheduled time point will be provided. Shifts from the Baseline 
value (described in Section 2.2) to the most severe/maximum score during each phase will be 
summarized. 
The maximum score assigned for each subject will also be summarized into one of three broad 
categories: No suicidal ideation or behavior (0), Suicidal ideation (1 - 5), Suicidal behavior (6 - 
10). Shifts from the Baseline value (described in Section 2.2) to the maximum category during 
each phase will be summarized. 
6.6.2. 
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 
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JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
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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). 
The MOAA/S is measured on each dosing day every 15 minutes from predose to t=+1 hours 
postdose or longer, if necessary, until the subject has a score of 5. 
x 
,IWKHVFRUHLV 3 at any time during the 1 hour postdose interval, the MOAA/S will be 
performed every 5 minutes until a score of 4 is reached (at which point a frequency of every 
15 minutes can be resumed until t=+1 hours postdose).  
x 
If a subject does not have a score of 5 at t=+1 hours postdose, they should continue to be 
monitored. For subjects with a score of 4, the assessment should be repeated every 15 minutes. 
For subjects ZLWKDVFRUHRI 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, changes from predose, and the proportion of subjects 
experiencing sedation (score less than or equal to 4) will be summarized at each scheduled time 
point. A bar chart over time for MOAA/S will be provided. 
6.6.3. 
Clinical Global Assessment of Discharge Readiness (CGADR) 
The CGADR will be used to measure a subject’s current clinical status and is the clinician’s 
assessment of the readiness to be discharged from the study site.  
The clinician will answer “Yes” or “No” to the question “Is the subject considered ready to be 
discharged based on their overall clinical status (e.g., sedation, blood pressure, and other adverse 
events)?” 
On each intranasal dosing day, the CGADR will be performed at 30 mins postdose, repeated every 
15 minutes if necessary until the response is ‘Yes’. On all intranasal treatment session days, 
subjects must remain at the clinical site until study procedures have been completed and the subject 
is ready for discharge. 
The proportion of subjects with a response of ‘No’ at each time point will be presented by each of 
the treatment phases. 
6.6.4. 
Computerized Cognitive Battery and Hopkins Verbal Learning 
Test-Revised (HVLT-R) 
The effect of intranasal esketamine on cognition will be assessed using HVLT-R. 
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Statistical Analysis Plan 54135419TRD3008  
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The computerized cognitive battery provides 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 HVLT-R is a measure of verbal 
learning and memory and is a 12-item word list recall test. The total number of correct responses 
are captured for 4 trials as well as the number of true-positive responses and false-positive errors 
in Trial 4 (Delayed Recall). The Total Recall will be derived as the sum of trials 1, 2 and 3. 
Retention % will be derived as (the number of correct responses in Trial 4) / (higher score of Trials 
2 and 3) * 100. Recognition Discrimination Index will be derived as the total number of true-
positives - the total number of false-positives. 
See Attachment 2 for details of this analysis. 
6.6.5. 
Physician’s Withdrawal Checklist, 20-item (PWC-20) 
At the request of the National Agency for the Safety of Medicines and Health Products in France, 
a 4-week Follow-up Phase was added to assess for potential withdrawal symptoms following 
cessation of intranasal esketamine using PWC-20 assessment. The PWC-20 will be performed at 
the Early Withdrawal/ End of Study Visit and every week during the 4-week Follow-up Phase 
after discontinuation of intranasal esketamine treatment. In order to better assess potential 
withdrawal symptoms from the intranasal medication it is recommended that any ongoing oral 
antidepressant medication be continued for the duration of the follow-up phase unless determined 
as not clinically appropriate.  
The PWC-20 is a 20-item simple and accurate method to assess potential development of 
discontinuation symptoms after stopping of study drug. The PWC-20 is a reliable and sensitive 
instrument for the assessment of discontinuation symptoms. Discontinuation symptoms occur 
early and disappear rather swiftly, depending upon speed of taper, daily medication dose, and drug 
elimination half-life. 
The proportion of subjects with withdrawal symptoms at the end of Optimization/Maintenance 
Phase will be presented for the subjects in France. In addition, symptoms at follow-up will be 
compared to the end of therapy visit and will be summarized using the following categories: new 
or worsened symptoms, symptoms present and unchanged, no symptoms, and improved. 
7. 
HEALTH ECONOMICS 
7.1. 
Healthcare Resource Use Questionnaire (HRUQ) 
Medical resource utilization data, associated with medical encounters, will be collected using the 
HRUQ during the optimization/maintenance phase. 
The number and percentage of subjects who visited at least one healthcare professional or had a 
hospital emergency room visit because of their depression in the 4 weeks preceding each time 
point will be summarized for each type of healthcare professional. The total number of visits to 
each type of healthcare professional, total number of visits to any healthcare professional, and the 
total number of hospital emergency room visits related to depression in the 4 weeks preceding 
each time point will be summarized at each time point with descriptive statistics. 
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Statistical Analysis Plan 54135419TRD3008  
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EuroQol Group. About EQ-5D. http://www.euroqol.org/about-eq-5d.html (accessed 18 June 2014). 
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EuroQol Group. EQ-5D-5L User Guide: basic information on how to use the EQ-5D-5L instrument. Version 
2.0; October 2013. 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/UserGuide_EQ-5D-
5L_v2.0_October_2013.pdf (accessed 6 August 2014) 
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Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. Department of Health, 
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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. 
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National Research Council, Panel on Handling Missing Data in Clinical Trials [2010]. The prevention and 
treatment of missing data in clinical trials. Available: KWWSZZZQDSHGXFDWDORJKWPO 
7. 
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. 
8. 
Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: the PHQ 
primary care study. JAMA. 1999; 282:1737-1744. 
9. 
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. 
 
 
 
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JNJ-54135419 (esketamine)  
 
 
 
Statistical Analysis Plan 54135419TRD3008  
41 
Approved, Date: 14 February 2023  
ATTACHMENTS 
i Attachment 1: 
Criteria of Markedly Abnormal Laboratory Values 
 
Markedly Abnormal Limits 
Laboratory Parameter 
Low 
High 
Albumin [g/L] 
24 
60 
Alkaline phosphatase [U/L] 
N/A 
250 
Alanine transaminase (SGPT) [U/L] 
N/A 
200 
Alanine transaminase (SGPT) [U/L] 
N/A 
>3X ULN 
Aspartate transaminase (SGOT) [U/L] 
N/A 
250 
Bicarbonate [mmol/L] 
15.1 
34.9 
Blood urea nitrogen [mmol/L] 
N/A 
17.9 
Calcium [mmol/L] 
1.5 
3 
Chloride [mmol/L] 
94 
112 
Creatine kinase (U/L) 
N/A 
990 
Creatinine [Pmol/L] 
N/A 
265.2 
Gamma glutamyl transferase [U/L] 
N/A 
300 
Glucose [mmol/L] 
2.2 
16.7 
Phosphate [mmol/L] 
0.7 
2.6 
Potassium [mmol/L] 
3.0 
5.8 
Sodium [mmol/L] 
125 
155 
Bilirubin, total [Pmol/L] 
N/A 
51.3 
Protein, total [g/L] 
50 
N/A  
Urine pH 
N/A 
8.0 
Hematocrit [fraction] - female 
0.28 
0.5 
 
- male 
0.24 
0.55 
Hemoglobin [g/L] 
80 
190 
Neutrophils, segmented [%] 
30 
90 
Monocytes [%] 
N/A 
20 
Eosinophils [%] 
N/A 
10 
Basophils [%] 
N/A 
6 
Lymphocytes [%] 
10 
60 
Platelet count [x109/L] 
100 
600 
Erythrocytes (RBC) [x1012/L] - female 
3.0 
5.5 
                                                 - male 
3.0 
6.4 
Leukocytes(WBC) [x109/L] 
2.5 
15.0 
 
 
 
Hy’s Law criteria: 
 
 
Alanine transaminase (SGPT) [U/L] 
 
>3X ULN 
AND 
 
 
Bilirubin, total [Pmol/L] 
 
>2X ULN 
Note: The same limits apply to both males and females unless gender is indicated; 
N/A = Not applicable. 
 
 
 
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Statistical Analysis Plan 54135419TRD3008  
42 
Approved, Date: 14 February 2023  
Attachment 2:  Statistical Analysis Plan for COGSTATE (dated of 07 Mar 
2019) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan 
 
 
AN OPEN-LABEL LONG-TERM EXTENSION SAFETY STUDY OF INTRANASAL ESKETAMINE IN TREATMENT-
RESISTANT DEPRESSION 
 
SAFETY AND SUSTENANCE OF ESKETAMINE TREATMENT RESPONSE WITH REPEATED DOSES AT 
INTERVALS DETERMINED BY SYMPTOM SEVERITY (SUSTAIN-3) 
Protocol Number: 54135419TRD3008 
 
 
 
Sponsor: 
Janssen Research & Development, LLC 
 
 
 
Address:  
Cogstate, Inc.  
Level 4, 195 Church Street 
New Haven, CT, USA, 06510 
 
 
 
 
 
 
 
 
 
 
 
 
SAP Version:  1 
SAP Date:  07 Mar 2019 
Protocol Version:  Approved; Amendment 2, Date: 9 May 2018 
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1. 
 Note 
Cogstate has prepared a Statistical Analysis Plan (SAP) for the Sponsor to review and sign-off for study 
54135419TRD3008. Analyses will be provided after this document has been finalized and officially signed. Anything in 
italics is taken directly from the protocol. For more details, please refer to the study protocol. 
 
2. 
Version History 
Version Number 
Date 
Author 
Reason for Revision 
1.0 
07 MAR 2019 
 
Initial Version 
 
 
 
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4. 
Table of Contents 
1.
Note .......................................................................................................................................................................... 2 
2.
Version History ......................................................................................................................................................... 2 
3.
Signature Page for SAP Approval ............................................................................................................................ 3 
4.
Table of Contents ..................................................................................................................................................... 4 
5.
Abbreviations ............................................................................................................................................................ 5 
6.
Introduction ............................................................................................................................................................... 6 
7.
Study Objectives Related to Cogstate ...................................................................................................................... 6 
8.
Study Design ............................................................................................................................................................ 6 
8.1. 
General Description ........................................................................................................................................ 6 
8.2. 
Schematic Design........................................................................................................................................... 7 
8.3. 
Scheduled Visits ............................................................................................................................................. 8 
9.
Analysis Set and Population ..................................................................................................................................... 8 
9.1. 
Unblinding Procedure ..................................................................................................................................... 8 
9.2. 
Analysis Set .................................................................................................................................................... 8 
9.2.1. 
All Enrolled Analysis Set .................................................................................................................. 8 
9.3. 
Sample Size and Analysis Population ............................................................................................................ 8 
9.4. 
Handling of missing data ................................................................................................................................ 8 
10. 
Analysis Endpoints, Baseline Definition, and Outcome Measures ........................................................................... 9 
10.1. Analysis Endpoints ......................................................................................................................................... 9 
10.2. Baseline Definitions ........................................................................................................................................ 9 
10.2.1. First Baseline (i.e., Comparison to Pre-Drug Exposure) ................................................................. 9 
10.2.2. Overall Baseline (i.e., Comparison Pre-Drug Exposure Within 54135419TRD3008) ..................... 9 
10.3. Outcome Measures Related to Cogstate Analysis ......................................................................................... 9 
10.4. The Reliable Change Index (RCI): Comparison of Individual Scores to Baseline ....................................... 12 
11. 
Data Quality Assurance .......................................................................................................................................... 12 
11.1. Test Completion Criteria ............................................................................................................................... 13 
12. 
Statistical Methodology ........................................................................................................................................... 13 
12.1. Analysis Overview ........................................................................................................................................ 13 
12.2. Analysis of Cogstate Computerized Battery and HVLT-R............................................................................ 14 
12.2.1. Primary Analyses ........................................................................................................................... 14 
12.2.2. Exploratory Analyses ..................................................................................................................... 14 
13. 
References ............................................................................................................................................................. 15 
 
 
 
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5. 
Abbreviations 
Abbreviation 
Description 
DET 
Detection Test 
EW  
Early Withdrawal 
GML 
Groton Maze Learning Test 
HVLT-R 
Hopkins Verbal Learning Test-Revised 
IDN 
Identification Test 
ISD 
Intra-Subject Standard Deviation 
OCL 
One Card Learning 
ONB 
One Back Test 
RCI 
RT 
Reliable Change Index 
Reaction Time 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
TLF 
Tables, Listings and Figures 
TRD 
Treatment-Resistant Depression 
 
 
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6. 
Introduction 
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the principal features of the 
analysis described in the 54135419TRD3008 Study Protocol related to Cogstate computerized battery and the Hopkins 
Verbal Learning Test – Revised (HVLT-R) and includes detailed procedures for executing the statistical analysis of the 
Cogstate battery data. 
 
The SAP is finalized and signed prior to database lock. If needed, revisions to the approved SAP may be made prior to 
database lock. Revisions will be version controlled. 
 
Any changes from the analyses planned in the SAP will be justified in the Cogstate statistical report. 
 
Prior to database lock, a review of all tables, listings, and figures will occur. This requires the sponsor to send Cogstate 
SDTM FT and SUPPFT datasets for both the computerized tests as well as the Hopkins Verbal Learning Test – 
Revised (HVLT-R), in addition to an ADSL dataset. The same datasets will be requested again immediately after 
database lock (for both the interim and final analyses) to perform the statistical analyses. 
7. 
Study Objectives Related to Cogstate 
The primary objective of this study is to assess the safety and tolerability of intranasal esketamine in subjects with 
Treatment-Resistant Depression (TRD), with special attention to potential long-term effects on cognitive function. 
8. 
Study Design 
8.1. 
General Description 
This is a multicenter, open-label long term extension study to evaluate the safety, tolerability, and efficacy of intranasal 
esketamine in subjects with TRD. This study has 2 open label phases: 
 
•     A 4-week induction phase  
•     A variable duration optimization/maintenance phase 
 
Induction Phase 
 
Subjects will self-administer open-label intranasal esketamine as a flexible dose regimen twice a week for 4 weeks [as 
outlined in Study Protocol Section 6.1.1]. 
 
At the end of the induction phase, subjects may be eligible to proceed to the optimization/maintenance phase, 
according to the investigator’s clinical assessment of the benefit versus risk for the subject. 
 
If a subject withdraws from the study before the end of the induction phase for reasons other than withdrawal of 
consent or is not eligible to proceed to the optimization/maintenance phase, an Early Withdrawal (EW) visit will be 
conducted within 1 week of the last intranasal dose. 
 
Subjects who are currently in the induction phase at the time the 54135419TRD3008 study is completed will conduct 
an “End of Study” visit as their final study visit within 1 week of the last intranasal dose. 
 
 
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Optimization/Maintenance Phase 
 
During this phase, the dose and intranasal treatment session frequency can be adjusted based on the criteria outlined 
in [Study Protocol Section 6.1.2]. 
 
If a subject withdraws from the study before the end of the optimization/maintenance phase for reasons other than 
withdrawal of consent, an EW visit will be conducted within 1 week of the last intranasal dose. 
 
Subjects who are currently in the optimization/maintenance phase at the time the 54135419TRD3008 study is 
completed will conduct an “End of Study” visit as their final study visit within 1 week of the last intranasal dose. 
8.2. 
Schematic Design 
Figure 1: Schematic Overview of Study 54135419TRD3008 
 
 
 
 
 
 
 
 
 
 
 
 
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8.3. 
Scheduled Visits  
Table 1: Visit Schedule for Cogstate Computerized Cognitive Battery and HVLT-R 
 
Analysis Phase 
Scheduled Daya 
Time Intervala 
(label on output) 
Time Intervala 
(Day) 
Target 
Time 
Pointa 
(Day) 
Analysis 
Visit 
IND 
1 
Baseline 
≤ 1 
1 
Yes 
28 
Day 28 (IND) 
2 to end of IND 
28 
Yes 
IND final visit 
End Point (IND) 
2 to end of IND 
 
Yes  
OP/MA 
i = 1, 2, 3… 
15 
Week 3 (OP/MA) 
1-60 
15 
Yes 
106 
Week 16 (OP/MA) 
16 – 148 
106 
Yes 
106 + i*84 
Week (16 + i*12) (OP/MA) 
65 + i*84 to 148 + i*84 
106 + i*84 
Yes 
OP/MA final visit 
End Point (OP/MA) 
1 to end of OP/MA 
 
Yes 
a For IND phase, time interval is relative to the first day of the induction phase. 
  For OP/MA phase, time interval is relative to the first day of the optimization/maintenance phase. 
9. 
Analysis Set and Population 
9.1. 
Unblinding Procedure 
As this study is open-label, blinding procedures are not applicable.   
9.2. 
Analysis Set 
9.2.1. 
All Enrolled Analysis Set 
All subjects who were eligible to enter this study and received at least one dose of intranasal esketamine. 
9.3. 
Sample Size and Analysis Population 
No formal sample size calculation was performed. The study population will include adult and elderly men and women 
who previously participated in studies ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, 
ESKETINTRD3004, or ESKETINTRD3005, or ESKETINTRD3006 (US sites only). 
9.4. 
Handling of missing data 
No imputations will be performed in the event of missing data due to dropouts or omitted visits. All incomplete subject 
profiles will be retained in the analysis. In view of issues of reliability, all analyses will be conducted with completion 
failures removed. 
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10. 
Analysis Endpoints, Baseline Definition, and Outcome 
Measures 
10.1. 
Analysis Endpoints 
The analysis endpoint for each of the tests in the Cogstate computerized cognitive battery and for the Hopkins Verbal 
Learning Test-Revised (HVLT-R) is change from baseline scores over time. 
10.2. 
Baseline Definitions 
10.2.1. 
First Baseline (i.e., Comparison to Pre-Drug Exposure) 
For all subjects enrolled in 54135419TRD3008 (except for those subjects entering from ESKETINTRD3006), baseline 
is defined as Baseline (IND) (i.e., Study Day 1) of the first study from which they have entered. For example, if a 
subject participated in study TRD3005 and went to TRD3004 and then finally joined 3008, the first baseline will be the 
Baseline (IND) from study TRD3005. 
10.2.2. 
Study Baseline (i.e., Comparison Pre-Drug Exposure Within 54135419TRD3008) 
For subjects who enter the study at the Induction Phase, study baseline is defined as the last observation prior to or on 
the start date of the Induction Phase. For subjects who enter the study at the Optimization/Maintenance Phase, study 
baseline is defined as the last observation prior to or on the start date of the Optimization/Maintenance Phase.   
10.3. 
Outcome Measures Related to Cogstate Analysis 
The cognitive tests administered include computerized tests from the Cogstate Battery as well as the HVLT-R.  
 
Detection (DET; Psychomotor Function) 
The Detection test is a measure of psychomotor function and uses a well-validated simple reaction time paradigm with 
playing card stimuli. In this test, the playing cards all depict the same joker. The subject is asked to press the Yes key 
as soon as the card in the center of the screen turns face up. The software records the mean reaction time (log10 ms).   
Duration of Test: 2 minutes 
 
Identification (IDN; Attention) 
The Identification test is a measure of visual attention and uses a well-validated choice reaction time paradigm with 
playing card stimuli. In this test, the playing cards are all either red or black jokers. The subject is asked whether the 
card displayed in the center of the screen is red. The subject responds by pressing the Yes key when the joker card is 
red and No when it is black. The software records the mean reaction time (log10 ms).  
Duration of Test: 2 minutes 
 
 
One Card Learning (OCL; Visual Learning) 
The One Card Learning test is a measure of visual learning and uses a well-validated pattern separation paradigm with 
playing card stimuli. In this test, the playing cards are identical to those found in a standard deck of 52 playing cards 
(without the joker cards). The subject is asked whether the card displayed in the center of the screen was seen 
previously in this test. The subject responds by pressing the Yes or No key. The software measures the accuracy 
across all responses (arcsine sqrt % correct).  
Duration of Test: 5 minutes 
 
 
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One Back (ONB; Working Memory) 
The One Back test is a measure of working memory and uses a well-validated n-back paradigm with playing card 
stimuli. In this test, the playing cards are identical to those found in a standard deck of 52 playing cards (without the 
joker cards). The subject is asked whether the card displayed in the center of the screen is the same as the card 
presented immediately previously. The subject responds by pressing the Yes or No key. Because no card has been 
presented yet on the first trial, a correct first response is always No. The software records the mean reaction time 
(log10 ms). 
Duration of Test: 3 minutes 
 
Groton Maze Learning Test (GML; Executive Function) 
The Groton Maze Learning test is a measure of problem solving and reasoning and uses a well-validated maze 
learning paradigm.  In this test, the subject is shown a 10 x 10 grid of boxes on a computer screen. A 28-step pathway 
is hidden among these 100 possible locations. Each box represents move locations, and the grid refers to the box 
array (i.e., 10 × 10). Subjects are required to find the hidden pathway guided by [four] search rules. These rules are: do 
not move diagonally, do not move more than one box (i.e., do not jump), do not move back on the pathway, and return 
to the last correct location after an error. At each step only the most recently selected box is shown. Feedback is given 
with visual and auditory cues (green check marks and red crosses) to indicate whether the selected box is correct or 
incorrect. The head of path, or the last correct location, flashes with a green check when two errors are made in 
succession to indicate to the subject that they must return to this location. There are [20] well-matched alternate 
pathways available. The software records counts of total errors made across all learning trials. 
Duration of Test: 5 minutes 
 
Hopkins Verbal Learning Test-Revised (HVLT-R) 
 
The HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. Administration includes 3 
learning trials, a delayed recall (20-minute) trial, and a 24-word recognition list (including 12 target and 12 foil words) 
(Benedict et al., 1998). The test administrator reads instructions and word lists aloud, and records words 
recalled/recognized by the subject. Scores include learning, delayed recall, and recognition. The HVLT-R is a well-
validated and widely used measure of verbal episodic memory. 
 
The tests will be administered in the following order: HVLT-R, computerized cognitive test battery, and HVLT-R 
Delayed. 
 
Although each of the Cogstate computerized cognitive tests yields multiple outcome measures, research by Cogstate 
has identified a set of measures that are optimal for the detection of cognitive change in clinical trials at both the group 
and individual level (Falleti et al., 2006; Maruff et al., 2009; Bland & Altman, 1996a; Bland & Altman, 1996b).    
 
For each Cogstate computerized cognitive test, a single primary outcome measure was selected prior to data analysis 
from each test in the battery to minimize experiment-wise error rates. Each primary outcome measure was selected 
because it has been shown to be optimal for the detection of change because:  
 
a) It is drawn from a data distribution that contains only a small probability of floor or ceiling effects and no 
restriction in the range of possible performance values (Falleti et al., 2006; Bland & Altman, 1996a; Bland & 
Altman, 1996b). 
b) It is drawn from a normal distribution or a distribution which can be corrected to normal through the use of 
appropriate mathematical transformation (e.g., logarithmic base 10, or arcsine) (Falleti et al., 2006; Bland & 
Altman, 1996a; Bland & Altman, 1996b). 
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Table 2 below summarizes the outcome measures for the Cogstate computerized battery and HVLT-R, with the tests 
from which they were derived, the operational definition, and the variable code. 
 
Table 2: Cogstate and HVLT-R Tests Administered in Study 54135419TRD3008, the Cognitive Domains they 
Assess, and their Primary Outcome Measures 
Test Type 
Test 
Cognitive Domain 
Assessed 
Primary Outcome 
Measure 
Interpretation of 
Primary Outcome 
Score 
Cogstate Battery 
Detection Test (DET) 
Psychomotor 
Function 
Speed of 
performance; mean 
of the log10 
transformed reaction 
times for correct 
responses 
Lower score = better 
performance 
Identification Test 
(IDN) 
Attention 
Speed of 
performance; mean 
of the log10 
transformed reaction 
times for correct 
responses 
Lower score = better 
performance 
One Card Learning 
Test (OCL) 
 
Visual Learning 
Accuracy of 
performance; arcsine 
transformation of the 
square root of the 
proportion of correct 
responses 
Higher score = better 
performance 
One Back Test 
(ONB) 
Working Memory 
Speed of 
performance; mean 
of the log10 
transformed reaction 
times for correct 
responses 
Lower score = better 
performance 
Groton Maze 
Learning Test (GML) 
Executive Function 
Total number of 
errors made while 
attempting to learn 
the same hidden 
pathway across the 
consecutive learning 
trials performed at a 
single assessment 
Lower score = better 
performance 
HVLT-R  
Total Recall 
Verbal Learning 
Total number of 
words recalled 
across trials 1-3 
Higher score = better 
performance 
Delayed Recall 
Delayed Verbal 
Memory 
Total number of 
words recalled after 
a 20-minute delay 
Higher score = better 
performance 
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Test Type 
Test 
Cognitive Domain 
Assessed 
Primary Outcome 
Measure 
Interpretation of 
Primary Outcome 
Score 
True Positives 
Recognition Memory 
Total number of true 
positives (words 
recognized) after a 
20-minute delay 
Higher score = better 
performance 
Recognition 
Discrimination Index 
Recognition Memory 
Total number of true 
positives (words 
recognized) minus 
total number of false 
positives after a 20-
minute delay 
Higher score = better 
performance 
10.4. 
The Reliable Change Index (RCI): Comparison of Individual Scores to Baseline 
To evaluate the magnitude of change for individual subjects relative to expected variation over repeated assessments, 
Reliable Change Index (RCI) scores are calculated for each test. The equation is as follows: 
ܴܥܫଶൌሺݔଶെݔଵሻכ ܯݑ݈ݐ݅݌݈݅ܿܽ݊݀
ߪଵכ ඥʹሺͳ െݎሻ
 
Where: 
x 
x2 = subject’s current score 
x 
x1 = subject’s baseline 
x 
σ1 = Standard Deviation of the age-matched normative sample  
x 
r = normative test-retest reliability 
 
As RCI scores will only be computed for the DET and IDN tests, the multiplicand will equal -1 as a lower score on these 
tests is indicative of better cognitive performance. 
 
Clinically meaningful change occurs when the RCI scores are less than or equal to -1.65. This threshold was chosen 
based on existing literature which states that an RCI score—an established measure of meaningful cognitive change—
of ≤ -1.65 is often considered significant at a 90% confidence level (Hinton-Bayre, 2010). 
11. 
Data Quality Assurance 
Cogstate Computerized Tests 
Data from the Cogstate Battery will be collected on computers at sites and uploaded to the Cogstate database for 
processing. Cogstate data management staff will query any data discrepancies. Queries will be confirmed and resolved 
with the sponsor. 
 
HVLT-R 
Before raters can administer the test to subjects, they are required to become certified as an HVLT-R rater by 
completing online training requirements (i.e., didactic training video and a demonstration video showing proper 
administration of the HVLT-R) and successfully complete an audio recorded HVLT-R practice/assessment 
administration. After viewing the online training videos, the rater is instructed to practice the administration of the 
HVLT-R several times to become proficient in the procedures before audio recording the final practice administration 
and submitting it to Cogstate for review. A neuropsychologist at Cogstate then evaluates the completed source 
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document and audio recording from the final practice administration and issues corrective feedback, if necessary. 
During the study, Cogstate monitors the HVLT-R data for clinically unusual patterns in test performance data, including 
test scores outside the expected range for the study population based on published data at any given timepoint or 
unusual score changes from one timepoint to the next, which may be indicative of an error made by the rater when 
deriving one or more of the scores for the test. The Cogstate Data Management team notifies the site if there are any 
outliers or other unusual values identified in the data, so that the rater can confirm that the obtained values were 
derived correctly or make any changes to the data if any errors had been made. 
11.1. 
Test Completion Criteria 
For each of the Cogstate tests, subjects must provide sufficient responses to allow computation of reliable performance 
measures. For the majority of Cogstate tests, the term “sufficient” has been defined as a Test Completion criterion. The 
number of trials required for Test Completion is unique to each test. They do not vary for different patient groups or 
study samples. 
 
The completion criteria set forth a priori for each test were as follows: 
 
Adult Tests:  
x 
DET: The number of responses provided by the subject is ≥ 75% of the desired number of trials (responses ≥ 
27) 
x 
IDN: The number of responses provided by the subject is ≥ 75% of the desired number of trials (responses ≥ 
23) 
x 
OCL: 75% of the desired number of trials were displayed to the subject (trials ≥ 60) 
x 
ONB: The number of responses provided by the subject is ≥ 75% of the desired number of trials (responses ≥ 
24) 
x 
GML: The subject provided 28 correct moves in each of the 5 learning trials 
12. 
Statistical Methodology 
12.1. 
Analysis Overview  
Cogstate is responsible for reporting the results from the Cogstate Battery and HVLT-R tests to assess the safety and 
tolerability of intranasal esketamine in subjects with TRD, with special attention to potential long-term effects on 
cognitive function.  
 
A subject listing including scores and change from baseline scores on each test will also be generated. 
 
All analyses will be done in SAS (v9.4). 
 
Mock shells of the tables, listings, and figures will be provided in a supplementary document. 
 
 
 
 
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12.2. 
Analysis of Cogstate Computerized Battery and HVLT-R 
12.2.1. 
Primary Analyses 
Note: For both comparisons of interest (i.e., against First Baseline and Study Baseline), all analyses summarized in 
this section will be conducted for all subjects as well as by age group (i.e., <65 years old and ≥ 65 years old). 
 
Score and change from baseline scores for the Cogstate Battery and HVLT-R tests will be tabulated descriptively (n, 
mean, median, SD, min, max) by timepoint across the induction phase and optimization/maintenance phases. Intra-
subject standard deviation, which is the standard deviation across all log10 transformed reaction times for correct 
responses made within a given test administration, will also be summarized across timepoints for the Detection and 
Identification tests. 
 
Line plots will be generated for the Cogstate Battery and HVLT-R tests, reflecting the Mean (+/-SE) of the scores at 
each timepoint for each dose level.  
12.2.2. 
Exploratory Analyses 
Note: For both comparisons of interest (i.e., against First Baseline and Study Baseline), all analyses summarized in 
this section will be conducted for the Detection and Identification tests in the ≥ 65 years old age group. 
 
The exploratory analyses that will be conducted are as follows: 
x 
Spaghetti plots reflecting RCI scores across timepoints including each subject  
x 
Line plots evaluating the relationship between the changes in RT and the clinical/treatment parameters listed 
below. Note: these plots will be generated by Janssen. 
o 
Age at Diagnosis 
o 
Duration of Current Depressive Episode 
o 
Concomitant Benzodiazepine Use 
o 
Modal Esketamine Dose in OP/MA 
o 
Baseline MADRS Total Score 
o 
Baseline PHQ-9 Total Score 
o 
Total MADRS Score Over Time  
o 
Total PHQ-9 Score Over Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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STAT001-TMP-001, V4 
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13. 
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Maruff, P., Thomas, E., Cysique, L., Brew, B., Collie, A., Snyder, P., & Pietrzak, R. H. (2009). Validity of the CogState 
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