A Randomized, Double-blind, Multicenter, Active-Controlled Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Treatment-resistant Depression
Phase: PHASE3
Conditions: Depressive Disorder, Treatment-Resistant
Sponsor: Janssen Research & Development, LLC

1
Status: Approved, Date: 4 April 2017
Janssen Research & Development*
Clinical Protocol
A Randomized, Double-blind, Multicenter, Active-controlled Study of Intranasal 
Esketamine Plus an Oral Antidepressant for Relapse Prevention in Treatment-resistant 
Depression
Sustenance of Esketamine Treatment Response With Repeated Doses at Intervals Determined by 
Symptom Severity (SUSTAIN-1)
Protocol ESKETINTRD3003; 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: 2014-004586-24
Status:
Approved
Date:
4 April 2017
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-93094733, 5.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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Clinical Protocol ESKETINTRD3003 Amendment 4
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Status: Approved, Date: 4 April 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
PROTOCOL AMENDMENTS....................................................................................................................... 7
SYNOPSIS.................................................................................................................................................. 35
TIME AND EVENTS SCHEDULE (Screening/Prospective Observational Phase and Open-
label Induction Phase).............................................................................................................................. 49
TIME AND EVENTS SCHEDULE (Optimization Phase) ......................................................................... 53
TIME AND EVENTS SCHEDULE (Maintenance Phase) ......................................................................... 57
TIME AND EVENTS SCHEDULE (Early Withdrawal/End of Maintenance Phase Visit and 
Follow-up Phase) ...................................................................................................................................... 61
ABBREVIATIONS ...................................................................................................................................... 63
1.
INTRODUCTION................................................................................................................................ 65
1.1.
Background .................................................................................................................................... 66
1.1.1.
Summary of Nonclinical Findings ............................................................................................... 66
1.1.2.
Clinical Studies ........................................................................................................................... 69
1.1.2.1.
Pharmacokinetics and Product Metabolism ............................................................................ 69
1.1.2.2.
Pharmacodynamics and Efficacy ............................................................................................ 71
1.1.2.3.
Safety and Tolerability............................................................................................................. 72
1.1.3.
Marketing Experience................................................................................................................. 76
1.2.
Active Comparators........................................................................................................................ 76
1.2.1.
Selective Serotonin Reuptake Inhibitors..................................................................................... 76
1.2.1.1.
Escitalopram............................................................................................................................ 76
1.2.1.2.
Sertraline ................................................................................................................................. 77
1.2.2.
Serotonin and Norepinephrine Reuptake Inhibitors ................................................................... 77
1.2.2.1.
Duloxetine................................................................................................................................ 77
1.2.2.2.
Venlafaxine Extended-release................................................................................................. 78
1.3.
Overall Rationale for the Study...................................................................................................... 79
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 80
2.1.
Objectives ...................................................................................................................................... 80
2.2.
Hypothesis ..................................................................................................................................... 81
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 81
3.1.
Overview of Study Design.............................................................................................................. 81
3.1.1.
Study Phases.............................................................................................................................. 82
3.1.2.
Definitions of Terms.................................................................................................................... 86
3.2.
Study Design Rationale.................................................................................................................. 87
3.2.1.
Study Population......................................................................................................................... 87
3.2.2.
Study Phases.............................................................................................................................. 89
3.2.3.
Blinding and Randomization....................................................................................................... 90
3.2.4.
Treatment Groups and Dose Selection ...................................................................................... 91
3.2.4.1.
Intranasal Study Drug.............................................................................................................. 91
3.2.4.2.
Oral Antidepressant................................................................................................................. 92
3.2.5.
Efficacy Measures ...................................................................................................................... 93
3.2.6.
Safety Evaluations...................................................................................................................... 94
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3.2.7.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations .............................. 95
3.2.8.
Other Assessments .................................................................................................................... 96
3.2.9.
Medical Resource Utilization Data Collection............................................................................. 96
4.
SUBJECT POPULATION.................................................................................................................. 97
4.1.
Inclusion Criteria ............................................................................................................................ 97
4.1.1.
Direct-entry Subjects .................................................................................................................. 97
4.1.2.
Transferred-entry Subjects ....................................................................................................... 100
4.1.3.
Direct-entry Subjects and Transferred-entry Subjects ............................................................. 100
4.2.
Exclusion Criteria ......................................................................................................................... 101
4.2.1.
Direct-entry Subjects ................................................................................................................ 101
4.2.2.
Transferred-entry Subjects ....................................................................................................... 105
4.3.
Prohibitions and Restrictions ....................................................................................................... 106
5.
TREATMENT ALLOCATION AND BLINDING............................................................................... 107
6.
DOSAGE AND ADMINISTRATION ................................................................................................ 109
6.1.
Intranasal Study Drug .................................................................................................................. 109
6.1.1.
Open-label Induction Phase ..................................................................................................... 110
6.1.2.
Optimization Phase................................................................................................................... 111
6.1.2.1.
Transferred-entry Subjects.................................................................................................... 111
6.1.2.2.
Direct-entry Subjects ............................................................................................................. 111
6.1.2.3.
Intranasal Treatment Session Frequency (All Subjects)....................................................... 111
6.1.3.
Maintenance Phase.................................................................................................................. 113
6.1.4.
Follow-up Phase....................................................................................................................... 114
6.2.
Oral Antidepressants.................................................................................................................... 115
6.2.1.
Screening/Prospective Observational Phase (Direct-entry Subjects Only).............................. 115
6.2.2.
Open-label Induction Phase (Direct-entry Subjects Only)........................................................ 115
6.2.3.
Optimization and Maintenance Phases (Direct-entry and Transferred-entry Subjects)........... 116
6.2.4.
Follow-up Phase....................................................................................................................... 116
7.
TREATMENT COMPLIANCE.......................................................................................................... 117
8.
PRESTUDY AND CONCOMITANT THERAPY .............................................................................. 117
9.
STUDY EVALUATIONS .................................................................................................................. 119
9.1.
Study Procedures......................................................................................................................... 119
9.1.1.
Overview................................................................................................................................... 119
9.1.2.
Screening/Prospective Observational Phase ........................................................................... 121
9.1.3.
Open-label Induction Phase ..................................................................................................... 122
9.1.4.
Optimization Phase................................................................................................................... 123
9.1.5.
Maintenance Phase.................................................................................................................. 124
9.1.6.
Early Withdrawal/End of Maintenance Phase .......................................................................... 124
9.1.7.
Follow-up Phase....................................................................................................................... 125
9.2.
Efficacy......................................................................................................................................... 126
9.2.1.
Evaluations ............................................................................................................................... 126
9.2.1.1.
Primary Efficacy Evaluation: Montgomery-Asberg Depression Rating Scale (MADRS)....... 126
9.2.1.2.
Clinical Global Impression - Severity (CGI-S) ....................................................................... 126
9.2.1.3.
Patient Health Questionnaire, 9-Item (PHQ-9)...................................................................... 126
9.2.1.4.
Generalized Anxiety Disorder, 7-item (GAD-7) ..................................................................... 127
9.2.1.5.
European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level (EQ-5D-5L) .................... 127
9.2.1.6.
Sheehan Disability Scale (SDS)............................................................................................ 127
9.2.2.
Endpoints.................................................................................................................................. 127
9.3.
Medical Resource Utilization........................................................................................................ 128
9.4.
Safety Evaluations ....................................................................................................................... 128
9.5.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations................................ 136
9.6.
Other Evaluations......................................................................................................................... 137
9.7.
Sample Collection and Handling.................................................................................................. 139
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10.
SUBJECT COMPLETION/WITHDRAWAL..................................................................................... 139
10.1.
Criteria for Completion ................................................................................................................. 139
10.2.
Withdrawal From the Study.......................................................................................................... 139
10.3.
Withdrawal From the Use of Samples in Future Research.......................................................... 141
11.
STATISTICAL METHODS............................................................................................................... 141
11.1.
Subject Information ...................................................................................................................... 142
11.2.
Sample Size Determination ......................................................................................................... 142
11.3.
Efficacy Analyses ......................................................................................................................... 143
11.4.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Analyses.................................... 144
11.5.
Medical Resource Utilization Analyses........................................................................................ 144
11.6.
Safety Analyses ........................................................................................................................... 144
11.7.
Interim Analysis............................................................................................................................ 146
11.8.
Independent Data Monitoring Committee .................................................................................... 146
12.
ADVERSE EVENT REPORTING .................................................................................................... 147
12.1.
Definitions .................................................................................................................................... 147
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 147
12.1.2.
Attribution Definitions................................................................................................................ 148
12.1.3.
Severity Criteria ........................................................................................................................ 149
12.2.
Special Reporting Situations........................................................................................................ 149
12.3.
Procedures................................................................................................................................... 149
12.3.1.
All Adverse Events.................................................................................................................... 149
12.3.2.
Serious Adverse Events ........................................................................................................... 150
12.3.3.
Pregnancy................................................................................................................................. 151
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 152
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 152
13.1.
Procedures................................................................................................................................... 152
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 152
14.
STUDY DRUG INFORMATION....................................................................................................... 152
14.1.
Physical Description of Study Drugs............................................................................................ 152
14.2.
Packaging .................................................................................................................................... 153
14.3.
Labeling........................................................................................................................................ 154
14.4.
Preparation, Handling, and Storage............................................................................................. 154
14.5.
Drug Accountability ...................................................................................................................... 154
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 155
16.
ETHICAL ASPECTS ....................................................................................................................... 156
16.1.
Study-specific Design Considerations ......................................................................................... 156
16.2.
Regulatory Ethics Compliance..................................................................................................... 158
16.2.1.
Investigator Responsibilities ..................................................................................................... 158
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 158
16.2.3.
Informed Consent ..................................................................................................................... 160
16.2.4.
Privacy of Personal Data .......................................................................................................... 161
16.2.5.
Long-term Retention of Samples for Additional Future Research............................................ 161
16.2.6.
Country Selection ..................................................................................................................... 162
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 162
17.1.
Protocol Amendments.................................................................................................................. 162
17.2.
Regulatory Documentation .......................................................................................................... 162
17.2.1.
Regulatory Approval/Notification .............................................................................................. 162
17.2.2.
Required Prestudy Documentation........................................................................................... 162
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 163
17.4.
Source Documentation................................................................................................................. 163
17.5.
Case Report Form Completion .................................................................................................... 164
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 165
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17.7.
Record Retention ......................................................................................................................... 165
17.8.
Monitoring .................................................................................................................................... 166
17.9.
Study Completion/Termination..................................................................................................... 166
17.9.1.
Study Completion ..................................................................................................................... 166
17.9.2.
Study Termination..................................................................................................................... 166
17.10.
On-Site Audits .............................................................................................................................. 167
17.11.
Use of Information and Publication.............................................................................................. 167
REFERENCES.......................................................................................................................................... 169
ATTACHMENTS....................................................................................................................................... 176
INVESTIGATOR AGREEMENT ............................................................................................................... 183
LIST OF ATTACHMENTS
Attachment 1:
Prohibited Concomitant Medications With Intranasal Study Medication 
(Esketamine or Placebo) .......................................................................................... 176
Attachment 2:
New York Heart Association Classification of Cardiac Disease............................... 179
Attachment 3:
Oral Antidepressant Titration Schedules for Open-label Induction Phase............... 180
Attachment 4:
Anticipated Events.................................................................................................... 181
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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Intranasal Esketamine Treatment Sessions: Open-label Induction Phase ............................ 111
Table 2:
Intranasal Esketamine Treatment Sessions: Optimization Phase (Direct entry 
Subjects) ................................................................................................................................. 112
Table 3:
Intranasal Esketamine or Placebo Treatment Sessions: Optimization Phase 
(Transferred-entry Subjects)................................................................................................... 113
Table 4:
Intranasal Esketamine or Placebo Treatment Sessions: Maintenance Phase....................... 114
Table 5:
Volume of Blood to Be Collected From Each Subject ............................................................ 120
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 86
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Status: Approved, Date: 4 April 2017
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
26 March 2015
Amendment INT-1
21 April 2015
Amendment 2
13 January 2016
Amendment 3
9 June 2016
Amendment 4
4 April 2017
Amendments below are listed beginning with the most recent amendment.
Amendment 4 (4 April 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: In order to enhance the number of clinically valid subjects proceeding to 
the Maintenance phase as stable remitters, the stable remission criteria have been revised.
Applicable Section(s)
Description of Change(s)
Rationale: The justification for allowing a single excursion of the MADRS total score or one missed MADRS 
assessment was made on the basis that it could be due to a life event and not the underlying illness, eg, having a bad 
day, difficulty in a family relationship, a setback at work or school, or a scheduling conflict.
Synopsis: Overview of Study Design, 
Definitions of Terms;
3.1.2. Definitions of Terms:
Optimization Phase
The definition of stable remission was modified (bold text added;
strikethrough text deleted):

Remission: MADRS total score 12

Stable remission: 

MADRS total score ≤12 for the last 4 weeks of the optimization 
phase 

MADRS total score ≤12 for at least 3 of the last 4 weeks of the 
optimization phase, but one excursion of a MADRS total score 
>12 or one missing MADRS assessment is permitted at 
Optimization week 13 or 14 only. The MADRS total score at 
weeks 15 and 16 must be ≤12.
3.2.2. Study Phases: Optimization 
Phase
For the primary analysis, a subject must be in stable remission (MADRS 
total score 12 for 4 consecutive weeks) for the last 4 weeks of this phase 
(see full definition, section 3.1.2) to enter the maintenance phase. 
Rationale: The definition of stable response was modified, as there is no longer a requirement to have a MADRS 
score of >12 at one of the last 2 weeks of the Optimization phase.
Synopsis: Overview of Study Design, 
Definitions of Terms;
3.1.2. Definitions of Terms:
Optimization Phase
The definition of stable response was modified as follows (bold text 
added; strikethrough text deleted):
Stable response: 50% reduction in the MADRS total score from baseline 
(Day 1 of induction phase; pre-randomization/prior to the first intranasal 
dose) in each of the last 2 weeks of the optimization phase, but does not 
meet criteria for stable remission. with at least 1 MADRS total score of 
>12 in these 2 weeks. Note: For transferred-entry subjects, Day 1 of the 
open-label induction phase will take place in ESKETINTRD3001 or 
ESKETINTRD3002.
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Applicable Section(s)
Description of Change(s)
3.2.2. Study Phases: Optimization 
Phase
Subjects with stable response (50% reduction in the MADRS total score 
from baseline [Day 1 of induction phase; pre-randomization/prior to the 
first intranasal dose]) in each of the last 2 weeks of the optimization phase 
with at least 1 MADRS total score of >12 in these 2 weeks but who do are 
not meet criteria for in stable remission, will also enter the maintenance 
phase, but will not be part of the primary analysis.
Rationale: Missing MADRS assessments during Weeks 5 to 12 of the Optimization phase will no longer be 
considered in determining subject’s eligibility to participate in the maintenance phase of the study. This 
modification has been made to reduce the impact of missing MADRS assessments, given the lengthiness of the trial
and need for weekly assessments. The justification for removing this criterion is made on the basis that, in general, 
rather than indicating poor compliance to study procedure, missing assessments may often be due to a family 
emergency or illness, vacation or travel plans, or change in work or school schedule. In order to enhance the number 
of clinically valid subjects proceeding to the Maintenance phase, the criterion has been removed.
Synopsis: Dosage and Administration,
Optimization phase;
6.1.2.3. Intranasal Treatment Session 
Frequency: All Subjects
The following text was modified (strikethrough text deleted):
Missed MADRS Assessments:

If 3 MADRS assessments are missed during the first 8 weeks of the 
optimization phase (Week 5 to Week 12), the subject can complete the 
optimization phase but is not eligible to participate in the maintenance 
phase.
9.1.4. Optimization Phase; 10.2. 
Withdrawal From the Study
A subject will not be eligible to proceed into the maintenance phase if he 
or she:

Misses 21 days of the oral antidepressant doses (total daily dose) 

Misses 3 MADRS assessments in the first 8 weeks (Weeks 5 to 12)
Rationale: Clarification that subjects in the Optimization phase at the time study closes are not required to complete 
the Optimization phase.
Synopsis: Optimization Phase; 3.1.1.
Study Phases: Optimization Phase
The following text was modified (bold text added;strikethrough text 
deleted):
At the time the study is stopped (for efficacy), subjects in the optimization 
phase will be able to complete the phase. After completing the phase, 
these subjects will have an Early Withdrawal Visit conducted and proceed 
directly to the follow-up phase.
10.1. Criteria for Completion
Subjects in the Screening Prospective Observational phase at the time 
of study termination may be eligible to proceed to the
54135419TRD3008 study.  
Subjects in the induction or optimization phase of the study at the time of 
study termination will be allowed to complete their current induction
phase, will complete an Early Withdrawal Visit, and continue into the 
follow up phase but will not be considered completers.
These subjects, after completing the Early Withdrawal visit, may 
proceed to the 54135419TRD3008 study, but will not be considered 
completers for this study. Subjects in the optimization phase at time of 
study termination will not need to complete this phase, and will 
complete an Early Withdrawal Visit, and continue into the follow up 
phase, but they will not be considered completers.
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Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Rationale: Clarification for subjects in different phases of the study at the time study is stopped (for efficacy) 
regarding whether they will complete their current phase.
Synopsis: Overview of Study Design; 
3.1.1. Study Phases; 16.1. Study-
specific Design Considerations
The following text was modified (bold text added; strikethrough text 
deleted):
The study will be stopped once 84 relapses (in the subjects with stable 
remission) occur during the maintenance phase, or earlier, based on the 
results of the interim analysis for efficacy or futility. At the time the study 
is stopped (for efficacy), subjects in the induction phase or optimization 
phase will be able to complete the Inductionrespective phase. 
Those subjects who are responders after completing an Early 
Withdrawal Visit may proceed to the 54135419TRD3008 study 
without completing the follow up phase. Those who are not 
responders will have an Early Withdrawal Visit and proceed directly 
to the follow-up phase. After completing the respective phase, these 
subjects and Ssubjects who are in the optimization or maintenance phase 
at the time the study is terminated will have an Early Withdrawal
Visit/End of Maintenance Visit conducted and proceed directly to the 
follow-up phase.
Synopsis: Open-label Induction Phase;
3.1.1. Study Phases: Open-label 
Induction Phase
At the time the study is stopped (for efficacy), subjects in the induction 
phase will be able to complete the phase.
Those who are responders, after completing an Early Withdrawal 
Visit, may proceed to the 54135419TRD3008 study without 
completing the follow up phase. Those who are not responders After 
completing the phase, these subjects will have an Early Withdrawal Visit 
conducted and proceed directly to the follow-up phase.
Rationale: To allow earlier access to open label esketamine treatment, subjects who relapse in the Maintenance 
phase and those who are responders at the end of induction at the time the study is stopped, will be allowed to
proceed to the open-label safety extension study, 54135419TRD3008, without completing the follow up phase (if 
clinically indicated).
Synopsis: Follow-up Phase;
Time and Events Schedule (Early 
Withdrawal/End of Maintenance 
Phase Visit and Follow-up Phase)
footnote a; 3.1.1. Study Phases:
Follow-up Phase;
9.1.6. Early Withdrawal/End of 
Maintenance Phase; 9.1.7. Follow-up 
Phase;
The following text was modified (bold text added; strikethrough text 
deleted):
This phase will include all subjects who have received at least 1 dose of 
intranasal study medication in this study. For those subjects who relapse 
in the Maintenance phase, if clinically indicated based on 
investigator’s judgment, after completing the end of maintenance 
visit, the subject may proceed to the open-label safety extension study, 
54135419TRD3008, without completing the follow up phase. 
Similarly, when the study is stopped, (for efficacy) subjects in the 
Induction phase who are responders, after completing the early 
withdrawal visit, if clinically indicated based on the investigator’s 
judgment, may proceed to the 54135419TRD3008 study, without 
completing the follow up phase.
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Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Synopsis: Maintenance Phase;
3.1.1. Study Phases: Maintenance 
phase
The following text was modified (bold text added; strikethrough text 
deleted):
Subjects who meet the relapse criteria and subjects who remain relapse-
free at study termination will have an End of Maintenance Phase Visit 
conducted and may proceed to the follow-up phase. If clinically 
indicated, subjects who have met relapse criteria after completing the 
End of Maintenance visit may proceed to the open-label safety 
extension study, 54135419TRD3008, without completing the follow up 
phase. Subjects who are participating in the maintenance phase at the time 
the study is stopped (for efficacy) will have an Early Withdrawal Visit 
conducted and proceed directly to the follow-up phase.
9.1.6. Early Withdrawal/End of 
Maintenance Phase; 
The following text was modified (bold text added): 
A subject meeting relapse criteria during the maintenance phase is not 
considered an early withdrawal. These subjects, and subjects in the 
maintenance phase who remain relapse-free at study termination, will have 
an End of Maintenance Phase Visit conducted, followed by the follow up 
phase. If clinically indicated, subjects who relapse in the Maintenance 
phase may proceed to the open-label safety extension study, 
54135419TRD3008, without completing the follow up phase.
10.2. Withdrawal from Study
The following text was modified (bold text added; strike through text 
deleted): 
A subject meeting relapse criteria during the maintenance phase is not 
considered an early withdrawal. If clinically indicated, after completing 
the End of Maintenance visit, subjects who have met relapse criteria 
may proceed to the open-label safety extension study, 
54135419TRD3008, without completing the follow up phase. For these 
subjects, and Subjects who remain relapse-free at study termination, will 
have an End of Maintenance Phase Visit conducted, followed by the 
follow-up phase.
Rationale: Early termination of the maintenance phase for futility, based on interim analysis results, is no longer 
applicable, because these results could indicate that once subjects become stable remitters on esketamine, the 
intranasal placebo plus oral antidepressant arm can be as good or potentially better at maintaining response as 
intranasal esketamine + oral antidepressant arm. This potential outcome is not a negative outcome, but rather may 
inform how to use esketamine in long term. As such, the study would not be considered futile.
Synopsis: Overview of Study Design,
Synopsis: Statistical Methods, Interim 
Analysis; 
3.1.1. Study Phases; 11.3. Efficacy 
Analyses;
11.7. Interim Analysis;
11.8. Independent Data Monitoring 
Committee;
16.1. Study-specific Design 
Considerations
Clarified that the results of the interim analysis would no longer be used to 
stop the study due to futility; the results could only indicate stopping due 
to efficacy (ie, futility was deleted).
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Applicable Section(s)
Description of Change(s)
Rationale: Clarification on Dosage and Administration of Intranasal Study Drug. Dose adjustment will be permitted 
on Days 15, 18, and 22 to allow more time for dosing to be optimized based on efficacy and tolerability
Synopsis: Dosage and Administration:
Open-label Induction Phase;
6.1.1. Open-label Induction Phase
Modified the following text (bold text added; strikethrough text deleted):
On Day 1, subjects will start with a dose of 56 mg. On Day 4, the dose 
may be increased to 84 mg or remain at 56 mg, as determined by the 
investigator based on efficacy and tolerability. On Day 8, the dose may be 
increased to 84 mg (if Day 4 dose was 56 mg), remain the same, or be 
reduced to 56 mg (if Day 4 dose was 84 mg), as determined by the 
investigator based on efficacy and tolerability. Similarly, on Days 11, 15, 
18, and 22, the dose may be increased to 84 mg (if Day 8 dose was 56 
mg), remain the same, or be reduced to 56 mg (if Day 8 dose was 84 mg), 
if applicable as determined by the investigator based on efficacy and 
tolerability. On Day 15, a dose reduction from 84 mg to 56 mg is 
permitted, if required for tolerability; no dose increase is permitted on 
Day 15. On Days 18, 22, and 25, a dose reduction from 84 mg to 56 mg 
is permitted if required for tolerability; no dose increase is permitted.
the dose must remain stable (unchanged). If there is no intranasal 
treatment session on Day 15 (eg, visit is missed), a dose reduction from 84 
mg to 56 mg is permitted on Day 18 if required for tolerability; no dose 
increase is permitted.
Rationale: Added information about 54135419TRD3008, an open-label safety extension study, that may be 
available for eligible subjects participating in ESKETINTRD3003.
Synopsis: Follow-up Phase; 3.1.1. 
Study Phases: Follow-up Phase; 9.1.7. 
Follow-up Phase
The following text was modified (bold text added; strikethrough text 
deleted):
An open-label safety extension study, 54135419TRD3008, may be 
available (pending country and site approval) for eligible subjects 
participating in the ESKETINTRD3003 study. Please refer to the 
54135419TRD3008 protocol for full details when available of potential 
pathways for entry.
Rationale: Restrictions for Day 28 of the Induction phase and visit 3.1 of the Optimization phase were relaxed to 
allow for some flexibility.
Time and Events Schedule 
(Optimization Phase, footnote b);
9.1.3. Open-label Induction Phase;
9.1.4. Optimization Phase
The following text was modified (bold text added; strikethrough text 
deleted):
Results for all assessments performed on Day 28 of the induction phase 
for direct-entry subjects (Visit 2.9) and transferred-entry subjects (Visit 
2.10 of Study ESKETINTRD3001 or ESKETINTRD3002) will serve as 
the baseline values for the optimization phase and will not be repeated as 
part of Visit 3.1. The Day 28 visit should must coincide exactly with Day 
28 (Visit 3.1) for this study. There is no gap allowed between studies. All 
transferred-entry subjects must meet all of the transferred-entry subject-
specific inclusion criteria and none of the exclusion criteria in order to be 
enrolled.
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
12
Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Rationale: Clarified the approach for collection of duplicate assessments during Optimization Phase and 
Maintenance Phase.
Time and Events Schedule
(Optimization Phase, footnote a);
The following text was modified (bold text added):
If a subject withdraws before the end of the optimization phase for reasons
other than withdrawal of consent, or is not eligible to continue into the 
maintenance phase, an Early Withdrawal Visit (Refer to Time and Events 
Schedule: Early Withdrawal/End of Maintenance Phase Visit and follow 
up phase) should be conducted. If the Early Withdrawal Visit is 
conducted on the same day as a scheduled visit, duplicate assessments 
are not required.
Time and Events Schedule 
(Maintenance Phase, footnote b)
If a subject withdraws before the end of the maintenance phase for reasons 
other than withdrawal of consent, an Early Withdrawal Visit should be 
conducted. A subject meeting relapse criteria is not considered to be an 
early withdrawal subject; for relapse subjects, and those subjects 
remaining relapse-free at the time of study termination, an End of 
Maintenance Phase Visit should be conducted. If the End of 
Maintenance Visit is conducted on the same day as a scheduled visit, 
duplicate assessments are not required. Refer to the Time and Events 
Schedule: Early Withdrawal/End of Maintenance Phase Visit and Follow-
up Phase. 
Rationale: Given the potential to cause increased sedation and potential impact on efficacy, benzodiazepine rescue 
medication is permitted only post-dose on the dosing day.
3.1.1. Study Phases: Open-label 
Induction Phase; 4.3. Prohibitions and 
Restrictions; 9.1.2. 
Screening/Prospective Observational 
Phase
The following text was modified (bold text added):
No dose increases beyond the equivalent of 6 mg/day of lorazepam, or 
new benzodiazepine medications are permitted during the induction phase, 
with the exception of the use of permitted benzodiazepine rescue 
medication (post-dose on the dosing day only). 
8. Prestudy and Concomitant Therapy
For agitation or anxiety: As required, midazolam (maximum dose 2.5 mg 
orally or IM) or short acting benzodiazepine (only permitted post-dose 
on the day of dosing).
Rationale: Updated language in Attachment 1 to align with the changes made regarding oral antidepressant 
requirements under INT-3 of 3003. Under that amendment, the dose of oral antidepressant medications can be 
adjusted in the screening/prospective phase.
Attachment 1
The following text was modified (bold text added; strikethrough text 
deleted):
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: If a medication is part of 
the antidepressant treatment regimen being taken at the time of signing the 
ICF (ie, start of screening/prospective observational phase), per protocol, 
the medication is continued it must be continued unchanged until the end 
of Week 4 of the screening/prospective observational phase, therefore this 
requirement is not applicable. In such cases the investigator may choose to 
taper the relevant medication during the up to 3-week taper period based 
on their clinical judgment.
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
13
Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Rationale: As clonidine is considered a safe and effective treatment option for blood pressure elevation, it is now 
permitted as a treatment for blood pressure control in the study.
Attachment 1
Episodic and continuous course of clonidine is now allowed as a treatment 
option for blood pressure control.
The following text was deleted (strikethrough text deleted):
Safety and PD Interaction
The following text was added (bold text added):
Use for blood pressure control is allowed
Episodic Use (As Needed) and Continuous Use were changed from No 
(N) to Yes (Y).
Rationale: (brief course of corticosteroids may be permitted to treat conditions including rash, asthma etc.): The 
Company considered that there is no increased risk in terms of safety or efficacy in allowing a brief course of 
corticosteroids, if clinically indicated, to treat an acute medical condition.
Attachment 1
The following text was added (bold text added):
Intermittent IM/IV/PO corticosteroids are permitted with sponsor 
approval (chronic use prohibited).
Rationale: (allowing brief course of opiates): Company considered that there is no increased risk in terms of safety 
or efficacy in allowing a brief course of opiates, if clinically indicated, to treat pain associated with recent surgery or 
acute injury.
Attachment 1
The following text was added (bold text added):
Note: With Sponsor approval, brief treatment with opiates may be 
allowed for treatment of acute injuries etc.
Rationale: Modafinil and armodafinil are deleted from the psychostimulants row of Attachment 1 (they are no 
longer permitted as psychostimulants) because they are potent CYP 3A4 inducers and therefore should be prohibited 
during the study.
Attachment 1
The following text was modified (strikethrough text deleted):
Psychostimulants 
(eg, amphetamines, methylphenidate, modafinil, armodafinil)
Rationale: Minor grammatical, formatting, and spelling errors were noted
Throughout the document
Minor errors were corrected. Minor formatting changes were made.
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
14
Status: Approved, Date: 4 April 2017
Amendment 3 (9 June 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: Based on feedback received from Investigators involved in the study, the 
subject entry criteria have been revised to improve recruitment.
Applicable Section(s)
Description of Change(s)
Rationale: To improve recruitment, the antidepressant treatment requirements at study entry (ie, time of signing the 
ICF) in inclusion criterion no. 3.1 were changed. In addition, the definition of non-response at the end of the 
screening/prospective observational phase was revised.
4.1.1.  Direct-entry 
Subjects
Inclusion criterion no. 3.1 was revised as follows (bold text added; strikethrough text 
deleted):
At the start of the screening/prospective observational phase, subject must have had non-
response (≤25% improvement) to ≥12 but ≤5 (if current episode is > 2 years, upper limit is
applicable to only the last 2 years) oral antidepressant treatments in the current episode of 
depression, assessed using the MGH-ATRQ and confirmed by documented records (eg, 
medical/pharmacy/prescription records/ or a letter from a treating physician, etc.). In 
addition, the sSubject must be is taking one of thea different oral antidepressant 
treatment(s) with nonresponse that is documented (on the MGH-ATRQ) for at least the 
previous 2 weeks (ie, this oral antidepressant treatment must have been taken for at least 6 
weeks at or above the minimumal therapeutic dose with a lack of clinically meaningful 
improvement) at the start of the screening/prospective observational phase.
-
For specific tricyclic antidepressants which are ongoing and being taken at a 
dose below the MGH-ATRQ minimum therapeutic dose, a blood level that is 
within the therapeutic (antidepressant) range, is acceptable to establish the 
adequacy of the antidepressant treatment.
-
Subjects must have beenbe adherent to the continued oral antidepressant 
treatment medication(s) (without adjustment in dosage) through the 
screening/prospective observational phase, as documented on the PAQ. Missing 
≥4 days of antidepressant medication in the prior 2-week period will be 
considered as inadequate adherence.
-
Subjects who are non-responders to their current oral antidepressant 
medication(s) from the screening/prospective observational phase (as assessed by 
independent, remote raters) may be eligible for randomization if all other entry 
criteria are met. Non-response at the end of the screening/prospective 
observational phase is defined as ≤25% improvement in the MADRS total score 
for 2 consecutive visits from Week 1 to Week 4 and a MADRS total score of 
≥28 for 2 consecutive visits on Week 2 and Week 4.  
Synopsis, Overview 
of Study Design; 
Synopsis, Dosage and 
Administration; 3.1.1. 
Study Phases; 3.2.2. 
Study Phases
Deleted text stating that the antidepressant treatment will continue unchanged at the same 
dosage during the screening/prospective observational phase.
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
15
Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Synopsis, Subject
Population; Synopsis, 
Dosage and 
Administration; 3.1.1.
Study Phases; 3.2.1. 
Study Population; 
6.2.1. 
Screening/Prospective 
Observational Phase; 
9.1.2.
Screening/Prospective 
Observational Phase
Text regarding antidepressant treatment during the screening/prospective observational 
phase was revised as follows (bold text added; strikethrough text deleted):
In addition, the subject isbe taking one of thea different oral antidepressant treatment(s)
with nonresponse (≤25% improvement) that will be documented (on the MGH ATRQ) for 
at least the previous 2 weeks (ie, this oral antidepressant treatment must have been taken
for at least 6 weeks at or above the minimum therapeutic dosewith a lack of clinically 
meaningful improvement). This antidepressant treatment, as well as any other ongoing 
medications being taken for depression (including adjunctive/augmentation therapies), will 
continue unchanged, at the same dosage, from the start of Week 1 through the end of 
Week 4 of the screening/prospective observational phase to confirm non-response 
prospectively. Dose adjustment is permitted per clinical judgment, but the oral 
antidepressant treatment is to remain at or above the minimum therapeutic dose (per 
the MGH-ATRQ) through the end of Week 4.
Synopsis, Subject 
Population; 3.1.1; 
Study Phases; 3.2.1. 
Study Population; 
9.1.2. 
Screening/Prospective 
Observational Phase
Criteria for the minimum number of oral antidepressant treatments in the current episode 
of depression with non-response at the start of the screening/prospective observational 
phase was revised from ≥2 to ≥1.
Synopsis, Overview 
of Study Design; 
Synopsis, Subject 
Population; 3.1. 
Overview of Study 
Design; 3.2.1. Study 
Population; 3.2.2. 
Study Phases; 6.2.1. 
Screening/Prospective 
Observational Phase; 
9.1.2. 
Screening/Prospective 
Observational Phase
Criteria for non-response at the end of the screening/prospective observational phase was 
revised as follows (bold text added; strikethrough text deleted):
Non-response at the end of the screening/prospective observational phase is defined as 
≤25% improvement in the MADRS total score for 2 consecutive visits from Week 1 to 
Week 4 and a MADRS total score of ≥ 28 for 2 consecutive visitson Week 2 and Week 4.
16.1. Study-specific 
Design 
Considerations
Text was revised as follows (bold text added; strikethrough text deleted):
For eligibility, subjects must have had non-response to at least 1 prior antidepressant 
treatment and TRD and be currently taking non-responders to their current an
antidepressant treatment with non-response being observed with at the start of the 
screening/prospective observational phase that will be continued as prospective 
treatment in the screening/prospective observational phase. Only subjects with non-
response to their current antidepressant treatment after 4 weeks of prospectively observed 
treatment (for a total duration of antidepressant treatment of at least 10 6 weeks by the end 
of the screening/prospective observational phase), will be eligible to proceed to the double-
blind induction phase, whenre all subjects will receive a new oral antidepressant in 
addition to intranasal esketamine or placebo.
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
16
Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Rationale: Inclusion criterion no. 11.1 was revised to specify the same requirements for contraception for female 
partners of male subjects as specified for female subjects.
4.1.1. Direct-entry 
Subjects
The text of inclusion criterion no. 11.1 has been changed as follows (bold text added; 
strikethrough text deleted):
During the study (ie, from Day 1 of the double-blind induction phase, prior to 
randomization) 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
-
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). who is sexually active with a 
woman of childbearing potential must 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.
12. 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 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: Exclusion criterion no. 11.1 was revised to delete the exclusion for first degree atrioventricular (AV) 
block, as the analyses of PR intervals from subjects in Phase 1 and Phase 2 esketamine studies showed no impact of 
esketamine on PR interval.
4.2.1. Direct-entry 
Subjects
Exclusion criterion no. 11.1 revised as follows (bold text added; strikethrough text 
deleted):
Subject has clinically significant ECG abnormalities at the start of the 
screening/prospective observational phase or on Day 1 of the open-label induction phase 
prior to randomization, defined as:
-
During screening, a QT interval corrected according to Fridericia’s formula 
(QTcF): ≥450 msec; if the QTcF is prolonged on the initial ECG, the average 
QTcF of three ECG’s, recorded 4 minutes apart, must not be ≥450 msec.
-
On Day 1 (predose), a QT interval corrected according to Fridericia’s formula 
(QTcF): ≥450 msec based on the site-evaluated ECG; if the QTcF is prolonged on 
the initial ECG, the average QTcF of three ECG’s, recorded 4 minutes apart, must 
not be ≥450 msec.
-
Evidence of 2nd and 3rd degree AV block, or 1st degree AV block with PR interval 
>200 msec (may repeat ECG once, and use average of both readings, if the initial 
PR interval is <240 msec), complete left bundle branch block (LBBB), or 
complete right bundle branch block (RBBB). 
-
Features of new ischemia.
Arrhythmia (except premature atrial contractions [PACs] and premature ventricular 
contractions [PVCs]).
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
17
Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Rationale: Exclusion criterion no. 14.1 was revised to allow prescription use of psychostimulants with dosing 
restrictions on intranasal treatment session days to allow subjects to safely use at other permitted times during study 
participation.
4.2.1. Direct-entry 
Subjects
Text in exclusion criterion no. 14.1 revised as follows (bold text added; strikethrough text 
deleted):
Subject has positive test result(s) for drugs of abuse (including barbiturates, methadone, 
opiates, cocaine, phencyclidine, and amphetamine/methamphetamine) at the start of the 
screening/prospective observational phase or Day 1 of the double-blind induction phase 
prior to randomization.
-
Subjects who have a positive test result at screening due to prescribed 
psychostimulants (eg, amphetamine, methylphenidate, etc.) taken for an 
indication other than MDD are permitted to continue to take this medication 
during the study in accordance with  Attachment 1.
-
Otherwise, Subjects subjects who have a positive test result at screening due to 
prescribed/over-the-counter opiates, or barbiturates, or amphetamines may be 
permitted to continue in the screening/prospective observational phase if the 
medication is discontinued at least 1 week or 5 half-lives, whichever is longer, 
before Day 1 of the double-blind induction phase (prior to randomization) in 
accordance with Attachment 1 restrictions. The result of the Day 1 (prior to 
randomization) test for drugs of abuse must be negative for the subject to be 
randomized.
o Retesting is not permitted for positive test result(s), except for reasons stated 
above.
Rationale: Clarifications made regarding the usage of antidepressant treatments for indications other than 
depression during the screening/prospective observational phase, and the use of corticosteroids, psychostimulants, 
and ADHD medications.
8. Prestudy and 
Concomitant Therapy
The following text was added:
Any medication that is listed on the MGH-ATRQ and is being taken at the start of the 
screening/prospective observational phase for an indication other than depression (eg, 
insomnia) should be continued during the screening/prospective observational phase but 
must be discontinued before the start of the double-blind induction phase.
Attachment 1
For antidepressants, changed 3rd bullet to read “Even if used for indications other than 
MDD (eg, trazodone primarily for sleep), trazodonethe use of any medication listed on 
the ATRQ is not permitted during the treatment phase” 
For corticosteroids, changed “oral” to “systemic”; allowed episodic use (previously 
prohibited); added that intermittent IM/IV corticosteroids are permitted (chronic use 
prohibited). 
For pseudoephedrine, clarified that is an orally administered agent (not intranasal).
For psychostimulants, allowed continuous use (previously prohibited); added that 
prescribed psychostimulants taken for indications other than MDD 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 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.
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
18
Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Rationale: In Amendment 2, inclusion of subjects who have thyroid-stimulating hormone (TSH) outside the normal 
ranges was permitted; however, the text indicating that a subject must have a normal TSH at screening was not 
removed from Amendment 2. This has been corrected in Amendment 3.
4.1.1. Direct-entry 
Subjects
The bullets in inclusion criterion no. 7 were revised as follows (bold text added; 
strikethrough text deleted):
-
Subjects with a pre-existing history of thyroid disease/disorder who are treated 
with thyroid hormones must be on a stable dosage for 3 months prior to the start 
of the screening/prospective observational phase and must have thyroid-
stimulating hormone (TSH) within normal range in the screening/prospective 
observational phase.
-
For any subject (regardless of thyroid history), if the thyroid-stimulating 
hormone (TSH) value is out of range, a free thyroxine (FT4) will be conducted. 
If the FT4 is normal, the subject can be enrolled. If the FT4 value is abnormal 
and considered to be clinically significant (after discussion with the medical 
monitor) out of range, the subject is not eligible.
Rationale: Based on feedback from the sites to allow subjects to proceed to the end of the optimization phase 
unless not clinically appropriate, the criterion specifying withdrawal of subjects with MADRS total score ≥22 for 
2 consecutive assessments during the optimization phase has been removed.
Synopsis, Dosage and 
Administration;
6.1.2.3. Intranasal 
Treatment Session 
Frequency (All 
Subjects); 9.1.4. 
Optimization Phase; 
10.2. Withdrawal 
From the Study
The following withdrawal criterion for the optimization phase and any text referring to this 
criterion have been deleted:
Any subject who has a MADRS total score ≥22 for 2 consecutive assessments separated 
by 5 to 15 days will be discontinued from the optimization phase.
Rationale: Definition of stable response during the optimization phase adjusted to be less rigid as this subgroup is 
an exploratory patient population in the maintenance phase. The duration of the response has been changed from the 
last 4 weeks of the optimization phase to the last 2 weeks of optimization.
Synopsis, Overview 
of Study Design; 
3.1.2. Definitions of 
Terms
Stable response redefined as ≥50% reduction in the MADRS total score from baseline in 
each of the last 2 weeks of the optimization phase, with at least 1 MADRS total score of 
>12 in these 2 weeks.
Rationale: Provide clarification regarding missed MADRS assessments. With the revision of the definition of 
stable response, stable responders are no longer required not to have missed the MADRS in all of the last 4 weeks of 
optimization.
Synopsis, Dosage and 
Administration; 
6.1.2.3.Intranasal 
Treatment Session 
Frequency (All 
Subjects)
The following text regarding missed MADRS assessments was deleted:
A subject that misses a MADRS assessment during the last 4 weeks of this phase (Week 
13 to Week 16) is not eligible to participate in the maintenance phase because eligibility 
criteria for stable remission or stable response cannot be confirmed. These subjects will be 
permitted to complete the optimization phase, if desired.
9.1.4. Optimization 
Phase
The following bullet was deleted from the list of  criteria for why a subject would not be 
eligible to proceed into the maintenance phase:
Misses a MADRS assessment in Weeks 13 to 16
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
19
Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
10.2. Withdrawal 
From the Study
Text regarding missed MADRS assessments was revised as follows (strikethrough text 
deleted):
Missed MADRS assessments: Subject misses ≥3 assessments in the first 8 weeks (Weeks 5 
to 12) or misses a MADRS assessment in Weeks 13 to 16 .
11.2. Sample Size 
Determination
Text was revised as follows (bold text added; strikethough text deleted):
The actual number of subjects randomized (which includes both those in stable remission 
and those with stable response [but who are not in stable remission]) will depend on the 
time it takes to obtain the necessary number of relapses.
Rationale: Provide clarification regarding when follow-up visits will be performed.
Synopsis, Overview 
of Study Design; 
Time and Events 
Schedule, Follow-up 
Phase; 3.1.1. Study 
Phases; 9.1.7. Follow-
up Phase
Specified that follow-up visits will be performed at 1 and 2 weeks after the last clinic visit 
(instead of after the last dose of intranasal study drug).
Rationale: Provide clarification regarding when the PWC-20 assessment will be administered.
9.4. Safety 
Evaluations
Text was revised as follows (bold text added; strikethough text deleted):
For those subjects who proceed to the optimization and maintenance phases, the PWC-20 
is conducted on the last day of intranasal dosingat the End of Study Visit. If subjects 
withdraw early from the study during any phase, the PWC-20 will be conducted at 
the Early Withdrawal Visit.
Rationale: Provide clarification in the footnotes regarding antidepressant treatment in the screening/prospective 
observational phase and guidance on repetition of the MADRS assessment.
Time and Events 
Schedule, Screening 
and Induction Phase
Text was revised as follows (bold text added; strikethough text deleted):
Footnote “a” revised to state: Subjects who do not require a taper and are thus eligible to 
immediately proceed to the open-label induction phase canwill have Visit 1.3 and Visit 2.1 
occurring on the same day or within 1 week of each other (if not occurring the same 
day, the antidepressant treatment regimen should be continued and discontinued 
prior to Visit 2.1).
Deleted “only” from footnote “k”.
Footnote “q” revised to state: The MADRS should be administered no more than 2 days 
prior to the subject’s scheduled targeted (not actual) clinic visit date (except Visit 2.9, 
which is within 1 day prior). If performed on the day of the scheduled clinic visit for an 
intranasal treatment session, the MADRS must be performed prior to the intranasal 
treatment session.
Rationale: Revise the visit window for Day 28 of the open-label induction phase to allow more flexibility for 
conducting the visit.
Time and Events 
Schedule, Open-label 
Induction Phase
For Visit 2.9 during the induction phase, the visit window was revised to ±1 day (rather 
than -1 day). 
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
20
Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Rationale: To obtain AE and concomitant therapy data in between clinic visits.
Time and Events 
Schedule, Follow-up 
Phase
The following statement was added as footnote “f” to the remote assessment during the 
follow-up phase:
At the “Remote Assessment ” visit, site staff will contact the subject by telephone to obtain 
information regarding adverse events and concomitant therapies
Rationale: To add drug accountability for the intranasal study medication to the list of procedures during the 
Optimization Phase.
Time and Events 
Schedule, 
Optimization Phase
Added a row in the Time and Events Schedule (under the subheading Study Drug) 
showing drug accountability for the intranasal study medication.
Added a footnote “r” stating:  Drug accountability for intranasal study medication should 
be performed weekly during Weeks 5 through 8 (inclusive) and then weekly or every other 
week from Weeks 9 through 15 (inclusive).
Rationale: Add information about 54135419TRD3008, an open-label safety extension study, that may be available 
for eligible subjects participating in ESKETINTRD3003.
Synopsis, Overview 
of Study Design; 
3.1.1. Study Phases; 
9.1.7. Follow-up 
Phase
The following text was added:
An open-label safety extension study, 54135419TRD3008, may be available (pending 
country and site approval) for eligible subjects participating in the ESKETINTRD3003 
study. Please refer to the 54135419TRD3008 protocol for full details when available.
Rationale: Removal of requirement to report arterial oxygen saturation <93% and any treatment-emergent change 
in the nasal examination as adverse events because adverse event reporting in these instances should be at the 
discretion of the PI.
9.4. Safety 
Evaluations
Text was revised as follows (bold text added; strikethough text deleted):
Any arterial oxygen saturation (SpO2) <93% should beand 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.
The following statement was deleted from the description of nasal examinations: Any 
treatment-emergent change or worsening from the baseline examination will be recorded 
as an adverse event.
Rationale: The maximum sertraline dose was changed from 150 mg/day to 200 mg/day as the maximum dose 
allowed by product labelling is 200 mg/day.
1.2.1.2. Sertraline; 
Attachment 3 
Maximum dose of sertraline changed from 150 mg/day to 200 mg/day. Titration schedule 
adjusted accordingly. 
Rationale: Revise text regarding uptitration of duloxetine dose, which referred to an incorrect phase of the study.
1.2.2.1. Duloxetine
Text revised to state that certain subjects may be started on a 30 mg dose of duloxetine and 
up-titrated to the therapeutic range of 60 mg by the start of Week 2 of the open-label 
induction phase (not the screening/prospective observational phase).
Rationale: Removal of LSD and MDMA from urine drug screen results that will lead to discontinuation as LSD is 
not measured in the current urine drug screen and prescribed psychostimulants are now permitted.
4.3. Prohibitions and 
Restrictions
Lysergic acid diethylamide (LSD) and MDMA were deleted from the list of drugs that will 
lead to discontinuation if detected in the urine drug screen during the study.
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Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of procedure to follow if subjects wish to withdraw from the study.
10.2 Withdrawal from 
the Study
Under “Withdrawal of Consent”, the following text was revised to state (bold text added): 
Subjects who wish to withdraw from the study should be asked if they are agreeable to 
continue to an Early Withdrawal Visit (if withdrawing from the induction, 
optimization or maintenance phase) and the follow up phase, or to be contacted to 
collect follow-up information.
Rationale: Added definition of treatment-resistant depression (TRD) to the synopsis.
Synopsis, Subject 
Population
The following definition of TRD from Section 3.2.1 was added to the synopsis under 
Subject Population:
Treatment-resistant depression is defined as a lack of clinically meaningful improvement 
after treatment with at least 2 different antidepressant agents prescribed in adequate doses 
for adequate duration.
Rationale: Clarification of adverse event reporting procedures in the instance of pregnancy. In addition, 
clarification that all SAEs must be reported using the SAE form.
12.3.1. All Adverse 
Events
Text revised as follows (bold text added; strikethrough text deleted):
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's 
last study-related procedure (which may include contact for follow-up of safety), with the 
exception of pregnancy which will be reported up to 6 weeks after the last dose of 
study medication (females) or 90 days after the last dose of study medication 
(partners of male participants).  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.
Rationale: Minor changes were made throughout the protocol for compliance with updated protocol template text.
Cover page
Updated Sponsor Statement to remove Janssen Infectious Diseases BVBA. 
4.1.1.  Direct-entry 
Subjects
The following text was added to inclusion criterion no. 9.1:
Contraceptive use by men or women should be consistent with local regulations regarding 
the use of contraceptive methods for subjects participating in clinical studies.
17.5 Case Report 
Form Completion
Deleted text stating “All data relating to the study must be recorded in CRF.”
References 
Removed edition number and date from reference 60. 
Attachment 3
Added the following text for footnote “a” as this was inadvertently omitted from the table 
in Amendment 1:
Subjects should be initiated with 60 mg/day. Subjects that have in the past shown 
increased sensitivity towards serotonin reuptake inhibitors (SSRI) /norepinephrine  
reuptake inhibitors (SNRI) can, at the discretion of the treating physician, be started on a 
30 mg dose and up-titrated into the therapeutic range of 60 mg by the start of Week 2.
Investigator 
Agreement Page
Removed the “LAST PAGE” designation.
NCT02493868

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Clinical Protocol ESKETINTRD3003 Amendment 4
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Status: Approved, Date: 4 April 2017
Amendment 2 (13 January 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: This amendment updates and clarifies the protocol based on ongoing 
feedback received during study initiation activities.
Applicable Section(s)
Description of Change(s)
Rationale: Clarification was needed that criteria are the same for transferred-entry subjects as for direct-entry 
subjects at the beginning of the optimization phase.
4.1.2. Inclusion 
Criteria, Transferred-
entry Subjects;
4.1.3. Inclusion 
Criteria, Direct-entry 
Subjects and 
Transferred-entry 
Subjects;
4.2.2. Exclusion 
Criteria, Transferred-
entry Subjects
The new Inclusion Criterion 15 and Exclusion Criterion 32 were added to clarify that 
transferred-entry subjects must meet the same criteria at the point of entry to this study as 
the direct-entry subjects at the same time point (ie, beginning of optimization phase).
Rationale: The effect of impaired renal clearance on the pharmacokinetic profile of intranasal esketamine is not 
fully known, and subjects with renal impairment may be more vulnerable to blood pressure increases; therefore, as 
an added safety precaution, subjects with severe renal impairment will be excluded from the study.
4.2.1. Exclusion 
Criteria, Direct-entry 
Subjects;
4.2.2. Exclusion 
Criteria, Transferred-
entry Subjects
The new Exclusion Criterion 31 was added, to exclude subjects with severe renal 
impairment (creatinine clearance <30 mL/min).
9.4. Safety 
Evaluations
Calculation of creatinine clearance was added.
Rationale: Eligibility criteria and definitions related to previous oral antidepressants (and nonresponse to them) 
needed to be expanded and clarified.
Synopsis, Overview of 
Study Design, Subject 
Population, Dosage 
and Administration;
3.2.1. Study
Population;
4.1.1. Inclusion 
Criteria, Direct-entry 
Subjects;
6.2.1. Screening/
Prospective 
Observational Phase 
(Direct-entry Subjects 
Only);
9.1.2. Screening/
Prospective 
Observational Phase

Definitions for nonresponse in the screening/prospective observational phase were 
clarified, as follows:
- For nonresponse at the beginning of the phase (for eligibility to enter into the 
study), Inclusion Criterion 3 and corresponding text (where relevant) now define
nonresponse as ≤25% improvement per Massachusetts General Hospital -
Antidepressant Treatment Response Questionnaire (MGH-ATRQ), which specifies 
at least 6 weeks of treatment at a minimum therapeutic dose.
- For nonresponse at the end of the phase (for eligibility to continue into the 
optimization phase), the definition is no longer blinded to investigators and is now 
stated as ≤25% improvement in the Montgomery-Asberg Depression Rating Scale
(MADRS) total score for 2 consecutive visits and a MADRS total score of ≥28 for 
2 consecutive visits.

For the ≥2 but ≤5 oral antidepressant treatments relevant to Inclusion Criterion 3 and 
associated descriptions, text was added to specify that the upper limit of 
≤5 antidepressants was only applicable to the past 2 years of a current episode of 
depression in cases where the current episode is >2 years.
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
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Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)

For the documentation to confirm nonresponse for Inclusion Criterion 3 and 
associated descriptions, acceptable sources were updated to add a letter from the 
subject's treating physician, etc.

In Inclusion Criterion 3 and associated descriptions, clarification was added about the 
requirement for a subject to be taking one of the aforementioned oral antidepressant 
treatment(s) with nonresponse that is documented on the MGH-ATRQ (ie, this oral 
antidepressant treatment must have been taken for at least 6 weeks at the minimal 
therapeutic dose with a lack of clinically meaningful improvement) at the start of the 
screening/prospective observational phase.
4.1.1. Inclusion 
Criteria, Direct-entry 
Subjects;
9.1.1. Overview
Inclusion Criterion 3 and related assessments were modified as follows:

Eligibility was modified for tricyclic antidepressant dose ingested versus therapeutic 
blood level attained (ie, if a subject is taking a specific tricyclic antidepressant at a 
dose below the MGH-ATRQ minimum therapeutic dose, then a blood level that is 
within the therapeutic [antidepressant] range is acceptable to establish the adequacy of 
the antidepressant treatment).

The table describing the volume of blood to be collected from each subject was 
updated to reflect this change.
Rationale: The scope of the Site Independent Qualification Assessment needed clarification.
Synopsis, Subject 
Population;
3.2.1. Study 
Population;
4.1.1. Inclusion 
Criteria, Direct-entry
Subjects;
9.1.2. Screening/
Prospective 
Observational Phase;
9.6. Other Evaluations
Inclusion Criterion 5 and other associated text about the Site Independent Qualification 
Assessment were edited to specify that this assessment confirms not only the subject's 
current major depressive episode and antidepressant treatment response in the current 
depressive episode, but also the severity of depression (required at Week 1 to be MADRS 
total score ≥28).
Rationale: Assessments and eligibility relevant to thyroid health needed to be expanded and clarified.
4.1.1. Inclusion 
Criteria, Direct-entry 
Subjects
In Inclusion Criterion 7, new parameters were added for all subjects (regardless of thyroid 
history). If the thyroid-stimulating hormone (TSH) value is outside the normal reference 
range, then the free thyroxine (FT4) level will be assessed. If the FT4 level is normal, then 
the subject can be enrolled. If the FT4 level is outside the normal reference range, then the 
subject is not eligible.
9.1.1. Overview;
9.4. Safety 
Assessments
The analysis of FT4 was added for cases where the TSH is outside of the normal reference 
range.
Attachment 1
Comments about thyroid hormone supplements were deleted, to harmonize this 
attachment with the associated Inclusion Criterion 7.
Rationale: Eligibility parameters and assessments related to childbearing potential and contraception needed to be 
clarified and strengthened. Many of these issues were related to changes in the sponsor's protocol template (ie, some 
of these issues may be generally applicable to all similar studies and may not be specific to this study). 
4.1.1. Inclusion 
Criteria, Direct-entry 
Subjects
Inclusion Criterion 9 was strengthened in its definitions of women who are not of 
childbearing potential and in its requirements for highly effective methods of 
contraception.
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
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Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
4.1.1. Inclusion 
Criteria, Direct-entry 
Subjects;
9.1.1. Overview
Inclusion Criterion 10 was edited to state that the serum test for β-human chorionic 
gonadotropin (β-hCG) must be highly sensitive, and to clarify the serum versus urine tests. 
The table that describes the volume of blood to be collected from each subject now 
specifies the highly sensitive nature of the β-hCG test.
4.1.1. Inclusion 
Criteria, Direct-entry 
Subjects
Inclusion Criterion 11 was strengthened in its requirements for men whose sperm could 
have come in contact with a woman via sexual activity or donation; requirements are 
specified both for male study subjects and for their female partners. 
Time and Events 
Schedules (All 
Phases);
9.6. Other Evaluations
Footnotes and text were added to clarify menstrual cycle tracking (the start date of the last 
menstrual period prior to the study visit). This tracking is captured as part of Module I of 
the Massachusetts General Hospital - Female Reproductive Lifecycle and Hormones 
Questionnaire (MGH-FRLHQ) at Week 1 of the screening/prospective observational 
phase, and then is tracked separately thereafter only for women with a menstrual cycle.
The redundant tracking was removed at Week 1 in the Time and Events Schedule of the 
screening/prospective observational phase, leaving only the MGH-FRLHQ at that first 
time point.
Rationale: The description of the studies that could precede this study needed to be corrected.
4.1.2. Inclusion 
Criteria, Transferred-
entry Subjects
In Inclusion Criterion 12, the induction phase of the ESKETINTRD3001 and 
ESKETINTRD3002 studies was revised from the incorrect open-label description to the 
correct double-blind description.
Rationale: Eligibility criteria and definitions related to previous procedural interventions for depression needed to 
be expanded and clarified.
Synopsis, Subject
Population;
4.2.1. Exclusion 
Criteria, Direct-entry 
Subjects
In the exclusion criteria about antidepressant procedures and the related synopsis section,

Exclusion Criterion 1 was modified so it is clearer that nonresponse to 
electroconvulsive therapy (ECT) may be either unilateral or bilateral ECT.

Exclusion Criterion 2 was modified to emphasize the stimulation of the vagal nerve 
rather than the method of stimulation; ie, the mention of the implant was deleted.
Rationale: The exclusionary features associated with (comorbid to) major depressive disorder (MDD) needed to be 
clarified and expanded.
Synopsis, Subject
Population;
4.2.1. Exclusion 
Criteria, Direct-entry 
Subjects
In Exclusion Criterion 3 and in the corresponding synopsis text.

Obsessive-compulsive disorder was clarified as being exclusionary only when current, 
not when prior.

The diagnostic codes for the exclusion related to intellectual disability were broadened 
from the previous 319 only to also include 317, 318.0, 318.1, 318.2, 315.8, or 319.

Autism spectrum disorder was added as exclusionary.

The terminology of "MDD with psychosis" was harmonized with terminology that 
already appeared elsewhere in the protocol, to read "MDD with psychotic features."
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
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Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Rationale: The exclusions and prohibitions related to cardiovascular health and medications needed clarification 
and modification.
4.2.1. Exclusion 
Criteria, Direct-entry 
Subjects

Exclusion Criterion 8 was modified to allow entry of patients who had 
revascularization procedures performed >12 months prior to screening and are now 
clinically stable and symptom-free in the investigator's clinical judgment.

In Exclusion Criterion 9, the term "antihypertensive medication regimen" was changed 
to "antihypertensive medication(s)."

In Exclusion Criterion 11,
- For QT interval corrected (QTc) according to Fridericia's formula (QTcF), text 
was clarified that the exclusionary abnormal result of ≥450 msec during screening 
or on Day 1 should be based on a repeated demonstration (ie, average of 
3 electrocardiograms [ECGs] with QTcF of ≥450 msec, recorded 4 minutes apart).
- For left or right bundle branch blocks, text was clarified that only "complete" 
block was exclusionary.
- For exclusionary first-degree atrioventricular block with PR interval >200 msec, 
text was modified to state that retesting was permitted if the initial PR interval was 
<240 msec, and that the average of both readings should then be used.

In Exclusion Criterion 12, the use of concomitant medications that prolong the 
QT/QTc interval was deleted (no longer excluding such subjects from study 
enrollment).
Rationale: Flexibility was needed for retesting of potentially transient abnormal alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) values, in case of collection/laboratory errors or other transient factors.
4.2.1. Exclusion 
Criteria, Direct-entry 
Subjects
Exclusion Criterion 13 was modified to allow one repeat of a screening test for abnormal 
ALT and AST during the screening period, per investigator discretion and provided there 
is an alternative explanation for the out of range value.
Rationale: Testing time points versus exclusion for cannabinoids needed clarification and harmonization.
4.2.1. Exclusion 
Criteria, Direct-entry 
Subjects;
9.4. Safety 
Evaluations
Exclusion Criterion 14 and related text were modified to clarify that testing for 
cannabinoids is to be conducted both during screening and at predose on Day 1; however, 
a positive result is not exclusionary during screening (as long as the subject does not meet 
the criteria for substance use disorder) but is exclusionary at predose on Day 1. 
Rationale: Exclusions related to diabetes needed clarification.
4.2.1. Exclusion 
Criteria, Direct-entry 
Subjects
In Exclusion Criterion 15, the redundant term "secondary diabetes" was removed, since
the criterion had already stated that any uncontrolled diabetes mellitus was exclusionary.
Rationale: Exclusions due to anatomical or medical conditions that could impede delivery or absorption of 
intranasal study drug needed modification.
4.2.1. Exclusion 
Criteria, Direct-entry 
Subjects
In Exclusion Criterion 17, text was added to clarify that the exclusion would be 
determined by the investigator's clinical judgment based on assessment. Examples of such 
conditions (eg, significant structural or functional abnormalities of the nose) were deleted.
The now-redundant Exclusion Criterion 18, which had described exclusionary conditions 
related to nasal septa, was similarly deleted.
Rationale: Eligibility related to sleep apnea needed to be clarified.
4.2.1. Exclusion 
Criteria, Direct-entry 
Subjects
In Exclusion Criterion 23, the parameter for effective treatment was clarified as reaching 
the previously stated apnea-hypopnea index (AHI) threshold of <30 (events per hour of 
sleep). 
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
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Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Rationale: Exclusions relevant to current or previous participation in other studies needed clarification.
4.2.1. Exclusion 
Criteria, Direct-entry 
Subjects
In Exclusion Criterion 24, text was clarified that previous participation in 2 or more 
studies of MDD must involve different investigational medications to be exclusionary, and 
that current enrollment in an investigational study must be interventional to be 
exclusionary. 
Rationale: Details about limitations on prior and concomitant therapies and interacting substances needed 
modifications and clarifications.
4.3. Prohibitions and 
Restrictions
Lysergic acid diethylamide (LSD) was added to the list of positive urine drug screen 
results that would lead to discontinuation during any treatment phase (open-label 
induction, optimization, or maintenance phases).
4.3. Prohibitions and 
Restrictions
The restriction was removed about ingesting grapefruit juice, Seville oranges, or quinine 
for 24 hours before an intranasal dose of study medication.
4.3. Prohibitions and 
Restrictions;
8. Prestudy and 
Concomitant Therapy

Cognitive behavioral therapy (CBT): Where the protocol previously had stated that 
subjects receiving CBT must have had it stable in terms of frequency for the last 
6 months, this parameter was made less stringent, to now read that CBT must have 
been ongoing for the last 3 months. The protocol now clarifies that new CBT is 
prohibited.

Non-CBT psychotherapy: Where the protocol previously had stated that subjects 
receiving psychotherapy must have had it stable in terms of frequency for the last 
6 months, this parameter was made less stringent, removing the time restriction and 
stating that subjects receiving psychotherapy can continue receiving psychotherapy, 
and that new non-CBT psychotherapy is allowed during the study.

For any kind of therapy: The protocol now clarifies that any change in existing therapy 
or any new therapy must be documented on the concomitant therapies form.
6.2.1. Screening/
Prospective 
Observational Phase
(Direct-entry Subjects 
Only);
4.3. Prohibitions and 
Restrictions;
8. Prestudy and 
Concomitant Therapy
Restrictions on the use of benzodiazepines and non-benzodiazepine sleeping medications 
were clarified, to state the following:

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) during the screening/prospective observational 
phase can continue these medications. 

No dose increases beyond the equivalent of 6 mg/day of lorazepam or new 
benzodiazepine medications are permitted during the induction phase, with the 
exception of the use of permitted benzodiazepine rescue medication.

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.
8. Prestudy and 
Concomitant Therapy
A previously included phrase was revised for clarity, to state that if a subject routinely 
takes his or her oral antihypertensive medication(s) in the morning, then the usual morning 
dose(s) should be taken prior to intranasal dosing.
8. Prestudy and 
Concomitant Therapy
A sentence was added to clarify that even antidepressant treatments which are not listed 
on the MGH-ATRQ but were used, or are currently being used, as antidepressant 
treatment in the current depressive episode must be recorded at the start of the 
screening/prospective observational phase.
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
27
Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Attachment 1

Additional examples were provided for existing classes of medications.

Prohibitions were deleted for cytochrome P450 subtype 3A4 (CYP3A4) inhibitors.

Prohibitions were added for pseudoephedrine-containing products in the 12 hours prior 
to an intranasal treatment session, for nonstimulant attention-deficit/hyperactivity 
disorder medications, and for non-vitamin K antagonist oral anticoagulation agents.

Prohibitions were clarified. In the section about antidepressants, clarification was 
added that trazodone is not permitted during study phases that include intranasal 
treatment, even if used primarily for sleep. In the section about benzodiazepines and 
nonbenzodiazepine sleeping medication, the allowable dosage was clarified (equal to 
or less than the equivalent of 6 mg/day lorazepam) and comments were consolidated.

Comments about thyroid hormone supplements were deleted, to harmonize this 
attachment with the associated inclusion criterion, as described above.
Rationale: Clarification was needed about how a subject's medications for depression must be maintained 
unchanged and then fully discontinued at the end of the screening/prospective observational phase for subjects 
eligible to enter the open-label induction phase.
Synopsis, Overview of 
Study Design and 
Dosage and 
Administration;
3.1.1. Study Phases;
3.2.2. Study Phases;
6.2.1. Screening/
Prospective 
Observational Phase
(Direct-entry Subjects 
Only);
9.1.2. Screening/
Prospective 
Observational Phase
Text was added and harmonized to clarify that all medication(s) being used for depression, 
including adjunctive/augmentation therapies and any other prohibited psychotropic 
medications, will be discontinued at the end of the screening/prospective observational 
phase for subjects eligible to enter the open-label induction phase. 
Attachment 1
The following details were added: If a medication is part of the antidepressant treatment 
regimen being taken at the time of signing the informed consent form (ie, start of 
screening/prospective observational phase), then it must be continued unchanged until the 
end of Week 4 of the screening/prospective observational phase; therefore, the prohibition 
terms are not applicable to those medications during that period. In such cases the 
investigator may choose to taper the relevant medication during the optional taper period 
of up to 3 weeks that may follow the screening/prospective observational phase, based on 
clinical judgment.
Rationale: The titration schedule with the oral antidepressant medication in the open-label induction phase needed 
to be clarified for all antidepressants and modified for duloxetine.
Synopsis, Dosage and 
Administration; 
3.2.4.2. Oral 
Antidepressant;
6.2.2. Open-label 
Induction Phase 
(Direct-entry Subjects 
Only)
For the lower limit, the time point for the minimum therapeutic dose was specified as the 
end of the induction phase. For the upper limit, the text was clarified that doses are not to 
exceed the maximum dose defined in the titration schedule. Statements were added to 
clarify that use of the titration schedule in Attachment 3 is mandatory.
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
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Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
1.2.2.1. Duloxetine; 
Attachment 3
For the duloxetine starting dose of 60 mg/day, this amendment adds flexibility for subjects 
who have in the past shown increased sensitivity towards selective serotonin reuptake 
inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Those 
subjects can, at the discretion of the treating physician, now be started on a 30-mg dose 
and then up-titrated into the therapeutic range of 60 mg by the start of Week 2 of the open-
label induction phase.
Rationale: The oral antidepressant was not scheduled to be dispensed frequently enough to ensure continuous 
coverage. (One dispensation had been omitted in error.)
Time and Events 
Schedule 
(Maintenance Phase)
In the row entitled "Dispensing oral antidepressant (open-label)," an X was added to the 
column at Week 16.
Rationale: Clarification was needed about the order of administering intranasal devices.
6.1.2.3. [Optimization 
Phase], Intranasal 
Treatment Session 
Frequency (All 
Subjects)
6.1.3. Maintenance 
Phase 
Footnotes were added to the tables that describe intranasal treatment sessions, clarifying 
that the intranasal devices for each intranasal treatment session should be administered in 
the medication kit order provided by the Interactive Web Response System (IWRS).
Rationale: The guidance for discontinuing any subjects who may develop ulcerative cystitis needed to be 
strengthened.
3.2.6. Safety 
Evaluations
The previous text stating that "if cystitis is considered to be associated with esketamine, 
subjects will be discontinued" was strengthened to state that if a subject is determined to 
have a diagnosis of ulcerative cystitis, the subject must be discontinued.
9.4. Safety 
Evaluations
Under the subheading for Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS), a 
new criterion for discontinuation was added: if a subject is determined to have a diagnosis 
of ulcerative cystitis, then the subject must be discontinued from the study and followed 
up with appropriate medical care.
Rationale: A guidance for discontinuing subjects who may develop abnormal ECG readings needed to be added.
9.4. Safety 
Evaluations;
10.2. Withdrawal 
From the Study
Text was added to specify that a subject must be discontinued at any time point after 
baseline (Day 1, predose), if either of the following criteria are met:

QTcF change from baseline is ≥60 msec and QTcF >480 msec, or 

QTcF >500 msec.
Rationale: Clarification was needed regarding training requirements for site staff who will be present with the 
subject during the intranasal treatment session and the postdose observation period.
Synopsis, Dosage and 
Administration; 
6.1. Intranasal Study 
Drug
Previous text that stated a physician, nurse, or other appropriate member of the site staff 
with recent (ie, within 1 year) training for cardiopulmonary resuscitation now states a site 
staff member with training in cardiopulmonary resuscitation (eg, a basic life support 
course or equivalent course) that is up to date per local regulations.
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
29
Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Rationale: The guidance for blood pressure monitoring on intranasal treatment session days needed to be more 
conservative, comprehensive, and clear.
6.1. Intranasal Study 
Drug

Regarding predose monitoring,
- Values that should prompt retesting (for a single observation), or postponing the 
dose (for same-day values), or referral for consultation (if persistent to the next 
visit) were made more conservative. The systolic blood pressure (SBP) alert 
parameter was lowered from ≥160 to >140 mm Hg and the diastolic blood pressure 
(DBP) alert parameter was lowered from ≥100 to >90 mm Hg, making these 
parameters consistent with those already stated in Exclusion Criterion 9.
- Text was added to clarify that the predose blood pressure requirements were also 
applicable to all intranasal treatment session days after Day 1.
- The period of rest between retesting was changed from a 10-minute period to an 
open-ended period.

Regarding both predose and postdose monitoring, "other specialist" was added as an 
option (along with cardiologist and primary care physician) to whom subjects should 
be referred if alert parameters were met.

Regarding postdose monitoring, 
- For subjects with SBP ≥160 mm Hg and/or DBP ≥100 mm Hg at 1.5 hours 
postdose, the handling options for the 30-minute assessments thereafter were 
updated.
- For subjects with SBP ≥180 mm Hg and/or DBP ≥110 mm Hg at 2 hours after 
dosing, a new parameter was added, stating that these subjects should be referred 
for immediate medical treatment.
- For subjects with SBP ≥180 but <200 mm Hg and/or DBP ≥110 but <120 mm Hg, 
conditions for continuing with intranasal dosing (after referral for assessment) 
were changed from "given approval" to if recommended by the referring doctor 
and considered appropriate according to clinical judgment.
- For subjects with SBP ≥200 mm Hg and/or DBP ≥120 mm Hg at any postdose 
time point, the handling was strengthened from should discontinue from further 
dosing to must discontinue from further dosing.
Rationale: Flexibility was needed for methods to measure blood pressure and pulse/heart rate.
9.4. Safety 
Evaluations
The emphasis on the completely automated device was decreased and the allowance for 
manual techniques was made broader.
Rationale: Cognition testing needed clarification.
Time and Events 
Schedule 
(Screening/Prospective 
Observational Phase);
9.4. Safety 
Evaluations 
The table and text were clarified to state that a practice session will be conducted only for 
the computerized cognitive battery, while the Hopkins Verbal Learning Test - Revised
(HVLT-R) has no practice session.
9.4. Safety 
Evaluations
The description of the HVLT-R was clarified and was revised to describe administration 
by a person rather than a computer.
Rationale: The University of Pennsylvania Smell Identification Test (UPSIT) and the Smell Threshold Test needed 
to be administered more frequently and more flexibly.
Time and Events 
Schedule (All Phases);
9.4. Safety 
Evaluations
Footnotes and text were added to indicate that if a subject has significant nasal congestion 
on the day of a scheduled assessment of sense of smell, then the site should consider 
postponing the UPSIT, Smell Threshold Test, or both (as applicable) to the next scheduled 
clinic visit.
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Applicable Section(s)
Description of Change(s)
Time and Events 
Schedule 
(Maintenance Phase)
An additional UPSIT assessment was added to Week 20 (Visit 4.5).
Rationale: Flexibility was needed for decongestants versus delay for a subject with congestion on an intranasal 
dosing day.
6.1. Intranasal Study 
Drug
For subjects with nasal congestion on a dosing day, the text was changed from "it is 
recommended that the dosing day be delayed" to "an intranasal decongestant can be used 
to reduce congestion or the dosing day can be delayed." This section had already stated 
that if an intranasal decongestant is used to reduce congestion, it cannot be used within 
1 hour prior to intranasal study drug dosing.
Rationale: Clarification was needed about repetition of safety assessments if a subject starts a scheduled clinic visit 
in which an intranasal treatment session is planned, but then a predose observation prompts the site staff to postpone 
the intranasal treatment session within the visit window.
Time and Event 
Schedules (Open-label 
Induction Phase, 
Optimization Phase, 
Maintenance Phase); 
9.4. Safety 
Evaluations
A paragraph and footnotes were added to describe which assessments must be repeated on 
the actual intranasal treatment session day after a postponement.
Rationale: The volume of blood to be collected needed to be updated.
9.1.1. Overview;
16.1. Study-specific 
Design Considerations
After adding conditional assessments as already described above in this section (for FT4 
and for tricyclic antidepressant level), and then reducing the volume of blood to be 
collected for biomarkers, the total volume of blood to be collected needed to be updated. It 
previously was stated as up to 210 or 231 mL, but now is stated as up to 189 mL.
Rationale: During the open-label induction phase, the Sheehan Disability Scale (SDS) was administered too 
infrequently to track the time course of improvement.
Time and Events 
Schedule, Open-label 
Induction Phase
An additional SDS assessment was added to Study Day 15.
Rationale: The windows and methods for remote MADRS assessment needed modification and clarification.
Time and Events 
Schedules 
(Screening/Prospective 
Observational Phase 
and Open-label 
Induction Phase)
The guidance about the window for remote MADRS monitoring was moved out of a table 
header row and into a footnote (associated with the MADRS row) providing similar 
guidance.
9.2.1.1. Primary 
Efficacy Evaluation: 
Montgomery-Asberg 
Depression Rating 
Scale (MADRS);
References
Information was added to clarify that the independent remote raters will be using the 
Structured Interview Guide for the MADRS. A reference was added to describe this guide.
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Status: Approved, Date: 4 April 2017
Applicable Section(s)
Description of Change(s)
Rationale: The definition of relapse updated to include completed suicide.
Synopsis, Overview of 
Study Design;
3.1.2. Definitions of 
Terms
The definition was updated to state that relapse was hospitalization for worsening 
depression or any other clinically relevant event determined per clinical judgment to be 
suggestive of a relapse of depressive illness such as suicide attempt, completed suicide, or 
hospitalization for suicide prevention. If hospitalized for any of these events, the start date 
of hospitalization will be used for the date of relapse. Otherwise the date of the event will 
be used if the subject is not hospitalized.
Rationale: Some template-based text that can be applicable to all of the sponsor's studies needed to be made more 
specific to the latest details about this study.
9.3. Medical Resource 
Utilization
The description of data to be collected was simplified and reduced.
12.3.2. Serious 
Adverse Events
In the list of hospitalizations that do not meet criteria for serious adverse events, 
hospitalizations for convenience "for the duration of the treatment period" were edited to 
read "at times during the treatment period."
15. Study-Specific 
Materials
The list of materials supplied to the investigator was updated to include the MGH-ATRQ 
guidance document.
17.4. Source 
Documentation
Text was deleted about parameters that would be recorded directly and considered to be 
source data.
Rationale: The protocol needed to be updated for better alignment with recent changes to one or more of the 
sponsor's general practices for all studies: an initiative to prevent missing data, the template for protocols, or other 
policies and procedures. (The underlying issues may be applicable to all of the sponsor's studies and are not 
necessarily specific to this study.)
4. Subject Population
The previous statement about "should consult the appropriate sponsor representative" was 
strengthened to "must consult," and the qualifier "and resolve any issues" was added. A 
statement was added that waivers are not allowed.
10.2. Withdrawal 
From the Study
This section was updated to include methods to prevent loss to follow-up and withdrawal 
of consent, and for documentation and notification of withdrawn consent.  
10.3. Withdrawal 
From the Use of 
Samples in Future 
Research;
16.2.5. Long-term 
Retention of Samples 
for Additional Future 
Research
The section that was previously a subheading ("Withdrawal From the Use of Samples for 
Future Research") under Section 10.2 was promoted to its own section. A cross-reference 
to this section from elsewhere in the protocol (ie, from Section 16.2.5) was updated.
12.3.1. All Adverse 
Events
This section was updated to describe how the sponsor will report suspected unexpected 
serious adverse reactions (SUSARs).
14.5. Drug 
Accountability
The "drug return form" was replaced with the "investigational product destruction form."
16.2.2. Independent 
Ethics Committee or 
Institutional Review 
Board
For the statement about annual review and reapproval of this study, the qualifier "where 
required" was added.
17.4. Source 
Documentation
The information was reorganized and expanded to include review of methods for source 
data collection with the investigator.
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Applicable Section(s)
Description of Change(s)
17.5. Case Report 
Form Completion
Roles and options were updated for handling corrections to an electronic case report form 
(eCRF) after the initial entry into the eCRF, and other clarifications were made.
Rationale: Minor errors were noted and clarifications were needed.
Time and Events 
Schedules 
(Screening/Prospective 
Observational Phase 
and Open-label 
Induction Phase)
For ECGs, the footnote was revised from expressing a range of visits ("Visits 2.3 to 2.8," 
which could have been incorrectly interpreted as intending every visit within that range) to 
instead match the specific visits already marked in the table: "Visits 2.3, 2.5, and 2.8."
Time and Events 
Schedule
(Screening/Prospective 
Observational Phase)
A footnote was added to Visit 2.1 C-SSRS (Since Last Visit) assessment, to indicate that it 
is only performed for subjects who do not have Visit 1.3 and 2.1 occur on the same day.
Time and Events 
Schedules 
(Maintenance Phase)
In the header and associated footnote, "From Week 21" was changed to "From Week 20."
1.1.1. Summary of 
Nonclinical Findings
Regarding the studies in dogs, one of the duplicative but inconsistent sections was 
modified. Both sections now state that the results are about ECGs, where previously one 
section indicated that the results were about EEGs (electroencephalograms).
2.1. Objectives
Medical resource utilization had previously been stated as an exploratory objective in the 
protocol synopsis but a secondary objective in the protocol body. The protocol body now 
has been updated to correctly state the exploratory nature. 
9.4. Safety 
Evaluations
In the section about pulse oximetry, one instance of "≤93%" was changed to "<93%" in 
the description of arterial oxygen saturation, and the section was revised for better clarity. 
(Another instance in this section had already stated the correct <93%.)
16.1. Study-specific 
Design Considerations
A sentence was revised from previous internal inconsistency ("had response . . . lack of 
response") to be internally consistent ("had nonresponse . . . lack of response").
Attachment 3
Country-specific titration schedules were removed for countries where no sites are 
participating in the study.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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Amendment INT-1 (21 April 2015)
This amendment is considered to be nonsubstantial 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, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.  
The overall reason for the amendment: The overall reason for the amendment is to correct an error in the Time 
and Events Schedule that is required for the Interactive Web Response System (IWRS) setup. 
Applicable Section(s)
Description of Change(s)
Rationale: Corrections made to the Time and Events Schedule to specify assessments for the Week 20 visit, and to 
clarify dosing instructions in case of a missed dose during the induction phase. 
Synopsis, 
Maintenance Phase; 
Time and Events 
Schedule 
(Optimization Phase, 
Maintenance Phase);
6.1.3. Maintenance 
Phase;
Table 5.
Collection of biomarkers was deleted at Visit 3.1 (Week 4, Day 28 ) of the optimization 
phase as it would have been collected twice at the same visit (is still being collected at 
Day 28 but as part of the induction phase Visit 2.9). Blood volume table (Table 5) was 
adjusted to reflect the lower volume of blood collected due to deletion of the duplicate 
collection.
During maintenance phase, a column which was missing in the table was added for 
Week 20, Visit 4.5 (Day 137). Timing of various procedures and assessments were revised 
accordingly to be performed at Week 20 visit. Subsequent visits now start with Visit 4.6 
(Week 21).
Text was adjusted where applicable. 
Synopsis, Dosage and 
Administration;
6.1.1. Open-label 
Induction Phase
Sentence was added to clarify in case of a missed dose during the induction phase: If there 
is no intranasal treatment session on Day 15 (eg, visit is missed), a dose reduction from 
84 mg to 56 mg is permitted on Day 18 if required for tolerability; no dose increase is 
permitted.
Rationale: Changes were made to simplify the algorithm and facilitate implementation by only allowing subjects to 
switch dosing frequency at fixed time points.
Synopsis, 
Optimization Phase; 
6.1.2.3. Intranasal 
Treatment Session 
Frequency
Clarified that the 2 fixed time points where adjustments to dosing frequency can be made 
are Week 8 and 12. The algorithms used to determine whether a frequency adjustment 
could be made (based on MADRS total score at Week 8 and Week 12) were clarified. 
Added guidance on how to determine if a change in dosing frequency is indicated in case 
of a missing MADRS assessment.
Synopsis, 
Maintenance Phase; 
Time and Events 
Schedule
(Maintenance Phase); 
6.1.3 Maintenance 
Phase
Clarified the guidance for dosing frequency adjustments at Week 16 and Week 20 and 
every 4 weeks until the end of the phase. Added guidance on how to determine if a change 
in dosing frequency is indicated in case of a missing MADRS assessment. 
Rationale: For consistency with other Phase 3 protocols, added language to specify that direct entry subjects 
requiring lower doses of the oral antidepressant than those prescribed in the protocol are allowed to complete the 
induction phase but not eligible to participate in the optimization phase. 
Synopsis, Oral 
Antidepressants; 
3.2.4.2. Oral 
Antidepressant;
6.2.2. Open-label 
Induction Phase
Added the sentence “While subjects requiring lower doses can continue in the study and 
complete the induction phase, such subjects will not be eligible to participate in the 
optimization phase and will proceed to the follow-up phase after completion of the 
induction phase.” 
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Applicable Section(s)
Description of Change(s)
Rationale: To add / revise information for dispensing, review, and collection of subject diaries for oral 
antidepressant 
Time and Events 
Schedule, all phases; 
6.2 Oral 
Antidepressants;
7. Treatment 
Compliance;
15. Study-Specific 
Materials
Rows / timepoints / text added for subject diaries for oral antidepressants. 
Rationale: To revise the amount of oral antidepressant dispensed at the End of Study visit from a 4 week supply to 
2 week supply, in order to comply with company regulations that drug accountability must be performed for all 
dispensed study medication.
Synopsis, Follow Up
Phase, Oral 
Antidepressant;
Time and Events 
Schedule (Induction, 
Optimization and 
Maintenance Phases); 
3.1.1. Study Phases; 
6.2.4. Follow-up 
Phase; 
9.1.7 Follow-up 
Phase;
16.1 Study Specific 
Design 
Considerations. 
Revised (or added where it wasn't present) text to indicate that subjects will be provided 
with an additional 2-week supply (rather than 4-week supply) of the oral antidepressant 
medication to ensure that there is no interruption of oral antidepressant therapy during the 
transition to further clinical/standard of care. 
Rationale: To clarify scoring of the PAQ assessment
9.6. Other 
Evaluations
Text describing scoring of the PAQ was revised to indicate it is based on Question 1 (not 
1c through 1f).
Rationale: Corrections made to the diagram of the study design, Safety Analyses section, and reference list.
Figure 1.
Relapse prevention phase replaced with maintenance phase for consistency with protocol 
text terminology.
11.6. Safety Analyses.
Deletion of sentences that defined baseline values for subsections on clinical laboratory 
tests, electrocardiograms, vital signs, nasal examination and nasal symptom questionnaire, 
and other safety and tolerability questionnaires and assessments. Details about relevant 
baseline will be provided within the Statistical Analysis Plan (SAP).
References.
Reference number 139 corrected (for PHQ-9).
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Status: Approved, Date: 4 April 2017
SYNOPSIS
A Randomized, Double-blind, Multicenter, Active-controlled Study of Intranasal Esketamine Plus 
an Oral Antidepressant for Relapse Prevention in Treatment-resistant Depression
EudraCT Number: 2014-004586-24
INTRODUCTION
Major depressive disorder (MDD) is a serious, recurrent, and disabling psychiatric illness, is the second 
leading cause of years lost to disability worldwide, and is associated with excess mortality (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). 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 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 for antidepressant therapy. The higher 
NMDA receptor affinity of esketamine versus ketamine allows a lower volume of medication to be 
administered via the noninvasive and rapidly absorbed intranasal route.
This study will investigate whether repeated use of intranasal esketamine plus an oral antidepressant can 
sustain the antidepressant effects of an induction course of intranasal esketamine plus an oral 
antidepressant in subjects with TRD, or whether the oral antidepressant alone is sufficient to maintain the 
antidepressant effect.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective of this study is to assess the efficacy of intranasal esketamine plus an oral 
antidepressant compared with an oral antidepressant (active comparator) plus intranasal placebo in 
delaying relapse of depressive symptoms in subjects with TRD who are in stable remission (see 
Definitions of Terms below) after an induction and optimization course of intranasal esketamine plus an 
oral antidepressant.
Secondary Objectives

To assess the efficacy of intranasal esketamine plus an oral antidepressant compared with an oral 
antidepressant (active comparator) plus intranasal placebo in delaying relapse of depressive 
symptoms in subjects with TRD with stable response (but who are not in stable remission) (see 
Definitions of Terms below) after an induction and optimization course of intranasal esketamine plus 
an oral antidepressant

To assess the effect of intranasal esketamine plus an oral antidepressant compared with an oral 
antidepressant (active comparator) plus intranasal placebo on:

Depressive symptoms

Overall severity of depressive illness
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
Functional impairment and associated disability 

Anxiety symptoms

Health-related quality of life and health status

To investigate the safety and tolerability of intranasal esketamine plus an oral antidepressant 
compared with an oral antidepressant (active comparator) plus intranasal placebo in subjects with 
TRD, with special attention to the following:

Treatment-emergent adverse events (TEAEs), including AEs of special interest

Local nasal tolerability

Effects on heart rate, blood pressure, respiratory rate, and blood oxygen saturation

Effects on alertness and sedation

Potential psychosis-like symptoms

Dissociative symptoms

Potential effects on cognitive function

Potential effects on suicidal ideation/behavior

Potential treatment-emergent symptoms of cystitis and/or lower urinary tract symptoms

Potential withdrawal and/or rebound symptoms following cessation of intranasal esketamine
treatment

Potential effects on sense of smell
Exploratory Objectives

To assess the potential relationship of biomarkers with response/non-response to intranasal 
esketamine plus an oral antidepressant or to an oral antidepressant plus intranasal placebo in adult 
subjects with TRD

To assess medical resource utilization
Hypothesis
The hypothesis for this study is that intranasal esketamine plus an oral antidepressant is more effective
than treatment with an oral antidepressant plus intranasal placebo in delaying relapse of depressive 
symptoms in subjects with TRD in stable remission. 
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, parallel-group, active-controlled, multicenter study to evaluate the 
efficacy, safety, and tolerability of intranasal esketamine plus an oral antidepressant compared with an 
oral antidepressant (active comparator) plus intranasal placebo in delaying relapse of depressive 
symptoms in adult men and women with TRD who are in stable remission after an induction and 
optimization course with intranasal esketamine plus an oral antidepressant. 
Approximately 211 subjects in stable remission (see Definition of Terms below) at the end of the 
optimization phase will be randomized in a 1:1 ratio to either continue intranasal esketamine (same dose) 
or be switched to intranasal placebo; all subjects will continue the same oral antidepressant at the same 
dose.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study.
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Subjects will enter the study either directly (referred to as direct-entry subjects) or after completing the 
double-blind induction phase of a short-term study (ESKETINTRD3001 or ESKETINTRD3002)
(referred to as transferred-entry subjects). 
The study has 5 phases:

A 4-week screening/prospective observational phase, with an optional taper of up to 3 weeks for oral 
antidepressant medication(s) (direct-entry subjects only)

A 4-week open-label induction phase (direct-entry subjects only)

A 12-week optimization phase (open-label for direct-entry subjects and double-blind for transferred-
entry subjects)

A maintenance phase (variable duration) 

A 2-week follow-up phase
The maximum duration of a subject's participation will be variable, depending on whether he or she enters 
the study directly or is transferred from one of the double-blind short-term studies, and whether he or she 
meets phase-specific criteria (eg, meets criteria for response at the end of the induction phase, is in stable 
remission/response at the end of the optimization phase, and when and if he or she relapses in the 
maintenance phase). Direct-entry subjects may participate in up to 5 phases and transferred-entry subjects 
may participate in up to 3 phases.
The study will be stopped once 84 relapses (in the subjects with stable remission) occur during the 
maintenance phase, or earlier based on the results of the interim analysis for efficacy. At the time the 
study is stopped, subjects in the induction phase will be able to complete the Induction phase. Those 
subjects who are responders, after completing an Early Withdrawal Visit may proceed to the 
54135419TRD3008 study without completing the follow-up phase. Those who are not responders will 
have an Early Withdrawal Visit and proceed directly to the follow-up phase. Subjects who are in the 
optimization or maintenance phase at the time the study is terminated will have an Early Withdrawal
Visit/End of Maintenance Visit conducted and proceed directly to the follow-up phase. 
Definitions of Terms:

Open-label Induction Phase

Response: 50% reduction in the MADRS total score from baseline (Day 1 prior to the first 
intranasal dose) to the end of the 4-week open-label induction phase.

Optimization Phase

Stable remission: 
o
MADRS total score ≤12 for at least 3 of the last 4 weeks of the optimization phase, 
but one excursion of a MADRS total score > 12 or one missing MADRS assessment 
is permitted at Optimization week 13 or 14 only. The MADRS total score at weeks 
15 and 16 must be ≤12.

Stable response: 50% reduction in the MADRS total score from baseline (Day 1 of induction 
phase; pre-randomization/prior to the first intranasal dose) in each of the last 2 weeks of the 
optimization phase, but does not meet criteria for stable remission. Note: For transferred-entry 
subjects, Day 1 of the open-label induction phase will take place in ESKETINTRD3001 or 
ESKETINTRD3002.

Maintenance Phase: Relapse is defined as any of the following:

MADRS total score 22 for 2 consecutive assessments separated by 5 to 15 days. The date of 
the second MADRS assessment will be used for the date of relapse.
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
Hospitalization for worsening depression or any other clinically relevant event determined per 
clinical judgment to be suggestive of a relapse of depressive illness such as suicide attempt, 
completed suicide, or hospitalization for suicide prevention. If hospitalized for any of these 
events, the start date of hospitalization will be used for the date of relapse. Otherwise the date of 
the event will be used if the subject is not hospitalized.

In case both relapse criteria are met, the earlier date will be defined as the date of relapse for 
this subject.
Screening/Prospective Observational Phase:
Direct-entry subjects will participate in this 4-week phase to prospectively assess treatment response to 
the subject’s current oral antidepressant treatment regimen. After 4 weeks of continuing the same 
treatment regimen, subjects who are non-responders to their current oral antidepressant treatment (as 
assessed by independent, remote raters) may be eligible to proceed to the open-label induction phase if 
they have ≤25% improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total 
score of ≥28 on Week 2 and Week 4.
Eligible subjects who are entering the open-label induction phase will discontinue their current oral 
antidepressant medication(s). If clinically indicated, a subject’s current antidepressant medication(s) may 
be tapered over an additional, optional period of up to 3 weeks per the local prescribing information or 
clinical judgment.
As a new oral antidepressant will be initiated on Day 1 of the open-label induction phase, eligible subjects 
who do not require a tapered discontinuation of their antidepressant medication(s) can immediately 
proceed into the open-label induction phase.
Open-label Induction Phase:
Eligible direct-entry subjects will receive intranasal esketamine (flexible dose: 56 mg or 84 mg) treatment 
sessions twice weekly for 4 weeks. In addition, all subjects will initiate a new, open-label oral 
antidepressant on Day 1 that will be taken daily for the duration of the induction phase. The assigned oral 
antidepressant will be 1 of 4 oral antidepressant medications (duloxetine, escitalopram, sertraline, or 
venlafaxine extended release [XR]), that the subject has not previously had a non-response to in the 
current depressive episode, has not been previously intolerant to (lifetime), and is available in the 
participating country.
At the end of the induction phase, 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 open-
label induction phase) may be eligible to proceed to the optimization phase. All subjects who do not 
proceed to the optimization phase will have an Early Withdrawal Visit conducted and proceed to the 
follow-up phase.
At the time the study is stopped, subjects in the induction phase will be able to complete the phase. Those 
who are responders, after completing an Early Withdrawal Visit, may proceed to the 54135419TRD3008 
study without completing the follow-up phase. Those who are not responders will have an Early 
Withdrawal Visit conducted and proceed directly to the follow-up phase.
Optimization Phase:
Eligible direct-entry subjects from the open-label induction phase and transferred-entry subjects from the 
2 double-blind short-term studies (ESKETINTRD3001 and ESKETINTRD3002) will participate in this 
12-week phase.
The intranasal treatment session frequency will be reduced from that in the induction phase (twice 
weekly) to weekly for the first 4 weeks of this phase. After the first 4 weeks, the frequency of intranasal 
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treatment sessions will be individualized to either once weekly or once every other week based on the 
severity of depressive symptoms, as assessed by the MADRS total score. The dose of intranasal 
esketamine will remain unchanged from the dose at the end of the induction phase. All subjects will 
continue taking the same oral antidepressant treatment (at the same dosage) that was initiated during the 
induction phase.
At the end of the optimization phase, subjects in stable remission and those with stable response (but who 
are not in stable remission) may be eligible to continue into the maintenance phase; all other subjects will 
have an Early Withdrawal Visit conducted and proceed to the follow-up phase.
For subjects in stable remission and those with stable response at the end of this phase, the last visit of the 
optimization phase (Visit 3.13; Week 16) also serves as the baseline visit (Visit 4.1; Week 16) of the 
maintenance phase. Subjects eligible for the maintenance phase will be randomized and receive their first 
double-blind intranasal treatment session of the maintenance phase at this visit.
At the time the study is stopped, subjects in the optimization phase will have an Early Withdrawal Visit 
conducted and proceed directly to the follow-up phase.
Maintenance Phase:
On Day 1 of this phase:

Approximately 211 subjects in stable remission at the end of the optimization phase (after treatment 
with intranasal esketamine plus an oral antidepressant) will be randomized in a 1:1 ratio to either 
continue with intranasal esketamine (same dose) and the same oral antidepressant or to continue with 
the same oral antidepressant (active comparator) but switch to intranasal placebo. The primary 
efficacy analysis will be performed for these subjects only. 

Additionally, subjects with stable response (but who are not in stable remission) at the end of the 
optimization phase (after treatment with intranasal esketamine plus an oral antidepressant) will be 
randomized in a 1:1 ratio (using a separate randomization list) to either continue with intranasal 
esketamine (same dose) and the same oral antidepressant or to continue with the same oral 
antidepressant (active comparator) but switch to intranasal placebo (for a secondary efficacy analysis
only). 

Transferred-entry subjects who achieve stable remission or stable response at the end of the 
optimization phase after treatment with an oral antidepressant plus intranasal placebo will continue 
to receive the same treatment in order to maintain the blinding for the ongoing short-term studies. 
These subjects will not be included in the efficacy analyses, but will be included in safety analyses.
The frequency of intranasal treatment sessions will be further individualized during the maintenance 
phase to once weekly or once every other week based on the severity of depressive symptoms, as assessed 
by the MADRS total score. Subjects will only be permitted to switch from weekly to every other weekly 
dosing a total of 3 times. After this time, if a given subject is unable to sustain improvement on every 
other week dosing they will remain on a weekly dosing regimen for the duration of this phase.
This phase will have a variable duration, continuing until 84 relapses occur in the subjects with stable 
remission, or earlier based on interim analysis results.
Subjects who meet the relapse criteria and subjects who remain relapse-free at study termination will have 
an End of Maintenance Phase Visit conducted and may proceed to the follow-up phase. If clinically 
indicated, subjects who have met relapse criteria after completing the end of maintenance visit may 
proceed to the open-label safety extension study, 54135419TRD3008, without completing the follow up 
phase. Subjects who are participating in the maintenance phase at the time the study is stopped will have 
an Early Withdrawal Visit conducted and proceed directly to the follow-up phase.
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Follow-up Phase:
This phase will include all subjects who have received at least 1 dose of intranasal study medication in 
this study. For those subjects who relapse in the Maintenance phase, if clinically indicated based on 
investigator’s judgment, after completing the end of maintenance visit, the subject may proceed to the 
open-label safety extension study, 54135419TRD3008, without completing the follow-up phase. 
Similarly, when the study is stopped, subjects in the Induction phase who are responders, after completing 
the early withdrawal visit, may proceed to the 54135419TRD3008 study, without completing the follow 
up phase.
Follow-up visits will be performed at 1 and 2 weeks after the last clinic visit.
At the start of the follow-up phase, further clinical/standard of care for the treatment of depression will be 
arranged by the study investigator and/or the subject’s treating physician. There will be no intranasal 
treatment administered during this phase. Subjects will be provided with an additional 2-week supply of 
the oral antidepressant medication to ensure that there is no interruption of oral antidepressant therapy 
during the transition to further clinical/standard of care. The decision to continue the oral antidepressant 
in this phase will be at the discretion of the investigator, however, in order to better assess potential 
withdrawal symptoms from intranasal study drug, the oral antidepressant should be continued during the 
2-week follow-up phase unless determined as not clinically appropriate.
An open-label safety extension study, 54135419TRD3008, may be available (pending country and site 
approval) for eligible subjects participating in the ESKETINTRD3003 study. Please refer to the 
54135419TRD3008 protocol for full details of potential pathways for entry.
SUBJECT POPULATION
Direct-entry Subjects
The study population will include adult men and women, 18 (or older if the minimum legal age of consent 
in the country in which the study is taking place is >18) to 64 years of age (inclusive), who meet the 
Diagnostic and Statistical Manual of Mental Disorders (5th Edition; DSM-5) diagnostic criteria for 
recurrent MDD or single-episode MDD (if a single episode, the duration of episode must be 2 years), 
without psychotic features, based upon clinical assessment, and confirmed by the Mini International 
Neuropsychiatric Interview. The subject must have an Inventory of Depressive Symptomatology-
Clinician rated, 30-item (IDS-C30) total score of 34, which corresponds to moderate to severe 
depression.
At the start of the screening/prospective observational phase, subjects must have had non-response (ie, 
lack of clinically meaningful improvement, defined as ≤25% improvement) to 1 but 5 (if current 
episode is >2 years, upper limit is applicable to only the last 2 years) different oral antidepressant 
treatments taken at adequate dosage and for adequate duration, as assessed on the Massachusetts General 
Hospital – Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and documented by
medical/pharmacy/prescription records or a letter from a treating physician, etc. for the current episode of 
depression. In addition, the subject is taking a different oral antidepressant treatment (on the MGH-
ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose.
Treatment-resistant depression is defined as a lack of clinically meaningful improvement after treatment 
with at least 2 different antidepressant agents prescribed in adequate doses for adequate duration.
The subject’s current major depressive episode and treatment response to antidepressant treatments used 
in the current episode (retrospectively assessed) must be deemed valid for participation in a clinical study 
based on the Site Independent Qualification Assessment. The Site Independent Qualification Assessment 
is a tool to facilitate subject selection for MDD clinical studies, with a goal to ensure enrollment of 
subjects who have symptoms that reflect the current state of illness, that these symptoms can be reliably 
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measured with appropriate measurement tools, and that the severity of depression is appropriate (required 
at Week 1 to be MADRS total score ≥28).
Potential subjects will be excluded from participating in the study if they have previously demonstrated 
non-response of depressive symptoms to any of the following: esketamine or ketamine in the current 
major depressive episode, all of the oral antidepressant treatment options available in the respective 
country for the open-label induction phase (ie, duloxetine, escitalopram, sertraline, and venlafaxine XR) 
in the current major depressive episode (based on MGH-ATRQ), or an adequate course of treatment with 
electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments 
with unilateral or bilateral ECT. Subjects who have received vagal nerve stimulation or deep brain 
stimulation in the current depressive episode will be excluded. Subjects will also be excluded if they have 
a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or 
related disorders (confirmed by the MINI), intellectual disability (DSM-5 diagnostic codes 317, 318.0, 
318.1, 318.2, 315.8, or 319), autism spectrum disorder, borderline personality disorder, antisocial 
personality disorder, histrionic personality disorder, or narcissistic personality disorder; if they have 
current obsessive-compulsive disorder; if they have homicidal ideation/intent or suicidal ideation with 
some intent to act within 6 months prior to the start of the screening/prospective observational phase per 
the investigator’s clinical judgment and/or based on the Columbia Suicide Severity Rating Scale (C-
SSRS); or if they have a history of moderate or severe substance or alcohol use disorder according to 
DSM-5 criteria.
Transferred-entry Subjects
Subjects who enter this study after participation in 1 of the short-term studies (ESKETINTRD3001 or 
ESKETINTRD3002) must have completed the double-blind induction phase in the short-term study and 
must have demonstrated response at the end of that phase (50% reduction in the MADRS total score 
from baseline [Day 1 pre-randomization] at the end of the 4-week double-blind induction phase).
DOSAGE AND ADMINISTRATION
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. In addition, equipment for supportive ventilation and resuscitation needs to be present.
All 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.
On all intranasal dosing days, subjects must remain at the 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 site. Subjects must not drive a car or work with machines for 24 hours after 
receiving intranasal study drug.
Prior to the first intranasal dose on Day 1 of the open-label induction phase, direct-entry subjects will 
practice spraying (into the air, not intranasally) a demonstration intranasal device that is filled with a 
placebo solution.
Open-label Induction Phase
This phase is for direct-entry subjects only. All subjects will self-administer intranasal esketamine twice a 
week for 4 weeks at the study site. The first treatment session will be on Day 1.
On Day 1, subjects will start with a dose of 56 mg. On Day 4, the dose may be increased to 84 mg or 
remain at 56 mg, as determined by the investigator based on efficacy and tolerability. On Day 8, the dose 
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may be increased to 84 mg (if Day 4 dose was 56 mg), remain the same, or be reduced to 56 mg (if Day 4 
dose was 84 mg), as determined by the investigator based on efficacy and tolerability. Similarly, on 
Days 11, 15, 18, and 22, the dose may be increased to 84 mg, remain the same, or be reduced to 56 mg, if 
applicable as determined by the investigator based on efficacy and tolerability. On Day 25, a dose 
reduction from 84 mg to 56 mg is permitted if required for tolerability; no dose increase is permitted.
Optimization Phase
Transferred-entry subjects: In this phase, subjects will continue the same double-blind intranasal study 
drug (same dose) from the double-blind induction phase of ESKETINTRD3001 or ESKETINTRD3002.
Direct-entry subjects: In the optimization phase, subjects will continue the same open-label intranasal 
esketamine treatment (same dose) from the open-label induction phase.
All subjects will continue their oral antidepressant medication (at the same dosage) during this phase.
Intranasal Treatment Session Frequency:
During this phase, the MADRS will be performed weekly by an independent, remote rater, and changes to 
the intranasal treatment session frequency will be based on the MADRS total score, if applicable
(see below).
For all subjects, the frequency of intranasal treatment sessions will be reduced from the twice-weekly 
frequency used in the induction phase to weekly for the first 4 weeks of the optimization phase (Week 5 
to Week 8).
During this phase, there are two fixed time points (Week 8 and Week 12) in which an adjustment to the 
frequency will be made if applicable.
Week 8:

Subjects with a MADRS total score >12 at Week 8 visit will continue to receive weekly intranasal 
treatment sessions for the remainder of the optimization phase. No further change to the treatment 
session frequency is permitted for the remainder of the optimization phase (through Week 16).

If the MADRS total score is 12 at Week 8, the subject will reduce the frequency to receive 
intranasal treatment sessions every other week for the next 4 weeks (ie, next treatment sessions will 
be at Weeks 10 and 12).

This is the only time during the optimization phase that a subject will be permitted to change to 
a frequency of every other week.

If the MADRS assessment is missed at Week 8, the last MADRS total score available prior to Week 
8 will be used to determine if a change in treatment session frequency is indicated at Week 8. In this 
case:

If the MADRS total score is ≤ 12, the subject will reduce the frequency to receive intranasal 
treatment sessions every other week for the next 4 weeks (ie, next treatment sessions will be at 
Weeks 10 and 12).

If the MADRS total score is >12, the subject will continue to receive weekly intranasal 
treatment sessions for the remainder of the optimization phase. No further change to the 
treatment session frequency is permitted for the remainder of the optimization phase (through 
Week 16).
Week 12 (only for those on an every other week treatment session frequency):
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
If the MADRS total score is >12 at Week 12, the frequency of intranasal treatment sessions will be 
increased to weekly for the remainder of the optimization phase; no further change to the treatment 
session frequency is permitted for the remainder of the optimization phase (through Week 16).

If the MADRS total score is ≤12 at Week 12, the subject will remain on the treatment session 
frequency of every other week for the next 4 weeks (ie, through to Week 16).

If the MADRS is missed at Week 12, the last MADRS total score available prior to Week 12 will be 
used to determine if a change in treatment session frequency is indicated at Week 12. In this case:

If MADRS total score is 12, the subject will remain on the treatment session frequency of 
every other week for the next 4 weeks (ie, through to Week 16).

If the MADRS total score >12 at that week, the frequency of intranasal treatment sessions will 
be increased to weekly for the remainder of the optimization phase; no further change to the 
treatment session frequency is permitted for the remainder of the optimization phase (through 
Week 16).
Maintenance Phase
All subjects will receive double-blind intranasal study medication in this phase, as described above 
(see Overview of Study Design, Maintenance Phase).
During this phase, the MADRS will continue to be assessed weekly by an independent, remote rater, and
changes to the intranasal treatment session frequency will occur at 4-week intervals, if applicable, and be 
based on the MADRS total score (see below). 
At the start of this phase (Visit 4.1; Week 16): 

Subjects who currently receive intranasal treatment sessions on a weekly basis will stay at the same 
weekly intranasal treatment session frequency for the first 4 weeks of this phase. 

For those on an every other week frequency:

If the MADRS total score is >12 at Week 16, the frequency of intranasal treatment sessions will 
be increased to weekly for the next 4 weeks.

If the MADRS total score is ≤12 at Week 16, the subject will stay at the same every other week
intranasal treatment session frequency for the next 4 weeks.
After the first 4 weeks of this phase (ie, starting from Week 20), the intranasal treatment session 
frequency will be adjusted (if applicable) at fixed, 4-week intervals (eg, Week 20, 24, 28, 32, 36, 40, 44 
and every 4 weeks until the end of the phase), based on the guidance below:

If the MADRS total score is 12 at that week:

If the frequency is weekly, the frequency will be changed to every other week.

If the frequency is every other week, there will be no change in frequency.

If the MADRS total score >12 at that week:

If frequency is weekly, there will be no change in frequency.

If frequency is every other week, the frequency will be changed to weekly

If the MADRS is missed at that week, the last MADRS total score available prior to that week will 
be used to determine if a change in treatment session frequency is indicated at that week. In this case:

If the MADRS total score is ≤12, and the frequency is every other week, there will be no change 
in frequency.
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
If the MADRS total score is ≤12, and the frequency is weekly, the frequency will be changed to 
every other week.

If the MADRS total score is >12, and the frequency is weekly, there will be no change in 
frequency.

If the MADRS total score is >12, and the frequency is every other week, the frequency will be 
changed to weekly. 
A maximum of 3 changes in intranasal treatment session frequency from weekly to every other week is 
permitted during the maintenance phase. After this time, if a given subject is unable to sustain 
improvement on every other week dosing they will remain on a weekly dosing regimen for the duration of 
this phase.
Oral Antidepressants
Study-site personnel will instruct subjects on how to store and take the oral antidepressant treatment
supplied during this study for at-home use.
On intranasal treatment sessions days, it is recommended that the oral antidepressant treatment not be 
taken until at least 3 hours after the treatment session.
Screening/Prospective Observational Phase (Direct-entry Subjects Only)
During this phase, direct-entry subjects will continue taking their current oral antidepressant treatment
regimen for the duration of the 4-week phase for prospective observation of response or non-response. 
The regimen must include a different oral antidepressant treatment (on the MGH-ATRQ) for at least the 
previous 2 weeks at or above the minimum therapeutic dose. This antidepressant treatment, as well as any 
other medication(s) being used for depression (including adjunctive/augmentation therapies), will 
continue from the start of Week 1 through the end of Week 4 of this phase. Dose adjustment is permitted 
per clinical judgment, but the oral antidepressant treatment is to remain at or above the minimum 
therapeutic dose (per the MGH-ATRQ) through the end of Week 4.
The sponsor will not supply these oral antidepressants. Antidepressant treatment adherence will be 
assessed during this phase using the Patient Adherence Questionnaire (PAQ). For subjects who are 
eligible to enter the open-label induction phase, after the completion of 4 weeks of prospective 
antidepressant treatment and confirmation of the antidepressant treatment non-response, all medication(s) 
being used for depression will be discontinued, including adjunctive/augmentation therapies. If clinically 
indicated (eg, antidepressant treatments with short half-lives, such as paroxetine and venlafaxine XR), the 
medication(s) being used for depression may be tapered off and discontinued over a period of up to 3
weeks per the local prescribing information or clinical judgment. Eligible subjects who do not require a 
taper of their medication(s) being used for depression can immediately proceed into the open-label 
induction phase.
Open-label Induction Phase (Direct-entry Subjects Only)
Starting on Day 1 of the open-label induction phase, a new, open-label oral antidepressant will be initiated 
in all direct-entry subjects. The oral antidepressant will be 1 of 4 oral antidepressant medications 
(duloxetine, escitalopram, sertraline, or venlafaxine XR). The antidepressant medication will be assigned 
by the investigator based on review of the MGH-ATRQ and relevant prior antidepressant medication 
information, and will be one that the subject has not previously had a non-response to in the current 
episode (based on MGH-ATRQ), has not been previously intolerant to (lifetime), and is available in the 
participating country.
Dosing of the oral antidepressant will begin on Day 1. A mandatory titration schedule is provided in the 
protocol. Doses are not to exceed the maximum dose defined in the titration schedule. If higher doses are 
not tolerated, a down-titration is permitted based on clinical judgment. However, the subject’s dose 
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should not be lower than the following minimum therapeutic doses at the end of the induction phase: 
sertraline (50 mg/day), venlafaxine XR (150 mg/day), escitalopram (10 mg/day), and duloxetine 
(60 mg/day). While subjects requiring lower doses can continue in the study and complete the induction 
phase, such subjects will not be eligible to participate in the optimization phase and will proceed to the 
follow-up phase after completion of the induction phase.
Optimization and Maintenance Phases (Direct-entry and Transferred-entry Subjects)
For all subjects, the same oral antidepressant treatment (duloxetine, escitalopram, sertraline, or 
venlafaxine XR) started on Day 1 of the induction phase will be continued through the optimization and 
maintenance phases. The oral antidepressant dosage at the end of the induction phase will remain 
unchanged through the maintenance phase.
Subjects who miss 21 days of the oral antidepressant doses (total daily dose) in the optimization phase 
will not be eligible to continue into the maintenance phase.
Follow-up Phase
At the start of the follow-up phase, further clinical/standard of care for the treatment of depression will be 
arranged by the study investigator and/or the subject’s treating physician.
No intranasal study medication will be administered during this phase. 
The decision to continue the oral antidepressant medication in this phase will be at the discretion of the 
investigator; however, in order to better assess potential withdrawal symptoms from the intranasal study 
medication, the oral antidepressant medication should be continued during the 2-week follow-up phase, 
unless determined as not clinically appropriate.
All subjects will be provided with an additional 2-week supply of the oral antidepressant medication at 
the last clinic visit prior to entering the follow-up phase, to ensure there is no interruption of 
antidepressant therapy during the transition to further clinical/standard of care.
EFFICACY EVALUATIONS/ENDPOINTS
Primary Efficacy Evaluation/Endpoint
The primary efficacy evaluation will include the MADRS total score as it pertains to relapses.
The primary efficacy endpoint includes only subjects who are in stable remission at the end of the 
optimization phase after treatment with intranasal esketamine plus an oral antidepressant, and is defined 
as the time between subject randomization and the first documentation (earliest date) of a relapse in the 
maintenance phase.
Secondary Efficacy Evaluations/Endpoints
Secondary efficacy evaluations/endpoints include the following:

The time between subject randomization and the first documentation (earliest date) of a relapse in the 
maintenance phase for subjects with stable response (not in remission) at the end of the optimization 
phase after treatment with intranasal esketamine plus an oral antidepressant.

The change from baseline (of maintenance phase) to endpoint in:
o
Depressive symptoms, using the MADRS and the self-reported Patient Health 
Questionnaire 9-item (PHQ-9) scale 
o
Overall severity of illness, using the Clinical Global Impression - Severity (CGI-S)
o
Symptoms of anxiety, using the Generalized Anxiety Disorder, 7-item (GAD-7) scale
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o
Health-related quality of life and health status, using the European Quality of Life 
(EuroQol) Group, 5-Dimension, 5-Level (EQ-5D-5L) questionnaire
o
Functioning and associated disability, using the Sheehan Disability Scale (SDS)
BIOMARKER, PHARMACOGENOMIC (DNA), AND EXPRESSION (RNA) EVALUATIONS
Assessment of biomarkers (protein and RNA) and their potential relationship to the different treatment 
groups and to maintenance/stabilization of response, non-response, and relapse will be explored. Blood 
samples will be collected to measure genetic and epigenetic markers (including but not limited to brain 
derived neurotrophic factor [BDNF] allelic variants) and protein markers (including but not limited to 
growth factors, inflammation, endocrine, or metabolic markers). Samples of DNA and biomarkers may be 
used to help address emerging issues and to enable the development of safer, more effective, and 
ultimately individualized therapies.
MEDICAL RESOURCE UTILIZATION
Medical resource utilization data, associated with healthcare encounters, will be collected using the 
Healthcare Resource Use Questionnaire (HRUQ) during the optimization, maintenance, and follow-up 
phases. The HRUQ includes information regarding utilization of healthcare services (including the 
duration and type of services), enabling changes in level and quantity of services to be considered as a 
variable in economic models.
SAFETY EVALUATIONS
Safety evaluations will include:

Monitoring of TEAEs, including TEAEs of special interest; clinical laboratory tests (including 
hematology, serum chemistry, and urinalysis), pregnancy testing (for women of childbearing 
potential), urine drug screen, 12-lead electrocardiogram, vital signs, pulse oximetry, physical 
examination, and body weight measurements

Nasal examinations and nasal symptom questionnaire

Columbia Suicide Severity Rating Scale (C-SSRS), to assess potential suicidal ideation and behavior

Clinician
Administered Dissociative States Scale (CADSS), to assess treatment-emergent 
dissociative symptoms

Four-item positive symptom subscale of the Brief Psychiatric Rating Scale (BPRS+), to assess 
potential treatment-emergent psychotic symptoms

Modified Observer’s Assessment of Alertness/Sedation (MOAA/S), to measure treatment-emergent 
sedation

Clinical Global Assessment of Discharge Readiness (CGADR), to document the subject’s current 
clinical status and is the clinician's assessment of the readiness to be discharged from the study site

Physician Withdrawal Checklist (PWC-20) includes 20 items to assess potential withdrawal 
symptoms following cessation of intranasal esketamine treatment

Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS), to monitor subjects for potential 
symptoms of cystitis, bladder pain, and interstitial cystitis

Computerized cognitive battery and Hopkins Verbal Learning Test-Revised (HVLT-R), to assess the 
effect of intranasal esketamine on cognition

University of Pennsylvania Smell Identification Test (UPSIT) and Smell Threshold Test, to assess 
any potential treatment-emergent effects on the sense of smell
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STATISTICAL METHODS
Subject Information
The full analysis sets for the primary efficacy evaluation are defined as follows:

At Interim Analysis: All subjects who are in stable remission at the end of the optimization phase
and who receive at least 1 dose of intranasal study drug and 1 dose of oral antidepressant during the 
maintenance phase at the time of the interim analysis data cutoff

At Final Analysis: All subjects who are in stable remission at the end of the optimization phase and 
who receive at least 1 dose of intranasal study drug and 1 dose of oral antidepressant during the 
maintenance phase
The safety analysis set for each phase is defined as all subjects who receive at least 1 dose of intranasal 
study drug or 1 dose of oral antidepressant during that phase.
Transferred-entry subjects who continue to receive an oral antidepressant plus intranasal placebo will be 
summarized separately in both optimization and maintenance phases.
Sample Size Determination
The maximum number of relapses (in the subjects with stable remission) required by this study is 84, 
which provides 90% power to detect a hazard ratio of 0.493 at the 1-sided significance level of 0.025 for a 
fixed-sample design to detect superiority of esketamine plus oral antidepressant over antidepressant alone 
in delaying relapse of depressive symptoms in subjects with stable remission. The calculation of sample 
size assumed that the time to the first relapse follows an exponential distribution, with a median time of 
6 months for oral antidepressant alone and 12.17 months for intranasal esketamine plus oral 
antidepressant (hazard ratio = 0.493). The corresponding 6-month relapse rates are 50% for oral 
antidepressant alone and 28.95% for oral antidepressant plus intranasal esketamine.
Assumptions were made for accrual period and rate, maximum study duration, and dropout rate. Based on 
such assumptions, calculations indicated that a total of approximately 211 subjects in stable remission 
need to be randomized (in a 1:1 ratio) in order to obtain 84 relapses.
Interim Analysis
To evaluate the assumptions used in sample size calculation, relapse rates will be monitored sequentially 
during the maintenance phase. In particular, a 2-stage group-sequential design will be adopted, with 
1 interim analysis to be performed when a total of 30 relapses are observed. Early termination of the 
maintenance phase for efficacy will be based on interim analysis results. If the interim analysis results 
show that the study should proceed to the second stage (ie, continue to record more relapses after the 
interim cutoff), sample size re-estimation will be performed based on the interim analysis results to 
determine how many additional relapses should be obtained. The study team will not know the 
adjustments that will be made to the sample size; however, the clinical supplies group will be informed of 
the decision made at the interim analysis so that only the required amount of study medication will be 
packaged.
Efficacy Analyses
The primary efficacy endpoint will be the time between subject randomization into the maintenance phase
and the first documentation of a relapse event. Subjects with stable remission who meet at least 1 of the 
relapse criteria for the primary analysis while receiving treatment in the maintenance phase at the time 
that the study is stopped are considered to have had a relapse. All other randomized subjects with stable 
remission who had entered the maintenance phase but do not have a relapse by the time that the study is 
stopped will be considered censored.
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The cumulative distribution function of the time to relapse will be estimated by the Kaplan-Meier method. 
Time to relapse will be summarized (number of relapses, number of censored subjects, median, 25th and 
75th percentile of time to relapse, if estimable) by treatment group. Treatment differences will be 
compared using a 2-sided log-rank test as the primary analysis. The estimate of the hazards ratio and its 
95% confidence interval will be based on the Cox proportional hazards model with treatment as a factor.
Treatment comparison between intranasal esketamine plus oral antidepressant and oral antidepressant 
(active comparator) plus intranasal placebo in the changes from baseline to endpoint of MADRS total 
score, PHQ-9, CGI-S, SDS, and GAD-7 during the maintenance phase will be performed using an 
analysis of covariance model with treatment and country as factors and baseline (maintenance phase) 
value as a covariate. Least-squares estimates of the treatment differences and 95% confidence intervals 
will be presented. Dimension scores of EQ-5D-5L data, health status index, and the overall health status 
score will be summarized over time. These analyses will be provided separately for stable remitters and 
stable responders (not in remission).
Additionally, the time between the randomization of a subject with stable response (but who are not in 
stable remission) and the first documentation of a relapse for that subject in the maintenance phase will be 
analyzed using the log-rank test as described above for the primary efficacy endpoint.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Analyses
Baseline biomarker values and changes from baseline biomarker values to the time points specified in the 
Time and Events Schedule will be summarized. Exploratory analyses may include comparison of 
biomarker measures between the treatment groups and correlation with baseline and change from baseline 
biomarker values in the efficacy and other measures. Additional exploratory analyses may also include 
relationship of baseline and change from baseline in biomarker measures to clinical response, 
maintenance/stabilization of response, relapse, and non-response.
Pharmacogenomic analyses may include candidate gene analyses or genome-wide association analyses in 
relation to treatment response, maintenance/stabilization of response, relapse, and non-response and 
MDD/TRD. Expression analyses may include testing of known mRNA/miRNA transcripts or 
transcriptome-wide analysis in relation to antidepressant treatment and MDD/TRD.
Medical Resource Utilization Analysis
Medical resource utilization data (including HRUQ results) will be analyzed descriptively.
Safety Analyses
All safety data will be analyzed separately for each phase.
For each adverse event, the percentage of subjects who experience at least 1 occurrence of any given 
adverse event will be summarized by treatment group. Data from clinical laboratory tests, 
electrocardiograms, and vital signs will be provided as descriptive statistics and frequency tabulations. 
Nasal examination results will be provided as a shift table for changes from baseline, while nasal 
tolerability questionnaire results will be summarized descriptively. The C-SSRS results will be 
summarized in incidence and shift tables. The BPIC-SS, BPRS+, CADSS, CGADR, computerized 
cognitive battery, HVLT-R, MOAA/S, Smell Threshold Test, PWC-20, and UPSIT results will be 
provided as descriptive statistics of scores and their changes (and/or percent changes) from predose or 
baseline, as appropriate per assessment.
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Status: Approved, Date: 4 April 2017
TIME AND EVENTS SCHEDULE (Screening/Prospective Observational Phase and Open-label Induction Phase)
Screening/Prospective 
Observational Phase
Open-label Induction Phase
Visit number
1.1
1.2
1.3 a
2.1 a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9 b
Week
Week 1
End of 
Week 2
End of 
Week 4
1
2
3
4
Study day
—
—
—
1
(baseline)
4
8
11
15
18
22
25
28
Clinic visit window (in days)
—
±2
±2
—
±1
±1
±1
±1
±1
±1
±1
±1
Clinic visit (C) or remote MADRS interview 
only (RM)
C
C
C
C
C
C
C
C
C
C
C
C
Screening/Administrative
Informed consent (ICF)
X
Medical history, psychiatric history, 
demographics, employment status
X
MINI
X
MGH-ATRQ
X
Site Independent Qualification Assessment
X
Height 
X
Inclusion/exclusion criteria 
X
X
Prestudy therapy
X
Preplanned surgery/procedures
X
STOP-Bang questionnaire (including 
assessment of BMI and neck circumference)
X
MGH-Female RLHQ: Module I
X
IDS-C30
X
Study Drug
Dispensing of new oral antidepressant 
(duloxetine, escitalopram, sertraline, or 
venlafaxine XR)
X
Xm
Practice session for use of intranasal device
X c
Intranasal esketamine 
X
X
X
X
X
X
X
X
Drug accountability
(intranasal study medication)
X
X
X
X
X
X
X
X
Drug accountability (oral antidepressant 
study medication)
X
X
Dispense subject diary for oral antidepressant
X
Review subject diary and update (if 
applicable)
X
X
X
X
X
X
X
X
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
50
Status: Approved, Date: 4 April 2017
Screening/Prospective 
Observational Phase
Open-label Induction Phase
Visit number
1.1
1.2
1.3 a
2.1 a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9 b
Week
Week 1
End of 
Week 2
End of 
Week 4
1
2
3
4
Study day
—
—
—
1
(baseline)
4
8
11
15
18
22
25
28
Clinic visit window (in days)
—
±2
±2
—
±1
±1
±1
±1
±1
±1
±1
±1
Clinic visit (C) or remote MADRS interview 
only (RM)
C
C
C
C
C
C
C
C
C
C
C
C
Oral antidepressant compliance check
X
X
X
X
Collect/return of subject diary
X
Safety Assessments (Site-completed)
Physical examination
X
X
X
Nasal examination c
X
X
X
Vital signs: blood pressure, pulse, respiratory 
rate, temperature c,p
X
X
X
X
X
X
X
X
X
Vital signs (postdose): blood pressure, pulse, 
respiratory rate d
X
X
X
X
X
X
X
X
Weight
X
X
X
12-lead ECG e,p
X
X
X
X
X
C-SSRS: Baseline/Screening version
X
C-SSRS: Since last visit version p
X
X
Xr
X
X
X
X
X
X
X
X
MOAA/S and pulse oximetry f,p
X
X
X
X
X
X
X
X
X
BPRS+ g,p
X
X
X
X
X
X
X
X
CADSS g,p
X
X
X
X
X
X
X
X
CGADR h
X
X
X
X
X
X
X
X
PWC-20 i
X
Safety Assessments (Subject-completed)
Nasal symptom questionnaire j
X
X
X
X
X
BPIC-SS c
X
X
X
Assessment of Sense of Smell
UPSIT c,o
X
X
X
Smell Threshold Test c,o
X
X
Efficacy Assessments (Clinician)
MADRS (7-day recall; performed by 
independent, remote raters)
X
X q
X q
X k,q
X c,q
X c,q
X c,q
X c,q
CGI-S c
X
X
X
X
X
X
X
X
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
51
Status: Approved, Date: 4 April 2017
Screening/Prospective 
Observational Phase
Open-label Induction Phase
Visit number
1.1
1.2
1.3 a
2.1 a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9 b
Week
Week 1
End of 
Week 2
End of 
Week 4
1
2
3
4
Study day
—
—
—
1
(baseline)
4
8
11
15
18
22
25
28
Clinic visit window (in days)
—
±2
±2
—
±1
±1
±1
±1
±1
±1
±1
±1
Clinic visit (C) or remote MADRS interview 
only (RM)
C
C
C
C
C
C
C
C
C
C
C
C
Subject-completed Assessments
PAQ
X
X
X
PHQ-9 c
X
X
X
X
SDS c
X
X
X
X
GAD-7 c
X
X
X
EQ-5D-5L c
X
X
X
X
Cognition Testing
Practice session for computerized cognitive
battery
X
Computerized cognitive battery and HVLT-R
X
X
Clinical Laboratory Assessments
TSH, HbA1c
X
Lipid panel (fasting)
X
Hematology, chemistry c
X
X
X
Urine drug screen c
X
X
X
X
Alcohol breath test
X
X
Urinalysis c
X
X
X
X
Serum pregnancy test
X
Urine pregnancy test c
X
X
X
Biomarkers
Blood sample collection (protein) c,l
X
X
X
X
Blood sample collection (RNA) c,l
X
X
X
X
Blood sample collection (DNA) c,l
X
X
Ongoing Subject Review
Concomitant therapy
Ongoing
Adverse events
Ongoing
Other
Menstrual cycle tracking (start date of last 
menstrual period prior to study visit) n
X
X
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
52
Status: Approved, Date: 4 April 2017
Footnotes:
Abbreviations: BMI = body mass index; BPIC-SS = Bladder Pain/Interstitial Cystitis Symptom Score; BPRS+ = 4-item positive symptom subscale of the Brief Psychiatric Rating Scale; C = clinic 
visit; CADSS = Clinician Administered Dissociative States Scale; CGADR = Clinical Global Assessment of Discharge Readiness; CGI-S = Clinical Global Impression – Severity; C-SSRS =
Columbia Suicide Severity Rating Scale; DNA = deoxyribonucleic acid; ECG = electrocardiogram;.EQ-5D-5L = EuroQol-5 dimension = 5-level; EW = early withdrawal; GAD-7 = Generalized 
Anxiety Disorder = 7-item scale; HbA1c = glycated hemoglobin test; HRUQ = Healthcare Resource Use Questionnaire;; HVLT-R = Hopkins Verbal Learning Test-Revised; IDS-C30 = Inventory of 
Depressive Symptomatology Clinician-rated, 30-item scale; MADRS = Montgomery-Asberg Depression Rating Scale; MGH-ATRQ = Massachusetts General Hospital Antidepressant Treatment 
History Questionnaire; MGH Female RLHQ = Massachusetts General Hospital Female Reproductive Lifecycle and Hormones Questionnaire; MINI = Mini International Neuropsychiatric 
Interview; MOAA/S = Modified Observer's Assessment of Alertness/Sedation; PAQ = Patient Adherence Questionnaire; PHQ-9 = Patient Health Questionnaire – 9; PWC-20 = Physician 
Withdrawal Checklist, 20 item scale; RNA = ribonucleic acid; SDS = Sheehan Disability Scale; STOP-Bang = Snoring, Tired, Observed Apnea, High Blood Pressure, Body mass index, Age, Neck 
Size, Gender (a questionnaire); TSH = thyroid-stimulating hormone; UPSIT = University of Pennsylvania Smell Identification Test.
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)
An additional, optional period of up to 3 weeks is permitted to taper and discontinue all current medication(s) being used for depression after completion of the Week 4 (Visit 1.3) assessments, 
per the local prescribing information or clinical judgment. Subjects who do not require a taper and are thus eligible to immediately proceed to the open-label induction phase can have Visit 1.3 
and Visit 2.1 occur on the same day or within 1 week of each other (if not occurring the same day, the antidepressant treatment regimen should be continued and discontinued prior to Visit 2.1) .
b)
If a subject withdraws before the end of the open-label induction phase (ie, before completing Visit 2.9/Day 28) for reasons other than withdrawal of consent, an Early Withdrawal Visit (refer to
Time and Events Schedule: Early Withdrawal/End of Maintenance Phase Visit and Follow-up Phase) should be conducted, followed by the follow-up phase. If the Early Withdrawal Visit is 
conducted on the same day as a scheduled visit, duplicate assessments are not required.
c)
Predose (if/when performed on intranasal dosing days). Predose subject-reported outcome assessments should be administered before all other study-related procedures during a clinic visit.
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 for blood pressure monitoring on intranasal dosing days.
e)
Twelve-lead ECG will be performed predose and at t = 1 hour postdose at Visit 2.1. Thereafter, 12-lead ECG will be performed at t = 1 hour postdose only (ie, no predose ECG is required) at 
Visits 2.3, 2.5, and 2.8. A time window of ±15 minutes will be permitted.
f)
The MOAA/S will not be performed at Visit 1.1 (pulse oximetry only). The MOAA/S will be performed every 15 minutes from predose to t = +1.5 hours postdose (please refer to Section 9.4
for further guidance on MOAA/S assessments). Pulse oximetry will be performed every 15 minutes from predose to t = 1.5 hours postdose (please refer to Section 9.4 for further guidance on 
timing of pulse oximetry assessments).
g)
The BPRS+ and CADSS will be performed predose and at 40 minutes and 1.5 hours postdose. 
h)
CGADR will be performed at 1 hour and 1.5 hours postdose; if the response is not “Yes” at 1.5 hour postdose, 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. A subject should not be discharged prior to the 1.5 hour time point.
i)
PWC-20 will be performed only if the subject is not continuing into the optimization phase.
j)
Nasal symptom questionnaire will be performed predose and at 1 hour postdose.
k)
Performed for subjects requiring a taper period during the screening/prospective observational phase; the result will be considered as the subject’s baseline MADRS for the open-label induction 
phase. For all other subjects, the baseline MADRS for the open-label induction phase will be the MADRS performed at the end of Week 4 of the screening/prospective observational phase.
l)
Blood samples should be collected prior to dosing. It is preferred that subjects adhere to a low fat diet on the day of sample collection.
m)
Additional 2-week supply of the oral antidepressant medication only for subjects entering the follow-up phase.
n)
At Week 1 of the screening/prospective observational phase, the start date of the last menstrual period prior to study visit is captured as part of the MGH-FRLHQ: Module I. Thereafter, 
menstrual cycle tracking is only applicable to women with a menstrual cycle and is documented separately.
o)
If the subject has significant nasal congestion on the day of a scheduled assessment of sense of smell, then the site should consider postponing the UPSIT, Smell Threshold Test, or both (as 
applicable) to the next scheduled clinic visit.
p)
If a subject has started a scheduled clinic visit in which an intranasal treatment session is planned, but then a predose observation (eg, blood pressure results) prompts the site staff to postpone 
the intranasal treatment session within the visit window, then all time points (including predose) of the footnoted assessments must be repeated on the actual intranasal treatment session day, as 
follows: vital signs (ie, blood pressure, pulse, respiratory rate, and temperature), 12-lead ECG, C-SSRS (since last visit), MOAA/S, pulse oximetry, BPRS+, and CADSS.
q)
The MADRS should be administered no more than 2 days prior to the subject’s targeted (not actual) clinic visit date (except Visit 2.9, which is within 1 day prior). If performed on the day of the 
scheduled clinic visit for an intranasal treatment session, the MADRS must be performed prior to the intranasal treatment session.
r)
Performed only if Visit 1.3 and Visit 2.1 do not occur on the same day.
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
53
Status: Approved, Date: 4 April 2017
TIME AND EVENTS SCHEDULE (Optimization Phase)
Phase
Optimization Phase a
Visit Number
3.1 b
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
3.10
3.11
3.12
3.13 c
Week
4
5
6
7
8
9
10
11
12
13
14
15
16
Day
28
32
39
46
53
60
67
74
81
88
95
102
109
Clinic (C) or remote MADRS only (RM) visit d
C
C
C
C
C
C or 
RM
C
C or 
RM
C
C or 
RM
C
C or 
RM
C
Study Procedures
Administrative
ICF (transferred-entry subjects only)
X
Inclusion/exclusion criteria (transferred-entry 
subjects only)
X
Efficacy Assessments (Clinician)
MADRS (7-day recall): independent remote rater 
Permitted window: -3 days
X
X
X
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X e
X
Xe
X
X e
X
X e
X
Subject-completed Assessments
PHQ-9 f
X
X
X
X
X
X
SDS f
X
X
X
GAD-7 f
X
X
X
X
EQ-5D-5L f
X
X
X
X
X
X
Study Drug
Intranasal treatment session 
X
X
X
X
X e
X
X e
X
X e
X
X e
Adjustment of intranasal treatment session 
frequency (if applicable)
X
X
Dispensing oral antidepressant (open-label) 
X
X
X
Xn
Dispense subject diary for oral antidepressant
X
Oral antidepressant compliance check, including 
review of subject diary
X
X
X
X
X
X
X
X
Collect/return of subject diary
X
Drug accountability (intranasal study medication)r
X
X
X
X
X
X
X
X
X
X
X
Drug accountability (oral antidepressant)
X
X
X
Safety Assessments (Site-completed)
Physical examination, nasal examination, weight
X
X
X
Vital signs (predose): blood pressure, pulse, 
respiratory rate, and temperature f,q
X
X
X
X
X e
X
X e
X
X e
X
X e
X
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
54
Status: Approved, Date: 4 April 2017
Phase
Optimization Phase a
Visit Number
3.1 b
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
3.10
3.11
3.12
3.13 c
Week
4
5
6
7
8
9
10
11
12
13
14
15
16
Day
28
32
39
46
53
60
67
74
81
88
95
102
109
Clinic (C) or remote MADRS only (RM) visit d
C
C
C
C
C
C or 
RM
C
C or 
RM
C
C or 
RM
C
C or 
RM
C
Study Procedures
Vital signs (postdose): blood pressure, pulse, and 
respiratory rate only g
X
X
X
X
X e
X
X e
X
X e
X
X e
12-lead ECG h,q
X
X
X e
X e
X
X e
X e
C-SSRS (since last visit version) q
X
X
X
X
X e
X
X e
X
X e
X
X e
MOAA/S and pulse oximetryi,q
X
X
X
X
X e
X
X e
X
X e
X
X e
BPRS+ and CADSS j,q
X
X
X
X
X e
X
X e
X
X e
X
X e
CGADR k
X
X
X
X
X e
X
X e
X
X e
X
X e
PWC-20 (only for subjects not entering 
maintenance phase)
X
Safety Assessments (Subject)
Nasal symptom questionnairel
X
X
X
X
Xe
X
Xe
X
Xe
X
Xc
BPIC-SS
X
X
X
X
Assessment of Sense of Smell
UPSITf,p
X
Smell Threshold Test p
X
Cognitive Testing
Computerized cognitive battery and HVLT-Rf
X
Clinical Laboratory Testsf
Hematology and chemistry
X
X
X
Urinalysis
X
X
X
Urine drug screen
X
X
X
Alcohol breath test
X
X
X
Urine pregnancy test
X
X
X
Medical Resource Utilization
HRUQ
X
X
X
X
X
X
Biomarkers
Blood sample collection (protein) f,m
X
X
Blood sample collection (RNA) f,m
X
X
Blood sample collection (DNA) f,m
X
X
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
55
Status: Approved, Date: 4 April 2017
Phase
Optimization Phase a
Visit Number
3.1 b
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
3.10
3.11
3.12
3.13 c
Week
4
5
6
7
8
9
10
11
12
13
14
15
16
Day
28
32
39
46
53
60
67
74
81
88
95
102
109
Clinic (C) or remote MADRS only (RM) visit d
C
C
C
C
C
C or 
RM
C
C or 
RM
C
C or 
RM
C
C or 
RM
C
Study Procedures
Ongoing Subject Review and Other
Menstrual cycle tracking (start date of last 
menstrual period prior to study visit) o
X
X
X
Concomitant therapy
Ongoing
Adverse events
Ongoing
Footnotes:
Abbreviations: BPIC-SS = Bladder Pain/Interstitial Cystitis Symptom Score; BPRS+ = Four-item Positive Symptom subscale of the Brief Psychiatric Rating Scale; C = clinic visit;
CADSS = Clinician-Administered Dissociative States Scale; 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 = European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level; GAD-7 = Generalized Anxiety 
Disorder, 7-item; HRUQ=Healthcare Resource Use Questionnaire; HVLT-R = Hopkins Verbal Learning Test - Revised; MADRS = Montgomery-Asberg Depression Rating Scale; 
MOAA/S = Modified Observer's Assessment of Alertness/Sedation; PHQ-9 = Patient Health Questionnaire, 9-item; PWC-20 = Physician Withdrawal Checklist, 20-item; RM = Remote 
MADRS; SDS = Sheehan Disability Scale; UPSIT = University of Pennsylvania Smell Identification Test.
Note: On intranasal dosing days, time 0 is defined as the time of the first intranasal spray.
a)
If a subject withdraws before the end of the optimization phase for reasons other than withdrawal of consent, or is not eligible to continue into the maintenance phase, an Early 
Withdrawal Visit (Refer to Time and Events Schedule: Early Withdrawal/End of Maintenance Phase Visit and follow up phase) should be conducted. If the Early Withdrawal Visit is 
conducted on the same day as a scheduled visit, duplicate assessments are not required.
b)
Results for all assessments performed on Day 28 of the induction phase for direct-entry subjects (Visit 2.9) and transferred-entry subjects (Visit 2.10 of Study ESKETINTRD3001 or 
ESKETINTRD3002) will serve as the baseline values for the optimization phase and will not be repeated as part of Visit 3.1. The Day 28 visit should coincide with Day 28 (Visit 3.1) 
for this study. All transferred-entry subjects must meet all of the transferred-entry subject-specific inclusion criteria and none of the exclusion criteria in order to be enrolled.
c)
Visit 3.13 (Week 16) serves as the last visit for the optimization phase and will also be the first visit (Visit 4.1; Week 16) of the maintenance phase for subjects who qualify to 
continue. Results for all assessments preformed at this visit will also serve as baseline for the maintenance phase and will be completed before randomization to double-blind 
intranasal study drug.
d)
Clinic visits (visit window ±3 days) will be conducted for all intranasal treatment sessions (weekly or every other week); otherwise only a remote MADRS (visit window: -3 days) 
will be conducted. 
e)
Performed only at clinic visits for intranasal treatment sessions (omitted if remote MADRS only).
f)
Predose (if/when performed on intranasal dosing days). Predose subject-reported outcome assessments should be administered before all other study-related procedures during a clinic 
visit.
g)
Postdose vital signs will be performed at t = +40 minutes, 1 hour, and 1.5 hours postdose. Please refer to Section 6.1 for guidance for blood pressure monitoring on intranasal dosing 
days.
h)
The 12-lead electrocardiogram will be performed at 1 hour postdose. A time window of ±15 minutes is permitted.
i)
The MOAA/S will be performed every 15 minutes from predose to t = 1.5 hours postdose (please refer to Section 9.4 for further guidance on MOAA/S assessments). Pulse oximetry 
will be performed every 15 minutes from predose to t = 1.5 hours postdose (please refer to Section 9.4 for further guidance on timing of pulse oximetry assessments).
j)
The BPRS+ and CADSS will be performed predose and at 40 minutes and 1.5 hours postdose.
k)
The CGADR will be performed at 1 hour and 1.5 hours postdose; if the response is not “Yes” at 1.5 hours postdose, 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. A subject should not be discharged prior to the 1.5 hour time point.
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
56
Status: Approved, Date: 4 April 2017
l)
The nasal symptom questionnaire will be performed predose and at 1 hour postdose.
m)
Blood samples should be collected prior to dosing. It is preferred that subjects adhere to a low fat diet on the day of sample collection.
n)
Additional 2-week supply of the oral antidepressant medication only for subjects entering the follow-up phase.
o)
Only applicable to women with a menstrual cycle.
p)
If the subject has significant nasal congestion on the day of a scheduled assessment of sense of smell, then the site should consider postponing the UPSIT or Smell Threshold Test (as 
applicable) to the next scheduled clinic visit.
q)
If a subject has started a scheduled clinic visit in which an intranasal treatment session is planned, but then a predose observation (eg, blood pressure results) prompts the site staff to 
postpone the intranasal treatment session within the visit window, then all time points (including predose) of the footnoted assessments must be repeated on the actual intranasal 
treatment session day, as follows: vital signs (ie, blood pressure, pulse, respiratory rate, and temperature), 12-lead ECG, C-SSRS (since last visit), MOAA/S, pulse oximetry, BPRS+, 
and CADSS.
r)
Drug accountability for intranasal study medication should be performed weekly during Weeks 5 through 8 (inclusive) and then weekly or every other week from Weeks 9 through 15 
(inclusive).
NCT02493868

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3003 Amendment 4
57
Status: Approved, Date: 4 April 2017
TIME AND EVENTS SCHEDULE (Maintenance Phase)
Phase
Maintenance Phase
Visit Number a,b
4.1 c
4.2
4.3
4.4
4.5
4.6 to 4.X
Study Procedure Frequency From Week 20 Through End of Phase
Week
16
17
18
19
20
Every 
week
Every 
2 weeks
Every 
4 weeks
Every 
8 weeks
Every 
12 weeks
Day
109
116
123
130
137
Every 
7 days
Every 
14 days
Every 
28 days
Every 
56 days
Every 
84 days
Clinic (C) or Remote MADRS only (RM) 
visit a
C
C/RM
C
C/RM
C
C/RM
C
C
C
C
Study Procedures
Study Drug d
Randomization: Primary (subjects in stable 
remission after treatment with intranasal 
esketamine and an oral antidepressant) 
X e
Randomization: Secondary (subjects with 
stable response after treatment with intranasal 
esketamine and an oral antidepressant)
X e
Intranasal treatment session (esketamine or 
placebo) 
X
Xf
X
Xf
X
X f
X f
Adjustment of intranasal treatment session 
frequency (if applicable)
X
X
X
Dispensing oral antidepressant (open-label)
X
X
X
Dispense subject diary for oral antidepressant
X
Oral antidepressant compliance check, 
including review of subject diary
X
X
X
X
Drug accountability for intranasal study 
medication
X
Xf
X
Xf
X
X f
Drug accountability for oral antidepressant
X
X
Efficacy Assessments (Clinician)
MADRS (7-day recall) h –
independent, remote rater 
X
X
X
X
X
CGI-S
X
X
X f
Subject-completed Assessments
PHQ-9 i
X
X
X
SDS i
X
X
GAD-7 i
X
X
EQ-5D-5L i
X
X
X
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Phase
Maintenance Phase
Visit Number a,b
4.1 c
4.2
4.3
4.4
4.5
4.6 to 4.X
Study Procedure Frequency From Week 20 Through End of Phase
Week
16
17
18
19
20
Every 
week
Every 
2 weeks
Every 
4 weeks
Every 
8 weeks
Every 
12 weeks
Day
109
116
123
130
137
Every 
7 days
Every 
14 days
Every 
28 days
Every 
56 days
Every 
84 days
Clinic (C) or Remote MADRS only (RM) 
visit a
C
C/RM
C
C/RM
C
C/RM
C
C
C
C
Safety Assessments (Site-completed)
Physical examination, nasal examination, and 
weight
X
X
Vital signs (predose): blood pressure, pulse, 
respiratory rate, and temperature s
X f
X
Xf
X
X f
Vital signs (postdose): blood pressure, pulse, 
and respiratory rate only j
X
Xf
X
Xf
X
X f
12-lead ECG k,s
X
X
X
C-SSRS (since last visit version) s
Xf
X
Xf
X
X f
MOAA/S and pulse oximetry l,s
X
Xf
X
Xf
X
X f
BPRS+ and CADSS m,s
X
Xf
X
Xf
X
X f
CGADR n
X
Xf
X
Xf
X
X f
PWC-20 (performed at last clinic visit of this 
phase)
Safety Assessments (Subject)
Nasal symptom questionnaire o
X
X
X
X
BPIC-SS 
X
X
Clinical Laboratory Testsi
Hematology and chemistry
X
X
Urinalysis (to be performed at same visit as 
BPIC-SS)
X
X
Urine drug screen
X
X
Alcohol breath test
X
X
Urine pregnancy test
X
X
Assessment of Sense of Smell
UPSIT r
X
X
Smell Threshold Test r
X
Cognition Testing e
Computerized cognitive battery and HVLT-R
X
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Phase
Maintenance Phase
Visit Number a,b
4.1 c
4.2
4.3
4.4
4.5
4.6 to 4.X
Study Procedure Frequency From Week 20 Through End of Phase
Week
16
17
18
19
20
Every 
week
Every 
2 weeks
Every 
4 weeks
Every 
8 weeks
Every 
12 weeks
Day
109
116
123
130
137
Every 
7 days
Every 
14 days
Every 
28 days
Every 
56 days
Every 
84 days
Clinic (C) or Remote MADRS only (RM) 
visit a
C
C/RM
C
C/RM
C
C/RM
C
C
C
C
Medical Resource Utilization
HRUQ
X
X
X
Biomarkers
Blood sample collection (protein) i,p
X
Blood sample collection (RNA) i,p
X
Blood sample collection (DNA) i,p
X
Ongoing Subject Review and Other
Menstrual cycle tracking (start date of last 
menstrual period prior to study visit) q
X
X
Concomitant therapy
Ongoing
Adverse events
Ongoing
Footnotes:
Abbreviations: BPIC-SS = Bladder Pain/Interstitial Cystitis Symptom Score. BPRS+ = Brief Psychiatric Rating Scale, positive symptom subscale; CADSS = Clinician-Administered 
Dissociative States Scale; CGADR = Clinical Global Assessment of Discharge Readiness; CGI-S = Clinical Global Impression - Severity; C-SSRS = Columbia Suicide Severity Rating 
Scale; EQ-5D-5L = European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level; GAD-7 = Generalized Anxiety Disorder, 7-item; HRUQ= Healthcare Resource Use Questionnaire; 
HVLT-R = Hopkins Verbal Learning Test - Revised; MADRS = Montgomery-Asberg Depression Rating Scale; MOAA/S = Modified Observer's Assessment of Alertness/Sedation; 
PHQ-9 = Patient Health Questionnaire, 9-item; PWC-20 = Physician Withdrawal Checklist, 20-item; SDS = Sheehan Disability Scale; UPSIT = University of Pennsylvania Smell 
Identification Test.
Note: On intranasal dosing days, time 0 is defined as the time of the first intranasal spray.
a)
Visits (clinic or remote contacts) will be conducted weekly during the maintenance phase. Clinic visits (visit window: ±3 days) will be conducted for all intranasal treatment sessions 
(weekly or every other week); otherwise only a remote visit for MADRS (visit window: -3 days) will be conducted. Due to the variable duration of this phase, following Visit 4.5 visit 
numbers will continue sequentially (eg, 4.6, 4.7, etc) until the subject completes the phase. The frequency of study procedures from Week 20 to the end of the phase is provided 
within the respective column (ie, every week, 2 weeks, 4 weeks, 8 weeks, and 12 weeks). 
b)
If a subject withdraws before the end of the maintenance phase for reasons other than withdrawal of consent, an Early Withdrawal Visit should be conducted. A subject meeting 
relapse criteria is not considered to be an early withdrawal subject; for relapse subjects, and those subjects remaining relapse-free at the time of study termination, an End of 
Maintenance Phase Visit should be conducted. If the End of Maintenance Visit is conducted on the same day as a scheduled visit, duplicate assessments are not required. Refer to the 
Time and Events Schedule: Early Withdrawal/End of Maintenance Phase Visit and Follow-up Phase.
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c)
Visit 3.13 (Week 16) serves as the last visit for the optimization phase and will also be the first visit (Visit 4.1; Week 16) of the maintenance phase for subjects who qualify to 
continue. Results for all assessments performed at this Visit 3.13 of the optimization phase will also serve as baseline for the maintenance phase and will be completed before 
randomization to double-blind intranasal study drug. Duplicate assessments are not required.
d)
Transferred-entry subjects who achieve stable remission or stable response in the optimization phase after treatment with an oral antidepressant plus intranasal placebo will continue 
to receive the same treatment in order to maintain the blinding for the ongoing short-term studies.
e)
Performed prior to intranasal dose administration.
f)
Performed only at clinic visits for intranasal treatment sessions (omit if remote contact visit).
g)
At the last clinic visit of this phase, an additional 2-week supply of the oral antidepressant medication is provided only for subjects entering the follow-up phase.
h)
The last MADRS assessment performed prior to the first intranasal treatment session of the maintenance phase will be the baseline value for this phase. 
i)
Predose (if/when performed on intranasal dosing days). Predose subject-reported outcome assessments should be administered before all other study-related procedures during a clinic 
visit.
j)
Postdose vital signs will be performed at t = +40 minutes, 1 hour, and 1.5 hours postdose. Please refer to Section 6.1 for guidance for blood pressure monitoring on intranasal dosing 
days.
k)
At clinic visits for intranasal treatment sessions, the 12-lead electrocardiogram will be performed at 1 hour postdose. A time window of ±15 minutes is permitted.
l)
The MOAA/S will be performed every 15 minutes from predose to t = 1.5 hours postdose (please refer to Section 9.4 for further guidance on MOAA/S assessments). Pulse oximetry 
will be performed every 15 minutes from predose to t=1.5 hours postdose (please refer to Section 9.4 for further guidance on timing of pulse oximetry assessments).
m)
The BPRS+ and CADSS will be performed predose and at 40 minutes and 1.5 hours postdose.
n)
The CGADR will be performed at 1 hour and 1.5 hours postdose; if the response is not “Yes” at 1.5 hours postdose, 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.
o)
At clinic visits for intranasal treatment sessions, the nasal symptom questionnaire will be performed predose and at 1 hour postdose.
p)
Blood samples should be collected prior to dosing. It is preferred that subjects adhere to a low fat diet on the day of sample collection.
q)
Only applicable to women with a menstrual cycle.
r)
If the subject has significant nasal congestion on the day of a scheduled assessment of sense of smell, then the site should consider postponing the UPSIT or Smell Threshold Test (as 
applicable) to the next scheduled clinic visit.
s)
If a subject has started a scheduled clinic visit in which an intranasal treatment session is planned, but then a predose observation (eg, blood pressure results) prompts the site staff to 
postpone the intranasal treatment session within the visit window, then all time points (including predose) of the footnoted assessments must be repeated on the actual intranasal 
treatment session day, as follows: vital signs (ie, blood pressure, pulse, respiratory rate, and temperature), 12-lead ECG, C-SSRS (since last visit), MOAA/S, pulse oximetry, BPRS+, 
and CADSS.
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TIME AND EVENTS SCHEDULE (Early Withdrawal/End of Maintenance Phase Visit and Follow-up Phase)
Phase
Early Withdrawal//End of 
Maintenance Phase a
Follow-up Phase b
Visit Number 
EW/EMP
5.1
5.2
Weeks After Last Clinic Visit
-
1
2
Clinic (C) or Remote Assessments Only (RA) Visit
C
RAf
C
Study Procedures
Study Drug
Drug accountability (oral antidepressant study medication)
X
X
Dispensing of additional supply of new oral antidepressant (duloxetine, 
escitalopram, sertraline, or venlafaxine XR)
X
Oral antidepressant compliance check
X
X
Collect/return of subject diary
X
Safety Assessments (Site-Completed)
Physical examination
X
X
Nasal examination
X
X
Vital signs: blood pressure, pulse, respiratory rate, temperature
X
X
12-lead electrocardiogram
X
X
C-SSRS: Since last visit version
X
X
PWC-20
X
X
X
Safety Assessments (Subject-Completed) c
BPIC-SS
X
X
Efficacy Assessments (Clinician-Completed)
MADRS (independent, remote blinded rater)
X
X
X
CGI-S 
X
X
Efficacy Assessments (Subject-Completed) c
PHQ-9
X
X
SDS
X
X
GAD-7
X
X
EQ-5D-5L
X
X
Assessment of Sense of Smell
UPSIT e
X
Smell Threshold Test e
X
Cognition testing
Computerized cognitive battery and HVLT-R
X
X
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Phase
Early Withdrawal//End of 
Maintenance Phase a
Follow-up Phase b
Visit Number 
EW/EMP
5.1
5.2
Weeks After Last Clinic Visit
-
1
2
Clinic (C) or Remote Assessments Only (RA) Visit
C
RAf
C
Medical Resource Utilization
HRUQ
X
X
Clinical Laboratory Assessments
Hematology and chemistry
X
X
Urinalysis
X
X
Serum pregnancy test
X
X
Biomarkers
Blood sample collection (protein)
X
X
Blood sample collection (RNA)
X
X
Blood sample collection (DNA)
X
Other Assessments
Menstrual cycle tracking (start date of last menstrual period prior to study visit) d
X
Concomitant therapy
X
Ongoing
Adverse events
X
Ongoing
Footnotes:
Abbreviations: BPIC-SS = Bladder Pain/Interstitial Cystitis Symptom Score; CGI-S = Clinical Global Impression - Severity; C-SSRS = Columbia Suicide Severity Rating Scale; 
EQ-5D-5L = European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level; GAD-7 = Generalized Anxiety Disorder, 7-item; HRUQ= Healthcare Resource Use Questionnaire; 
HVLT-R = Hopkins Verbal Learning Test - Revised; MADRS = Montgomery-Asberg Depression Rating Scale; PHQ-9 = Patient Health Questionnaire, 9-item; PWC-20 = Physician 
Withdrawal Checklist, 20-item; RA = remote assessment only; SDS = Sheehan Disability Scale.
a)
If a subject withdraws before the end of the induction, optimization, or maintenance phase for reasons other than withdrawal of consent, or has completed the induction or 
optimization phase but is not eligible to continue to the next treatment phase, an Early Withdrawal Visit should be conducted followed by the follow-up phase. If the Early 
Withdrawal Visit is conducted on the same day as a scheduled visit, duplicate assessments are not required. A subject meeting relapse criteria is not considered to be an early 
withdrawal subject; for these subjects, and subjects currently in the maintenance phase at the time the study is terminated, will conduct an End of Maintenance Phase Visit. For those 
subjects who relapse in the Maintenance phase, if clinically indicated based on investigator’s judgment, after completing the end of maintenance visit, the subject may proceed to the 
open-label safety extension study, 54135419TRD3008, without completing the follow up phase.  Similarly, when the study is stopped, subjects in the Induction phase who are 
responders, after completing the early withdrawal visit, if clinically indicated based on the investigator’s judgment, may proceed to the 54135419TRD3008 study, without completing 
the follow up phase.
b)
Visit window will be ±3 days.
c)
Subject-reported outcome assessments should be administered before all other study-related procedures during a clinic visit.
d)
Only applicable to women with a menstrual cycle.
e)
If the subject has significant nasal congestion on the day of a scheduled assessment of sense of smell, then the site should consider postponing the UPSIT and Smell Threshold Test to 
the next scheduled clinic visit.
f)
At the “Remote Assessment” visit, site staff will contact the subject by telephone to obtain information regarding adverse events and concomitant therapies.
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ABBREVIATIONS
AHI
apnea-hypopnea index
ASA
American Society of Anesthesiologists
AUC
area under the plasma concentration-time curve
BDNF
brain-derived neurotrophic factor
BPIC-SS
Bladder Pain/Interstitial Cystitis Symptom Score 
BPRS
(the full 18-item) Brief Psychiatric Rating Scale
BPRS+
(the 4-item) Brief Psychiatric Rating Scale, positive-symptom subscale
CADSS
Clinician-Administered Dissociative States Scale
CGADR
Clinical Global Assessment of Discharge Readiness
CGI-S
Clinical Global Impression - Severity
Cmax
maximum plasma concentration
CRF
case report form
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
cytochrome P450, with any appended letters (2B6, 3A4, etc) indicating subtypes
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, fourth edition
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, fifth edition
ECG
electrocardiogram
eCRF
electronic case report form
ECT
electroconvulsive therapy
eDC
electronic data capture
EQ-5D-5L
European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level (questionnaire)
EQ-VAS
EuroQol Group: visual analogue scale
EU
European Union
FT4
free thyroxine
GAD-7
Generalized Anxiety Disorder, 7-item (scale)
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
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
IDS-C30
Inventory of Depressive Symptomatology - Clinician-rated, 30 item 
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
IWRS
interactive web response system
MADRS
Montgomery-Asberg Depression Rating Scale
MAOI
monoamine oxidase inhibitor
MedDRA
Medical Dictionary for Regulatory Activities
MINI
Mini International Neuropsychiatric Interview
MMRM
mixed-effects model for repeated measures
MOAA/S
Modified Observer's Assessment of Alertness/Sedation
MDD
major depressive disorder
MGH-ATRQ
Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire
MGH-FRLHQ
Massachusetts General Hospital - Female Reproductive Lifecycle and Hormones Questionnaire
NMDA
N-methyl-D-aspartate
PAQ
Patient Adherence (to Antidepressant Medication) Questionnaire
PCP
phencyclidine
PHQ-9
Patient Health Questionnaire, 9-item
PQC
product quality complaint
PWC-20
Physician Withdrawal Checklist, 20-item
QTc
QT interval corrected
QTcB
QT interval corrected according to Bazett's formula
QTcF
QT interval corrected according to Fridericia's formula
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SAP
statistical analysis plan
SD
standard deviation
SDS
Sheehan Disability Scale
SE
standard error
SmPC
Summary of Product Characteristics
SNRI
serotonin-norepinephrine reuptake inhibitor
SpO2
saturation of peripheral blood oxygen
SSRI
selective serotonin reuptake inhibitors
STOP-Bang
Snoring, Tiredness, Observed Apnea, High Blood Pressure, Body Mass Index, Age, Neck Size, 
Gender (questionnaire)
SUSAR
suspected unexpected serious adverse reaction
TEAEs
treatment-emergent adverse events
TRD
treatment-resistant depression
UPSIT
University of Pennsylvania Smell Identification Test
US
United States
XR
extended-release
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1.
INTRODUCTION
Major depressive disorder (MDD) is a serious, recurrent, and disabling psychiatric illness; is the 
second leading cause of years lost to disability worldwide; and is associated with excess 
mortality (the estimated median years of potential life lost is 10 years).134,135,140 About 30% of 
patients fail to achieve remission despite treatment with multiple antidepressant medications, and 
are considered to have treatment-resistant depression (TRD).44,113 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.113,118 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.26,33
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.65 The desired analgesic-anesthetic effects of ketamine and esketamine are 
attributed to the blockade of ionotropic N-methyl-D-aspartate (NMDA) glutamate 
receptors.82,101,145
Monoamines (serotonin, norepinephrine, and/or dopamine) are only modulatory transmitters; 
therefore, conventional monoaminergic antidepressants would not be expected to robustly affect 
synaptic transmission, activity-dependent release of brain-derived neurotrophic factor (BDNF), 
or synaptogenesis.33 In contrast, the mechanism of action of ketamine and esketamine is distinct 
from conventional antidepressants because both ketamine and esketamine profoundly affect fast 
excitatory glutamate transmission, increase BDNF release, and stimulate synaptogenesis.33
Most literature reports of the antidepressant effects of ketamine describe studies using IV 
administration of the racemate, with a few exceptions.71 Janssen Research & Development (JRD) 
is developing intranasal esketamine as an antidepressant therapy because it has higher NMDA 
receptor affinity, which allows a lower volume to be administered via the intranasal route.80,95,103
For the most comprehensive nonclinical and clinical information regarding esketamine
(JNJ-54135419), please refer to the latest edition of the Investigator's Brochure.60
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.
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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)65:
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.
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.60
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.60
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.60
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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. 
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.60
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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.60
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.60
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.39 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. 
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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.60 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.60
1.1.2.
Clinical Studies
1.1.2.1.
Pharmacokinetics and Product Metabolism
Metabolism
Excretion
Intravenous Esketamine 
 
 
 
 
 
 
 
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Intranasal Esketamine
, 
 
 
 
 
 
 
 
 
 
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1.1.2.2.
Pharmacodynamics and Efficacy
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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.51,66,108,125
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Adverse Events Associated With Short-term Use of Intranasal Esketamine in Patients with 
MDD
According to the SmPC for esketamine,66 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.64
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 
intranasal esketamine 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).15 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 intranasal esketamine (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.116 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 received no further study medication.
The event resolved on the same day and 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. Study medication was stopped 
following this event, which resolved on the same day. The 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 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.116
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Dissociative symptoms measured on the Clinician-Administered Dissociative States Scale 
(CADSS) 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 intranasal esketamine 
administration.

The mean (SD) peak systolic blood pressure 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 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 
drugs.88 Eighty percent of the participants were retested at the end of 1 year. Cognitive deficits 
(including impairment in spatial working memory, pattern recognition memory, and category 
fluency) 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 
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there is little evidence of any link between chronic, heavy use of ketamine and diagnosis of a 
psychotic disorder.86
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.22,85,87,93 Overall, infrequent or recreational 
ketamine use does not appear to be associated with long-term cognitive impairment.93 The most 
robust findings are that frequent ketamine users (more than 5 times a week) exhibit impairments 
in both short- and long-term memory.87 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.88
Ketamine-induced ulcerative cystitis is a recently identified complication.86 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 literature,56,61,84,99 but no large-
scale studies, and so the incidence of ketamine dependence is largely unknown.86 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.89 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.123 There is conflicting evidence 
of the existence of a "withdrawal syndrome" after cessation of ketamine use.86 Cravings seem to 
be a key problem in 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.86 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.20,76 However, a specific ketamine withdrawal syndrome has not yet been described.86
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Please refer to the Investigator’s Brochure for a summary of the adverse events reported in 
ketamine and esketamine studies.60
1.1.3.
Marketing Experience
No intranasal formulation of esketamine is currently marketed.
1.2.
Active Comparators
Subjects will be assigned to receive 1 of 4 commercially available oral antidepressant 
medications from 2 different classes of antidepressant medications, selective serotonin reuptake 
inhibitors (SSRIs: escitalopram or sertraline), or serotonin and norepinephrine reuptake 
inhibitors (SNRIs: duloxetine or venlafaxine extended release [XR]). The oral antidepressant 
medication will be started on Day 1 of the open-label induction phase and continued in the 
optimization, maintenance, and follow-up (if clinically indicated) phases.
The indications and safety information provided below for each oral antidepressant are from the 
United States (US) prescribing information.32,32,75,132 For further information, please refer to the 
appropriate package insert applicable to the local country in which the study is being conducted.
In the US, all of the oral antidepressant options include a black box warning in the prescribing 
information regarding suicidality and antidepressant drugs. The black box warning informs the 
prescriber that antidepressant treatments increased the risk compared with placebo of suicidal 
thinking and behavior (suicidality) in children, adolescents, and young adults in short-term 
studies of MDD and other psychiatric disorders. It states that anyone considering using the 
antidepressant in this population must balance the risk with the clinical need. Refer to the US
prescribing information for the entire content of the black box warning.
1.2.1.
Selective Serotonin Reuptake Inhibitors
1.2.1.1.
Escitalopram
Escitalopram is indicated in adults for acute and maintenance treatment of MDD and acute 
treatment of generalized anxiety disorder.
The starting dosage for MDD in the US prescribing information is 10 mg once daily, with a 
maximum of 20 mg once daily. If the dosage is increased to 20 mg, this should occur after a 
minimum of 1 week. No additional benefits have been seen at 20 mg/day dose.
In adult MDD subjects treated with escitalopram, the most commonly observed adverse reactions 
with escitalopram (incidence of approximately 5% or greater and approximately twice the 
incidence in placebo subjects) were insomnia, ejaculation disorder (primarily ejaculatory delay), 
nausea, sweating increased, fatigue, and somnolence.
Contraindications to the use of escitalopram include serotonin syndrome and monoamine oxidase 
inhibitor (MAOI) use (concomitant use with MAOIs intended to treat psychiatric disorders, 
linezolid, or IV methylene blue; use within 14 days of stopping treatment with an MAOI 
intended to treat psychiatric disorders [in addition, an MAOI should not be used within 14 days 
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of stopping escitalopram]); concomitant use with pimozide; and known hypersensitivity to 
escitalopram or citalopram or any of the inactive ingredients.
As with most SSRIs, a gradual reduction in the dosage rather than abrupt cessation of 
escitalopram treatment is recommended whenever possible.
1.2.1.2.
Sertraline
Sertraline hydrochloride is indicated in adults for the treatment of MDD, obsessions and 
compulsions in patients with obsessive compulsive disorder, panic disorder (with or without 
agoraphobia), post-traumatic stress disorder, premenstrual dysphoric disorder, and social anxiety 
disorder.
According to the US prescribing information, sertraline should be administered at a dose of 
50 mg once daily for the treatment of MDD. While a relationship between dose and effect has 
not been established for MDD, obsessive compulsive disorder, panic disorder, post-traumatic 
stress disorder, or social anxiety disorder, patients were dosed in a range of 50-200 mg/day in the 
clinical trials demonstrating the effectiveness of sertraline for the treatment of these indications. 
Consequently, a dose of 50 mg, administered once daily, is recommended as the initial 
therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose increases up to 
a maximum of 200 mg/day. Given the 24-hour elimination half-life of sertraline, dose changes 
should not occur at intervals of less than 1 week. The maximum dose of sertraline in the current 
study is 200 mg/day.
Contraindications to the use of sertraline include serotonin syndrome and MAOI use 
(concomitant use with MAOIs intended to treat psychiatric disorders, linezolid, or IV methylene 
blue; use within 14 days of stopping treatment with an MAOI intended to treat psychiatric 
disorders); concomitant use with pimozide; and known hypersensitivity to sertraline or any of the 
inactive ingredients.
In adult subjects, the most common TEAEs associated with the use of sertraline (incidence of at 
least 5% for sertraline or at least twice that for placebo within at least one of the indications) 
were ejaculation failure, dry mouth, increased sweating, somnolence, tremor, dizziness, fatigue, 
pain, malaise, abdominal pain, anorexia, constipation, diarrhea/loose stools, dyspepsia, nausea, 
agitation, insomnia, and decreased libido.
As with most SSRIs, a gradual reduction in the dosage rather than abrupt cessation treatment is 
recommended whenever possible.
1.2.2.
Serotonin and Norepinephrine Reuptake Inhibitors
1.2.2.1.
Duloxetine
Duloxetine is indicated in adults for MDD, generalized anxiety disorder, diabetic peripheral 
neuropathic pain, fibromyalgia, and chronic musculoskeletal pain.
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The starting dosage for MDD in the US prescribing information is 40 to 60 mg/day. The dosage 
for acute treatment is 40 to 60 mg/day, with maintenance treatment at 60 mg/day. For some 
patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to 
the medication before increasing to 60 mg once daily.
In the current study, subjects should be initiated with 60 mg/day. Subjects that have in the past 
shown increased sensitivity towards SSRI/SNRIs can, at the discretion of the treating physician, 
be started on a 30 mg dose and up-titrated to the therapeutic range of 60 mg by the start of Week 
2 of the open-label induction phase. 
The maximum dosage is 120 mg/day, although there is no evidence that dosages greater than 
60 mg/day confer any additional benefits. The maximum dose to be used in this study is 
60 mg/day.
For pooled studies for all approved indications, the most commonly observed adverse reactions 
in duloxetine-treated subjects (incidence of at least 5% and at least twice the incidence in 
placebo subjects) were nausea, dry mouth, somnolence, fatigue, constipation, decreased appetite, 
and hyperhidrosis. As observed in diabetic peripheral neuropathy studies, duloxetine treatment 
worsens glycemic control in some subjects with diabetes.
Contraindications to the use of duloxetine include use of an MAOI concomitantly or within 
2 weeks of MAOI use; and use in patients with uncontrolled narrow-angle glaucoma.
A gradual reduction in the dosage rather than abrupt cessation is recommended whenever 
possible.
1.2.2.2.
Venlafaxine Extended-release
Venlafaxine XR is indicated in adults for MDD and social anxiety disorder.
The starting dosage for MDD in US prescribing information is 75 mg/day (in some patients, 
37.5 mg/day for 4 to 7 days), with a dosage increase by 75 mg/day at intervals of 4 days or 
longer, and a maximum dosage of 225 mg/day. Dosage reductions are recommended for hepatic 
impairment (including mild) and renal impairment.
Contraindications to the use of venlafaxine XR include serotonin syndrome and MAOI use 
(concomitant use with MAOIs intended to treat psychiatric disorders, linezolid, or IV methylene 
blue; use within 14 days of stopping treatment with an MAOI intended to treat psychiatric 
disorders); concomitant use with pimozide; and known hypersensitivity to venlafaxine XR or any 
of the inactive ingredients.
In adult subjects with MDD, adverse events in short-term studies that occurred in at least 5% of 
the subjects receiving venlafaxine XR capsules and at a rate at least twice that of the placebo 
group were abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), 
central nervous system complaints (dizziness, somnolence, and abnormal dreams), and sweating.
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Sustained hypertension is noted within the Warnings and Precautions section. Preexisting 
hypertension should be controlled before treatment with venlafaxine XR. It is recommended that 
patients receiving venlafaxine hydrochloride XR tablets have regular monitoring of blood 
pressure. For patients who experience a sustained increase in blood pressure while receiving 
venlafaxine XR, either dosage reduction or discontinuation should be considered.
Across most indications, a dose-related increase in supine systolic and diastolic blood pressure 
was evident in venlafaxine XR-treated patients. Across all clinical studies, 1.4% of subjects in 
the venlafaxine XR-treated groups experienced a 15-mm Hg increase in supine diastolic blood 
pressure, with blood pressure 105 mm Hg, compared with 0.9% of subjects in the placebo 
groups. Similarly, 1% of subjects in the venlafaxine XR-treated groups experienced a 
20-mm Hg increase in supine systolic blood pressure, with blood pressure 180 mm Hg, 
compared with 0.3% of subjects in the placebo groups.
A gradual dosage reduction, individualized as necessary, is recommended to avoid 
discontinuation symptoms.
1.3.
Overall Rationale for the Study
In contrast to available data about short-term antidepressant effects of esketamine/ketamine, 
much less is known about how to sustain the antidepressant effect over the long term. No 
systematic studies have yet described sustaining the response to ketamine. The only available 
data are case reports and anecdotal reports from clinicians who have been using ketamine over 
extended periods of time to sustain the initial response to ketamine.7 On average, the duration of 
response from a single IV dose of ketamine is approximately 5 to 7 days.146 The duration of 
response after the last IV session following repeated administration studies (up to 6 sessions over 
2 weeks) varies highly between subjects; the time to relapse has been reported as a median of 
18 days (range, 2 to >83 days)90 or a mean of 16 days (range, 7 to 28 days).122
In the abovementioned Study KETIVTRD2002, in the group that received IV ketamine twice per 
week for 4 weeks, all subjects maintained the response for at least 15 days following the last IV
ketamine dose. Similarly, in the abovementioned Study ESKETIVTRD2001, subjects maintained 
their response for approximately 2 weeks following the last IV esketamine dose.
Long term maintenance of efficacy could be achieved either through repeated intranasal dosing 
as is the case with most antidepressant medications or possibly by an oral antidepressant alone. 
Studies to assess whether venlafaxine or lithium may be able to maintain the antidepressant 
response induced by ketamine are underway by other sponsors.18,19
A number of studies have assessed maintenance of the benefit from ECT with continuation of 
pharmacotherapy. The relapse rates in these studies are typically around 50% within 6 months, 
despite vigorous use of pharmacotherapy.62 The relapse rates correlate with the degree of 
treatment resistance. Patients with TRD are less likely to achieve remission and, when they do, 
are much more prone to relapse.45 Relapse rates with placebo after ECT are extremely high: 
remission may be lost as early as the first few weeks after the acute course,63 ~65% in 
3 months,73 and 84% at 6 months.114 Relapse rates after ECT are reduced with pharmacotherapy 
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alone: 60% at 6 months on nortriptyline alone and 39% at 6 months on nortriptyline plus 
lithium.114 Most relapses occurred within 5 weeks of completion of ECT.114 The role of 
pharmacotherapy in more treatment resistant subjects is also questioned.115 Consequently, 
clinicians have adopted maintenance ECT to prolong remission. Recent studies have 
demonstrated that pharmacotherapy plus continued maintenance ECT is significantly more 
effective at preventing relapse than pharmacotherapy alone following induction of antidepressant 
response with a course of ECT.94,143 The frequency of maintenance ECT is challenging to 
determine. A fixed schedule is considered suboptimal due to the large inter-patient variability. 
Therefore, one study developed a strategy based on symptom severity to guide the frequency of 
ECT treatment, aiming to reduce the number of relapses within 1 month after completion of 
ECT.77 Back-testing of this algorithm would have prevented nearly 100% of the subjects from 
relapsing.77
This study is modeled after the ECT literature to investigate whether repeated use of intranasal 
esketamine plus an oral antidepressant can sustain the antidepressant effects of an induction 
course of intranasal esketamine plus an oral antidepressant in subjects with TRD, or whether the 
oral antidepressant alone is sufficient to maintain the antidepressant effect. As outlined below, 
the sponsor designed this study using an individualized approach, with the frequency of 
intranasal esketamine treatment sessions driven by the severity of depressive symptoms.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective of this study is to assess the efficacy of intranasal esketamine plus an oral 
antidepressant compared with an oral antidepressant (active comparator) plus intranasal placebo 
in delaying relapse of depressive symptoms in subjects with TRD who are in stable remission
(see Section 3.1.2, Definitions of Terms) after an induction and optimization course of intranasal 
esketamine plus an oral antidepressant.
Secondary Objectives

To assess the efficacy of intranasal esketamine plus an oral antidepressant compared with an 
oral antidepressant (active comparator) plus intranasal placebo in delaying relapse of 
depressive symptoms in subjects with TRD with stable response (but who are not in stable 
remission) (see Section 3.1.2, Definitions of Terms) after an induction and optimization 
course of intranasal esketamine plus an oral antidepressant

To assess the effect of intranasal esketamine plus an oral antidepressant compared with an 
oral antidepressant (active comparator) plus intranasal placebo on:

Depressive symptoms

Overall severity of depressive illness

Functional impairment and associated disability 

Anxiety symptoms
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
Health-related quality of life and health status

To investigate the safety and tolerability of intranasal esketamine plus an oral antidepressant
compared with an oral antidepressant (active comparator) plus intranasal placebo in subjects 
with TRD, with special attention to the following:

Treatment-emergent adverse events (TEAEs), including AEs of special interest

Local nasal tolerability

Effects on heart rate, blood pressure, respiratory rate, and blood oxygen saturation

Effects on alertness and sedation 

Potential psychosis-like symptoms

Dissociative symptoms

Potential effects on cognitive function

Potential effects on suicidal ideation/behavior

Potential treatment-emergent symptoms of cystitis and/or lower urinary tract symptoms

Potential withdrawal and/or rebound symptoms following cessation of intranasal 
esketamine treatment

Potential effects on sense of smell
Exploratory Objective

To assess the potential relationship of biomarkers with response/non-response to intranasal 
esketamine plus an oral antidepressant or to an oral antidepressant plus intranasal placebo in 
adult subjects with TRD.

To assess medical resource utilization.
2.2.
Hypothesis
The hypothesis for this study is that intranasal esketamine plus an oral antidepressant is more 
effective than treatment with an oral antidepressant plus intranasal placebo in delaying relapse of 
depressive symptoms in subjects with TRD in stable remission.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind, parallel-group, active-controlled, multicenter study to 
evaluate the efficacy, safety, and tolerability of intranasal esketamine plus an oral antidepressant 
compared with an oral antidepressant (active comparator) plus intranasal placebo in delaying 
relapse of depressive symptoms in adult men and women with TRD who are in stable remission 
after an induction and optimization course with intranasal esketamine plus an oral antidepressant. 
Approximately 211 subjects in stable remission (see Section 3.1.2, Definition of Terms) at the 
end of the optimization after treatment with intranasal esketamine plus an oral antidepressant 
will be randomized in a 1:1 ratio to either continue intranasal esketamine (same dose) or be 
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switched to intranasal placebo; all subjects will continue the same oral antidepressant, at the 
same dose.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study 
(see Section 11.8).
3.1.1.
Study Phases
Subjects will enter the study either directly (referred to as direct-entry subjects) or after 
completing the double-blind induction phase of a short-term study (ESKETINTRD3001 or 
ESKETINTRD3002) (referred to as transferred-entry subjects). 
The study has 5 phases:

A 4-week screening/prospective observational phase, with an optional taper of up to 3 weeks 
for oral antidepressant medication(s) (direct-entry subjects only)

A 4-week open-label induction phase (direct-entry subjects only)

A 12-week optimization phase (open-label for direct-entry subjects and double-blind for 
transferred-entry subjects)

A maintenance phase (variable duration)

A 2-week follow-up phase 
The maximum duration of a subject's participation will be variable, depending on whether he or 
she enters the study directly or is transferred from one of the double-blind short-term studies, and 
whether he or she meets phase-specific criteria (eg, meets criteria for response at the end of the 
induction phase, is in stable remission/response at the end of the optimization phase, and when 
and if he or she relapses in the maintenance phase). Direct-entry subjects may participate in up to 
5 phases and transferred-entry subjects may participate in up to 3 phases. 
The study will be stopped once 84 relapses (in the subjects with stable remission) occur during 
the maintenance phase, or earlier based on the results of the interim analysis for efficacy. At the 
time the study is stopped, subjects in the induction phase will be able to complete the Induction
phase. Those subjects who are responders after completing an Early Withdrawal Visit may 
proceed to the 54135419TRD3008 study without completing the follow up phase. Those who are 
not responders will have an Early Withdrawal Visit and proceed directly to the follow-up phase.
Subjects who are in the optimization or maintenance phase at the time the study is terminated 
will have an Early Withdrawal Visit/End of Maintenance Visit conducted and proceed directly to 
the follow-up phase.
Screening/Prospective Observational Phase
Direct-entry subjects will participate in this phase, which prospectively assesses treatment 
response to the subject’s current oral antidepressant treatment regimen. 
At the start of the screening/prospective observational phase, the subject must have had 
documented non-response to at least 1 antidepressant treatment (based on MGH-ATRQ) in the 
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current episode of depression, and the subject is taking a different oral antidepressant treatment
(listed on the MGH-ATRQ) for at least the previous 2 weeks at or above the minimum 
therapeutic dose. This antidepressant treatment, as well as any other ongoing medications being 
taken for depression at screening (including adjunctive/augmentation therapies), will continue 
from the start of Week 1 through the end of Week 4 of the screening/prospective observational 
phase. Dose adjustment is permitted per clinical judgment, but the oral antidepressant treatment 
is to remain at or above the minimum therapeutic dose (per the MGH-ATRQ) through the end of 
Week 4.
After 4 weeks, subjects who are non-responders to their current oral antidepressant treatment 
may be eligible to proceed to the open-label induction phase. Non-response at the end of the 
screening/prospective observational phase is defined as ≤25% improvement in the MADRS total 
score from Week 1 to Week 4 and a MADRS total score of ≥28 on Week 2 and Week 4. 
Eligible subjects who are entering the open-label induction phase will discontinue all of their 
current antidepressant treatment(s), including adjunctive/augmentation therapies. Of note, 
subjects 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) 
during the screening/prospective observational phase can continue these medications. No dose 
increases beyond the equivalent of 6 mg/day lorazepam, or new benzodiazepine are permitted 
during the screening/prospective observational phase. If clinically indicated, a subject’s current 
antidepressant treatment(s) may be tapered and discontinued over an additional, optional period 
of up to 3 weeks per the local prescribing information or clinical judgment.
Open-label Induction Phase
Eligible direct-entry subjects will receive intranasal esketamine (flexible dose: 56 mg or 84 mg) 
treatment sessions twice weekly for 4 weeks. In addition, all subjects will initiate a new, open-
label oral antidepressant on Day 1 that will be taken daily for the duration of the induction phase. 
The assigned oral antidepressant will be 1 of 4 oral antidepressant medications (duloxetine, 
escitalopram, sertraline, or venlafaxine extended release [XR]), that the subject has not 
previously had a non-response to in the current depressive episode, has not been previously 
intolerant to (lifetime), and is available in the participating country.
Subjects 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) 
during the screening/prospective observational phase can continue these medications during the 
induction phase. No dose increases beyond the equivalent of 6 mg/day of lorazepam, or new 
benzodiazepine medications are permitted during the induction phase, with the exception of the 
use of permitted benzodiazepine rescue medication (post-dose on the dosing day only).
Subjects will self-administer (under clinical supervision) open-label intranasal esketamine during 
a scheduled treatment session twice a week for 4 weeks, with titration to a dose individualized 
per efficacy and tolerability (either 56 or 84 mg). At the end of the induction phase, 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 open-label induction phase) may be eligible 
to proceed to the optimization phase. All subjects who do not proceed to the optimization phase
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will have an Early Withdrawal Visit conducted and proceed to the follow-up phase 
(see Section 3.1.2).
At the time the study is stopped, subjects in the induction phase will be able to complete the 
phase. Those who are responders, after completing an Early Withdrawal Visit, may proceed to 
the 54135419TRD3008 study without completing the follow up phase. Those who are not 
responders will have an Early Withdrawal Visit conducted and proceed directly to the follow-up 
phase.
Optimization Phase
Eligible direct-entry subjects from the open-label induction phase and transferred-entry subjects 
from the 2 double-blind short-term studies (ESKETINTRD3001 and ESKETINTRD3002) will 
participate in this 12-week phase.
The intranasal treatment session frequency will be reduced from that in the induction phase 
(twice weekly) to weekly for the first 4 weeks of this phase. After the first 4 weeks, the 
frequency of intranasal treatment sessions will be individualized to either once weekly or once 
every other week based on the severity of depressive symptoms, as assessed by the MADRS total 
score. The dose of intranasal esketamine will remain unchanged from the dose at the end of the 
induction phase. All subjects will continue taking the same oral antidepressant treatment (at the 
same dosage) that was initiated during the induction phase.
At the end of the optimization phase, subjects in stable remission and those with stable response 
(but who are not in stable remission) may be eligible to continue into the maintenance phase; all 
other subjects will have an Early Withdrawal Visit conducted and proceed to the follow-up 
phase.
For subjects in stable remission and those with stable response at the end of this phase, the last 
visit of the optimization phase (Visit 3.13; Week 16) also serves as the baseline visit (Visit 4.1; 
Week 16) of the maintenance phase. Subjects eligible for the maintenance phase will be 
randomized and receive their first double-blind intranasal treatment session of the maintenance 
phase at this visit. 
At the time the study is stopped, subjects in the optimization phase will have an Early 
Withdrawal Visit conducted and proceed directly to the follow-up phase.
Maintenance Phase
On Day 1 of this phase:

Approximately 211 subjects in stable remission at the end of the optimization phase (after 
treatment with intranasal esketamine plus an oral antidepressant) will be randomized in a 
1:1 ratio to either continue with intranasal esketamine (same dose) and the same oral 
antidepressant or to continue with the same oral antidepressant (active comparator) but 
switch to intranasal placebo. The primary efficacy analysis will be performed for these 
subjects only. 
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
Additionally, subjects with stable response (but who are not in stable remission) at the end 
of the optimization phase (after treatment with intranasal esketamine plus an oral 
antidepressant) will be randomized in a 1:1 ratio (using a separate randomization list) to 
either continue with intranasal esketamine (same dose) and the same oral antidepressant or 
to continue with the same oral antidepressant (active comparator) but switch to intranasal 
placebo (for a secondary efficacy analysis only). 

Transferred-entry subjects who achieve stable remission or stable response at the end of the 
optimization phase after treatment with an oral antidepressant plus intranasal placebo will 
continue to receive the same treatment in order to maintain the blinding for the ongoing 
short-term studies. These subjects will not be included in the efficacy analyses, but will be 
included in safety analyses.
The frequency of intranasal treatment sessions will be further individualized during the 
maintenance phase to once weekly or once every other week based on the severity of depressive 
symptoms, as assessed by the MADRS total score. Subjects will only be permitted to switch 
from weekly to every other weekly dosing a total of 3 times. After this time, if a given subject is 
unable to sustain improvement on every other week dosing they will remain on a weekly dosing 
regimen for the duration of this phase.
This phase will have a variable duration, continuing until 84 relapses occur in the subjects with 
stable remission, or earlier based on interim analysis results.
Subjects who meet the relapse criteria and subjects who remain relapse-free at study termination 
will have an End of Maintenance Phase Visit conducted and may proceed to the follow-up phase.
If clinically indicated, subjects who have met relapse criteria after completing the end of 
maintenance visit may proceed to the open-label safety extension study, 54135419TRD3008, 
without completing the follow up phase. Subjects who are participating in the maintenance phase 
at the time the study is stopped will have an Early Withdrawal Visit conducted and proceed 
directly to the follow-up phase.
Follow-up Phase
This phase will include all subjects who have received at least 1 dose of intranasal study 
medication in this study. For those subjects who relapse in the Maintenance phase, if clinically 
indicated based on investigator’s judgment, after completing the end of maintenance visit, the 
subject may proceed to the open-label safety extension study, 54135419TRD3008, without 
completing the follow up phase. Similarly, when the study is stopped, subjects in the Induction 
phase who are responders, after completing the early withdrawal visit, may proceed to the 
54135419TRD3008 study, without completing the follow up phase.
Follow-up visits will be performed at 1 and 2 weeks after the last clinic visit.
At the start of the follow-up phase, further clinical/standard of care for the treatment of 
depression will be arranged by the study investigator and/or the subject’s treating physician. 
There will be no intranasal treatment administered during this phase. Subjects will be provided 
with an additional 2-week supply of the oral antidepressant medication to ensure that there is no 
interruption of oral antidepressant therapy during the transition to further clinical/standard of 
care. The decision to continue the oral antidepressant in this phase will be at the discretion of the 
investigator, however, in order to better assess potential withdrawal symptoms from intranasal 
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study drug, the oral antidepressant should be continued during the 2-week follow-up phase 
unless determined as not clinically appropriate.
An open-label safety extension study, 54135419TRD3008, may be available (pending country 
and site approval) for eligible subjects participating in the ESKETINTRD3003 study. Please 
refer to the 54135419TRD3008 protocol for full details of potential pathways for entry.
A diagram of the study design is provided in Figure 1.
Figure 1:
Schematic Overview of the Study
AC = active comparator; AD = antidepressant; DB = double-blind; ESK = esketamine; OL = open-label; PBO = 
placebo. TRD = treatment-resistant depression.
The study will end when 84 relapses are reached. An interim analysis will be performed at 30 relapses.
3.1.2.
Definitions of Terms
Open-label Induction Phase

Response: 50% reduction in the MADRS total score from baseline (Day 1 prior to the first 
intranasal dose) to the end of the 4-week open-label induction phase
Optimization Phase

Stable remission: 
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
MADRS total score ≤12 for at least 3 of the last 4 weeks of the optimization phase, but 
one excursion of a MADRS total score >12 or one missing MADRS assessment is
permitted at Optimization week 13 or 14 only. The MADRS total score at weeks 15 and 
16 must be ≤12.

Stable response: 50% reduction in the MADRS total score from baseline (Day 1 of 
induction phase; pre-randomization/prior to the first intranasal dose) in each of the last 
2 weeks of the optimization phase, but does not meet criteria for stable remission. Note: For 
transferred-entry subjects, Day 1 of the open-label induction phase will take place in 
ESKETINTRD3001 or ESKETINTRD3002.
Maintenance Phase
Relapse is defined as any of the following:

MADRS total score 22 for 2 consecutive assessments separated by 5 to 15 days. The date 
of the second MADRS assessment will be used for the date of relapse.

Hospitalization for worsening depression or any other clinically relevant event determined 
per clinical judgment to be suggestive of a relapse of depressive illness such as suicide 
attempt, completed suicide, or hospitalization for suicide prevention. If hospitalized for any 
of these events, the start date of hospitalization will be used for the date of relapse. 
Otherwise the date of the event will be used if the subject is not hospitalized.

In case both relapse criteria are met, the earlier date will be defined as the date of relapse for 
this subject. 
3.2.
Study Design Rationale
3.2.1.
Study Population
Subjects will enter the study either directly (referred to as direct-entry subjects) or after 
completing the double-blind induction phase of a short-term study (ESKETINTRD3001 or 
ESKETINTRD3002) (referred to as transferred-entry subjects). Both patient populations are 
considered similar as both have met the same rigorous criteria for TRD, including prospective 
confirmation of non-response in the screening/prospective observational phase prior to the 
4-week induction phase.
Direct-entry Subjects
The study population will include adult men and women, therefore the age range of 18 (or older 
if the minimum legal age of consent in the country in which the study is taking place is >18) to 
64 years of age (inclusive) is considered appropriate.
Subjects will meet DSM-5 diagnostic criteria for single-episode MDD (if single episode,
duration of episode must be 2 years) or recurrent MDD, without psychotic features, based upon 
clinical assessment, and confirmed by the Mini. At the start of the screening/prospective 
observational phase, subjects must have an Inventory of Depressive Symptomatology-Clinician 
rated, 30-item (IDS-C30) total score of 34, which corresponds to moderate to severe depression.
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Treatment-resistant depression is defined as a lack of clinically meaningful improvement after 
treatment with at least 2 different antidepressant agents prescribed in adequate dosages for 
adequate duration. At the start of this study, subjects must have had non-response (defined as 
≤25% improvement) to 1 but 5 (if current episode is >2 years, upper limit is applicable to only 
the last 2 years) oral antidepressant treatments taken at adequate dosage and for adequate 
duration, 
as 
assessed 
on 
the 
MGH-ATRQ 
and 
documented 
by 
records 
(eg, 
medical/pharmacy/prescription records or a letter from the treating physician, etc.) for the current 
episode of depression. Subjects who have had some initial response but then lose the response 
(eg, tolerance effects/bradyphylaxis) to an antidepressant treatment will not be considered to 
have failed that antidepressant treatment. The use of historical data to define non-response to 
treatment prior to patient enrollment in a treatment study is considered practical and valid. The
MGH-ATRQ is a validated tool assessing treatment response. 
In addition, at the start of the screening/prospective observational phase, the subject is taking a 
different oral antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at 
or above the minimum therapeutic dose. This antidepressant treatment, as well as any other 
ongoing medications being taken for depression at screening (including adjunctive/ augmentation 
therapies), will continue from the start of Week 1 through the end of Week 4 of the 
screening/prospective observational phase. Dose adjustment is permitted per clinical judgment, 
but the oral antidepressant treatment is to remain at or above the minimum therapeutic dose (per 
the MGH-ATRQ) through the end of Week 4.
Non-response at the end of the screening/prospective observational phase is defined as ≤25% 
improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total score of 
≥28 on Week 2 and Week 4.
The subject’s current major depressive episode, depression symptom severity (Week 1 MADRS 
total score ≥28 required), and antidepressant treatment response in their current depressive 
episode (retrospectively assessed) must be deemed valid for participation in the clinical study 
based on a Site-Independent Qualification Assessment. The Site Independent Qualification 
Assessment is a tool to facilitate subject selection for MDD clinical studies, with a goal to ensure 
enrollment of subjects who have symptoms that reflect the current state of illness and that these 
symptoms can be reliably measured with appropriate measurement tools, as well as to minimize 
placebo response.
Transferred-entry Subjects
The same study population (ie, same inclusion and exclusion criteria) will be enrolled into the 
2 short-term studies (ESKETINTRD3001 and ESKETINTRD3002). The transferred-entry 
subjects in this study are subjects who complete the double-blind induction phase and have 
demonstrated response at the end of this phase in 1 of the short-term studies.
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3.2.2.
Study Phases
Screening/Prospective Observational Phase
The 4-week duration of the screening/prospective observational phase for direct-entry subjects 
will provide adequate time to assess subject eligibility according to the study entry criteria, while 
also allowing for a prospective confirmation of non-response to the current antidepressant 
treatment(s) that is continued for the duration of this phase. This method of recruitment allows 
subjects to enter the study on a variety of different antidepressant medications that they had been 
taking, which mimics clinical practice and yet allows for prospective demonstration of treatment 
resistance to the current antidepressant treatment. Even though there is no depression rating score 
available at the start of the antidepressant treatment, the subjects at screening will have to meet 
criteria for moderate to severe depression. After 4 weeks of prospective observation of 
continuation of the current antidepressant treatment and assessment of treatment response, 
subjects who meet the predefined non-response criteria (≤25% improvement in the MADRS total 
score from Week 1 to Week 4 and a MADRS total score of ≥28 on Week 2 and Week 4) and are 
eligible to enter the open-label induction phase will discontinue all of the current antidepressant 
treatments, including adjunctive/augmentation therapies, prior to starting the next phase. 
Non-responders that are eligible to enter the open-label induction phase are permitted to have up 
to 3 additional weeks to taper and discontinue the all current medication(s) being used for 
depression prior to entry into the open-label induction phase, per the local prescribing 
information or clinical judgment (eg, tolerability concerns). The duration of up to 3 weeks is 
expected to provide an adequate amount of time for taper and discontinuation. 
Open-label Induction Phase
The 4-week duration of the open-label induction phase for direct-entry subjects was selected 
based upon the onset of effect of typical antidepressants, with a 4-week duration considered to be 
sufficiently long to show the antidepressant effects of the active comparator. Preliminary 
findings from an analysis of antidepressants were presented recently, as well as a completed 
analysis of 24 recent MDD studies that compared study durations of 4, 6, and 8 weeks. 
Exploratory analyses were conducted for each of the study durations using mixed-model 
repeated measures (MMRM), but excluding data beyond the duration of interest. These 
preliminary findings suggest that it is plausible to shorten study duration down to 4 weeks.68,142
Similarly, it has been demonstrated that improvement of 25% on the Hamilton Depression 
Rating Scale on Day 14 was a significant cutoff value to predict response after 5 weeks of 
treatment, and a lack of improvement (ie, <25%) by Day 14 predicted poor response after 
5 weeks of treatment96.All together, these results suggest that a 4-week duration should be 
adequate to assess antidepressant response.
Optimization Phase
The fixed duration of 12 weeks for the optimization phase for both direct-entry and transferred-
entry subjects allows for a reduction in the frequency of intranasal treatment sessions and 
subsequent individualization and stabilization of the treatment session frequency (weekly or 
every other week) for a given subject (using the MADRS total score to assess depressive 
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symptoms). For the primary analysis, a subject must be in stable remission (see full definition,
section 3.1.2) to enter the maintenance phase. This duration of the optimization phase is critical 
to the time to relapse. Shorter duration of stabilization (referred to as the optimization phase in 
this study) is associated with faster relapses. A recent meta-analysis showed that beyond 16 
weeks, the effects of duration of stabilization did not appear to impact relapses.3
Subjects with stable response (50% reduction in the MADRS total score from baseline [Day 1 
of induction phase; pre-randomization/prior to the first intranasal dose]) in each of the last 
2 weeks of the optimization phase who do not meet criteria for stable remission, will also enter 
the maintenance phase, but will not be part of the primary analysis. Although not part of the 
primary analysis, this subject population is of clinical interest. A 2-week duration to confirm 
stable response is considered appropriate to ascertain the subject’s status prior to the next 
treatment phase.
Maintenance Phase
The duration of the maintenance phase is variable, and the phase will continue until the required 
number of relapses is achieved or until the study is recommended to be stopped based on the 
interim analysis results. Assumptions regarding the duration of time to relapse are provided in 
Section 1.3, Overall Rationale for the Study. While all subjects will enter this phase at the same 
frequency of intranasal treatment sessions that they had in the optimization phase, the frequency 
of intranasal treatment sessions will continue to be individualized to once weekly or once every 
other week based on the severity of depression, as assessed by the MADRS total score, during 
this phase; however, there will be a limit (ie, no more than 3 times) on the number of times a 
subject can be switched from weekly to every other week. This is considered a sufficient number 
of times to evaluate if a subject can sustain antidepressant efficacy with every -other -week 
dosing.
Follow-up Phase
The 2-week duration of the follow-up phase will allow sufficient time to assess safety and 
tolerability after cessation of intranasal dosing, including potential withdrawal symptoms. At the 
start of this phase, further clinical/standard of care for the treatment of depression will be 
arranged by the study investigator and/or the subject’s treating physician.
3.2.3.
Blinding and Randomization
Blinded intranasal treatment will be used in the optimization phase (for transferred-entry 
subjects) to avoid unblinding the short-term studies at the individual level, and in the 
maintenance phase (for all subjects) to reduce potential bias during data collection and 
evaluation of clinical endpoints.
Randomization will be used in the maintenance phase for subjects in stable remission (primary 
analysis) and subjects with stable response but who are not in stable remission (secondary 
analysis) to minimize bias in the assignment of subjects to treatment groups, to increase the 
likelihood that known and unknown subject attributes (eg, demographic and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
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statistical comparisons across treatment groups. The randomizations will be stratified by country 
with an allocation ratio of 1:1 to intranasal placebo or intranasal esketamine. The stratification is 
aimed at balancing treatment groups across country.
Transferred-entry subjects who achieve stable remission or stable response after treatment with 
intranasal placebo plus an oral antidepressant will continue to receive the same treatment in order 
to maintain the blinding for the ongoing short-term studies. These subjects will not be 
randomized during the maintenance phase.
3.2.4.
Treatment Groups and Dose Selection
3.2.4.1.
Intranasal Study Drug
Open-label Induction Phase
All direct-entry subjects will receive intranasal esketamine during this phase. The dose selection 
(56 mg and 84 mg) 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.
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 open-label induction phase. In addition, the 56-mg and 
84-mg dosages were generally well tolerated by subjects.
The use of flexible dosing for intranasal esketamine 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 Phase
There will be no changes to the intranasal dose permitted during the optimization phase. Subjects 
will continue to receive the same intranasal treatment (esketamine or placebo) from the induction 
phase; therefore, direct-entry and transferred-entry subjects will continue to receive open-label 
and double-blind intranasal treatment, respectively.
The intranasal treatment session frequency will be reduced from that in the induction phase 
(twice weekly) to weekly for the first 4 weeks of this phase. After the first 4 weeks, the 
frequency of intranasal treatment sessions will be individualized to once weekly or once every 
other week based on the severity of depression, as assessed by the MADRS total score. This 
reduction in frequency and individualization is intended to allow subjects to sustain the 
antidepressant response while minimizing the frequency of intranasal treatment sessions 
required.
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Maintenance Phase
Subjects in stable remission after treatment with intranasal esketamine plus an oral 
antidepressant will be randomized in a 1:1 ratio to either continue with intranasal esketamine 
(same dose) and the same oral antidepressant or to continue with the same oral antidepressant 
(active comparator) but switch to intranasal placebo (for the primary efficacy analysis). 
Subjects with stable response (but who are not in stable remission) after treatment with intranasal 
esketamine plus an oral antidepressant will be randomized in a 1:1 ratio (using a separate 
randomization list) to either continue with intranasal esketamine (same dose) and the same oral 
antidepressant or to continue with the same oral antidepressant (active comparator) but switch to 
intranasal placebo (for secondary efficacy analysis only). 
Transferred-entry subjects who achieve stable remission or stable response after treatment with 
intranasal placebo plus an oral antidepressant will continue to receive the same treatment in order 
to maintain the blinding for the ongoing short-term studies. These subjects will not be included 
in the efficacy analyses, but will be included in safety analyses.
The frequency of intranasal treatment sessions will be individualized to once weekly or once 
every other week based on the severity of depression, as assessed by the MADRS total score. As 
noted above, however, there will be a limit (ie, no more than 3 times) to the number of times the 
frequency can be switched from weekly to every other week. This further individualization of 
treatment session frequency is intended to allow subjects to sustain the antidepressant response 
while minimizing the frequency of intranasal treatment sessions required.
3.2.4.2.
Oral Antidepressant
On Day 1 of the open-label induction phase, a new, open-label oral antidepressant treatment will 
be initiated for all direct-entry subjects. Each subject will be assigned to receive 1 of 4 oral 
antidepressant medications from 2 different classes of antidepressant treatments, an SSRI 
(escitalopram or sertraline) or an SNRI (duloxetine or venlafaxine XR). The assignment of the 
oral antidepressant will be done by the investigator based on review of the MGH-ATRQ and 
relevant prior antidepressant medication information.
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These 2 classes were selected because they are the most commonly prescribed antidepressant 
classes in this population and are generally well-tolerated. The oral antidepressant treatment 
assigned will be one that the subject has not previously had a non-response to in the current 
episode, has not been previously intolerant to (lifetime), and is available in the participating 
country. Dosing of the oral antidepressant will begin on Day 1 of the open-label induction phase 
A mandatory titration schedule is provided in Attachment 3. Doses are not to exceed the 
maximum dose defined in the titration schedule, to ensure that the oral antidepressant is taken at 
an adequate dosage and duration for assessment of potential maintenance of effect. If higher 
doses are not tolerated, a down-titration is permitted based on clinician’s judgment. However, the 
subject’s dose should not be lower than the following minimum therapeutic doses at the end of 
the induction phase: sertraline (50 mg/day), venlafaxine XR (150 mg/day), escitalopram 
(10 mg/day), and duloxetine (60 mg/day). While subjects requiring lower doses can continue in 
the study and complete the induction phase, such subjects will not be eligible to participate in the 
optimization phase and will proceed to the follow-up phase after completion of the induction 
phase.
For all subjects, the same oral antidepressant treatment will be continued throughout the 
optimization, maintenance, and follow-up (if clinically indicated) phases.
The rationale for initiating and continuing an oral antidepressant in combination with intranasal 
esketamine treatment is provided in Section 1.3, Overall Rationale for the Study.
3.2.5.
Efficacy Measures
MADRS
The 10-item clinician-administered MADRS was designed to be used in subjects with MDD to 
measure the overall severity of depressive symptoms.83 The MADRS scale has been selected as 
an efficacy measure for this study because it is validated, reliable, and acceptable to regulatory 
health authorities as a primary scale to determine efficacy in major depression. 
Response is defined as a 50% reduction in the initial symptom score, and remission is defined 
as a total score of 12. At the end of the open-label induction phase, subjects who meet this 
criterion for response (ie, 50% reduction in the initial symptom score) will be considered 
responders and are eligible to continue into the optimization phase. 
During the optimization phase, the MADRS will be used to measure severity of depressive 
symptoms to individualize intranasal treatment session frequency as well as to determine stable 
remission and response for eligibility to enter the maintenance phase.
During the maintenance phase, the primary efficacy evaluation will include the MADRS total 
score as it pertains to relapses. A MADRS total score 22 for 2 consecutive assessments 
separated by 5 to 15 days (the date of the second MADRS assessment in the 2-week period will 
be used for the date of relapse) is a relapse criteria in this study. In addition, it will continue to be 
used to measure severity of depressive symptoms to further individualize intranasal treatment 
session frequency.
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PHQ-9

The PHQ-9 will be used as a patient-reported measure of depressive symptomatology.128
Please refer to Section 9.2.1.3 for additional information regarding PHQ-9.
SDS 

The Sheehan Disability Scale (SDS) is patient-reported outcome measure included as an 
assessment of functional impairment and associated disability.74,121 Please refer to 
Section 9.2.1.6 for additional information regarding SDS.
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.50 Please refer to Section 9.2.1.2 for additional information 
regarding CGI-S.
GAD-7

The GAD-7 is included as a brief and validated measure of overall anxiety.127 Please refer to 
Section 9.2.1.4 for additional information regarding GAD-7.
EQ-5D-5L

The EQ-5D-5L is included as a standardized patient-completed instrument for use as a 
measure of health-related quality of life and health status.41,42 Please refer to Section 9.2.1.5
for additional information regarding EQ-5D-5L.
3.2.6.
Safety Evaluations
Physical examination, body weight, vital signs (including blood pressure measurements), 12-lead 
ECG, pulse oximetry, clinical laboratory tests, nasal examinations, and evaluation of TEAEs and 
concomitant therapies will be performed throughout the study to monitor subject safety.
TEAEs of special interest will be examined separately grouped in the following categories: drug 
abuse, dependence and withdrawal [standardized Medical Dictionary for Regulatory Activities 
(MedDRA)
queries (SMQ)], increased blood pressure, increased heart rate, transient 
dizziness/vertigo; impaired cognition; anxiety and cystitis.
A subject-completed nasal symptom questionnaire will also be conducted as per the Time and 
Event Schedule to assess for any treatment-emergent nasal tolerability symptoms.
The C-SSRS will be performed to assess suicidal ideation and behavior, the CADSS will be 
administered to assess treatment-emergent dissociative symptoms, the Brief Psychiatric Rating 
Scale (BPRS+; four-item positive symptom subscale) will be administered to assess treatment-
emergent psychotic symptoms, the MOAA/S will be used to measure treatment-emergent 
sedation, the CGADR will be used to measure the subject’s readiness for discharge based on 
parameters including sedation, blood pressure, and adverse events, and the PWC-20 will be 
administered (as applicable) to assess potential withdrawal symptoms after cessation of 
esketamine treatment.
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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.
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 symptoms of 
cystitis, bladder pain, and interstitial cystitis using the subject-completed BPIC-SS at specific 
time points.55 A score >18 on the BPIC-SS scale is considered as probable cystitis, and any 
subjects meeting this cut-off will have a urinalysis and culture conducted at that visit to assess 
for potential urinary tract infection. Those without evidence of an ongoing urinary tract infection 
will be referred to a specialist for diagnostic workup. There are no definitive tests for diagnosing 
ulcerative cystitis. If a subject is determined to have a diagnosis of ulcerative cystitis, the subject 
must be discontinued from the study and followed up with appropriate medical care.
The effect of intranasal esketamine on cognition over the 4-week open-label induction phase will 
be assessed 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.
The University of Pennsylvania Smell Identification Test (UPSIT) and Smell Threshold Test will 
be performed to assess any treatment-emergent effects on the sense of smell.
On all intranasal dosing days, subjects must remain at the 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 site. 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 as general guidance for the 
investigator (but is not all-inclusive).
3.2.7.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) 
Evaluations 
Assessment of biomarkers (protein and RNA) and their potential relationship to the different 
treatment groups and to maintenance/stabilization of response, non-response, and relapse will be 
explored. Blood samples will be collected to measure genetic and epigenetic markers (including 
but not limited to BDNF allelic variants) and protein markers (including but not limited to 
growth factors, inflammation, endocrine, or metabolic). Samples of DNA and biomarkers may be 
used to help address emerging issues and to enable the development of safer, more effective, and 
ultimately individualized therapies.
Genetic variation can be an important contributory factor to interindividual differences in drug 
distribution and response and can also serve as a marker for disease susceptibility and prognosis. 
Pharmacogenomic research may help to explain interindividual variability in clinical outcomes 
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and may help to identify population subgroups that respond differently to a drug or subgroups 
that are more susceptible to relapse. In addition, pharmacogenomics research may allow for the 
identification of genetic factors that influence the PK, pharmacodynamics, efficacy, safety, or 
tolerability of the different treatment groups, and for the identification of genetic factors 
associated with TRD or MDD. Specifically, genetic and epigenetic changes in genes known to be 
in pathways relevant to depression (eg, hypothalamic-pituitary-adrenal axis, inflammation, 
growth factors, monoamine transporters, ion channels, and circadian rhythm) will be evaluated.
Protein, metabolite, and RNA biomarkers may aid in the elucidation of the mechanism of action 
of the different treatment groups or help to explain interindividual variability in clinical 
outcomes or may help to identify population subgroups that respond differently to a drug or may 
help to identify subgroups that are more susceptible to relapse. The goal of the biomarker 
analyses is to evaluate the pharmacodynamics of the different treatment groups, and aid in 
evaluating the drug-clinical response relationship. 
On the day of biomarker sample collection, it is preferred that subjects adhere to a low fat diet 
(as an alternative to fasting) to reduce the level of postprandial lipemia in blood samples, since 
moderately or grossly lipemic specimens may interfere with assay results.
3.2.8.
Other Assessments
Patient Adherence Questionnaire
During the screening/prospective observational phase, the self-reported PAQ will be used to 
assess how often the subject has taken, and whether he or she has made any changes to, his or 
her antidepressant treatment regimen in the last 2 weeks. This assessment will provide 
confirmation of medication compliance when evaluating antidepressant treatment response. 
Subjects who report missing 4 days of antidepressant medication during a 2-week recall period 
will be discontinued because of inadequate adherence.
3.2.9.
Medical Resource Utilization Data Collection
Delay of relapse and maintenance of response/remission may result in lower utilization of
healthcare services (such as outpatient visits, emergency room visits, or hospitalization) 
associated with relapse of symptoms of depression; therefore, comparison will be done across 
treatment groups. The Healthcare Resource Use Questionnaire (HRUQ) will be used to assess 
medical resource utilization. It includes information regarding utilization of healthcare services 
over the course of the study, including the type and duration of services, enabling changes in 
level and quantity of services to be considered as a variable in economic models.
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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.
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
The sponsor will evaluate and approve/reject requests to rescreen an individual subject on a case-
by-case basis.
4.1.
Inclusion Criteria
4.1.1.
Direct-entry Subjects
The following criteria apply only to those subjects entering directly into the study. Each potential 
subject must satisfy all of the following criteria to be enrolled in the study. 
1.
At the time of signing the informed consent form (ICF) the subject, a man or woman, must 
be 18 (or older if the minimum legal age of consent in the country in which the study is 
taking place is >18) to 64 years of age, inclusive.
2.
At the start of the screening/prospective observational phase, each subject must meet 
Diagnostic and Statistical Manual of Mental Disorders - fifth edition (DSM-5) diagnostic 
criteria for single-episode MDD (if single-episode MDD, the duration must be 2 years) or 
recurrent MDD, without psychotic features, based on clinical assessment and confirmed by 
the Mini International Neuropsychiatric Interview (MINI).
3.
Criterion modified per Amendment 2:
3.1. Criterion modified per Amendment 3:
3.2. At the start of the screening/prospective observational phase, subject must have had 
non-response (≤25% improvement) to 1 but 5 (if current episode is >2 years, upper limit 
is applicable to only the last 2 years) oral antidepressant treatments in the current episode of 
depression, assessed using the MGH-ATRQ and confirmed by documented records (eg, 
medical/pharmacy/prescription records or a letter from a treating physician, etc.). In 
addition, the subject is taking a different oral antidepressant treatment (on the MGH-ATRQ) 
for at least the previous 2 weeks at or above the minimum therapeutic dose.

For specific tricyclic antidepressants which are ongoing and being taken at a dose below 
the MGH-ATRQ minimum therapeutic dose, a blood level that is within the therapeutic 
(antidepressant) range, is acceptable to establish the adequacy of the antidepressant 
treatment.

Subjects must be adherent to the continued oral antidepressant treatment medication(s) 
through the screening/prospective observational phase, as documented on the PAQ. 
Missing 4 days of antidepressant medication in the prior 2-week period will be 
considered as inadequate adherence.
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
Subjects who are non-responders to their current oral antidepressant medication(s) from 
the screening/prospective observational phase (as assessed by independent, remote 
raters) may be eligible to continue to the open-label induction phase. Non-response at 
the end of the screening/prospective observational phase is defined as ≤25% 
improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total 
score of ≥28 on Week 2 and Week 4.
4.
At the start of the screening/prospective observational phase, each subject must have an 
Inventory of Depressive Symptomatology, Clinician-rated, 30-item (IDS-C30) total score of 
34.
5.
Criterion modified per Amendment 2:
5.1. The subject's current major depressive episode, depression symptom severity (Week 1 
MADRS total score ≥28 required), and antidepressant treatment response in the current 
depressive episode, must be confirmed using the Site Independent Qualification Assessment.
6.
Subject must be medically stable on the basis of physical examination, medical history, vital 
signs (including blood pressure), pulse oximetry, and 12-lead ECG performed in the 
screening/prospective observational phase. 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.
7.
Criterion modified per Amendment 2:
7.1. Criterion modified per Amendment 3:
7.2 Subject must be medically stable on the basis of clinical laboratory tests performed in 
the screening/prospective observational phase. 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 recorded in the subject's source documents and initialed by the 
investigator.

Subjects with a pre-existing history of thyroid disease/disorder who are treated with 
thyroid hormones must be on a stable dosage for 3 months prior to the start of the 
screening/prospective observational phase.

For any subject (regardless of thyroid history), if the thyroid-stimulating hormone 
(TSH) value is out of range, a free thyroxine (FT4) will be conducted. If the FT4 value 
is abnormal and considered to be clinically significant (after discussion with the medical 
monitor), the subject is not eligible.
8.
Subject must be comfortable with self-administration of intranasal medication and be able to 
follow the intranasal administration instructions provided.
9.
Criterion modified per Amendment 2:
9.1. Criterion modified per Amendment 3:
9.2. 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:
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a.
Not of childbearing potential defined as:
o
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.
o
permanently sterile 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, 
bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy.
b.
Of childbearing potential and
o
practicing a highly effective method of contraception (failure rate of <1% per year 
when used consistently and correctly).
Examples of highly effective contraceptives include 

user-independent methods:
implantable progestogen-only hormone contraception associated 
with 
inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-
releasing system (IUS); vasectomized partner; sexual abstinence (sexual 
abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with 
the study drug. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
subject.)

user-dependent methods:
combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal, and transdermal; 
progestogen-only hormone contraception associated with inhibition of 
ovulation: oral and injectable
Typical use failure rates may differ from those when used consistently and 
correctly. Use should be consistent with local regulations regarding the use of 
contraceptive methods for subjects participating in clinical studies.
Hormonal contraception may be susceptible to interaction with the study drug, 
which may reduce the efficacy of the contraceptive method.
o
agrees to use a highly effective method throughout the study and for at least 
6 weeks after the last dose of study drug
Note: If the childbearing potential changes after start of the study or the risk of pregnancy 
changes (eg, a woman who is not heterosexually active becomes active,) a woman must 
begin a highly effective method of contraception, as described throughout the inclusion 
criteria.
10. Criterion modified per Amendment 2:
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10.1. A woman of childbearing potential must have a negative highly sensitive serum (β-
human chorionic gonadotropin [β-hCG]) at the start of the screening/prospective 
observational phase and a negative urine pregnancy test must be obtained before the first 
dose of study drug on Day 1 of the open-label induction phase prior to randomization.
11. Criterion modified per Amendment 2:
11.1. Criterion modified per Amendment 3:
11.2 During the study (ie, from Day 1 of the open-label induction phase, prior to intranasal 
dosing) 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.
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.
4.1.2.
Transferred-entry Subjects 
The following criteria apply to subjects who enter this study after participation in a short-term 
study (ESKETINTRD3001 or ESKETINTRD3002). Each potential subject must satisfy the 
following criteria to be enrolled in the study:
12. Criterion modified per Amendment 2:
12.1. The subject must have
completed the double-blind
induction
phase in 
ESKETINTRD3001 or ESKETINTRD3002 and must have demonstrated response at the 
end of that phase (50% reduction in the MADRS total score from baseline [Day 1 pre-
randomization] at the end of the 4-week double-blind induction phase).
Note that the following criterion is intentionally not numbered sequentially:
15. Criterion added per Amendment 2: Transferred-entry subjects must meet the same criteria at 
the point of entry to this study as the direct-entry subjects at the same time point (ie,
beginning of optimization phase).
4.1.3.
Direct-entry Subjects and Transferred-entry Subjects 
The following inclusion criteria apply to both groups of subjects; ie, those entering the study 
directly or those who have completed
a
short-term study
(ESKETINTRD3001
or
ESKETINTRD3002):
13. Each subject must be willing and able to adhere to the prohibitions and restrictions specified 
in this protocol.
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14. Each subject must sign an informed consent form (ICF) indicating that he or she understands 
the purpose of and procedures required for the study and is willing to participate in the 
study.
15. Criterion added per Amendment 2, in Section 4.1.2.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.
4.2.1.
Direct-entry Subjects
The following exclusion criteria only apply to those subjects entering directly into the study:
1.
Criterion modified per Amendment 2:
1.1. Subject's depressive symptoms have previously not responded to any of the following:

Esketamine or ketamine in the current major depressive episode per clinical judgment, 
or

All of the oral antidepressant treatment options available in the respective country for 
the open-label induction phase (ie, duloxetine, escitalopram, sertraline, and venlafaxine 
XR) in the current major depressive episode (based on MGH-ATRQ), or

An adequate course of treatment with electroconvulsive therapy (ECT) in the current 
major depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT.
2.
Criterion modified per Amendment 2:
2.1. Subject has received vagal nerve stimulation (VNS) or has received deep brain 
stimulation (DBS) in the current episode of depression.
3.
Criterion modified per Amendment 2:
3.1. Subject has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with 
psychotic features, bipolar or related disorders (confirmed by the MINI), obsessive 
compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes 317, 
318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, borderline personality 
disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic 
personality disorder.
4.
Subject has homicidal ideation/intent, per the investigator’s clinical judgment, or has 
suicidal ideation with some intent to act within 6 months prior to the start of the 
screening/prospective observational phase, 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) for suicidal ideation on the C-SSRS, or a history of suicidal 
behavior within the past year prior to the start of the screening/prospective observational 
phase. Subjects reporting suicidal ideation with intent to act or suicidal behavior prior to the 
start of the open-label induction phase should be excluded.
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5.
Subject has a history of moderate or severe substance or alcohol use disorder according to 
DSM-5 criteria, except nicotine or caffeine, within 6 months before the start of the 
screening/prospective observational phase. 

A history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide 
(LSD), or 3,4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use 
disorder is exclusionary.
6.
Subject has a current or past history of seizures (uncomplicated childhood febrile seizures 
with no sequelae are not exclusionary).
7.
Subject has an UPSIT total score 18, indicative of anosmia, in the screening/prospective 
observational phase.
8.
Criterion modified per Amendment 2:
8.1. Subject has one of the following cardiovascular-related conditions:

Cerebrovascular disease with a history of stroke or transient ischemic attack.

Aneurysmal vascular disease (including intracranial, thoracic, or abdominal aorta, or 
peripheral arterial vessels).

Coronary 
artery 
disease 
with 
myocardial 
infarction, 
unstable 
angina, 
or 
revascularization procedure (eg, coronary angioplasty or bypass graft surgery) within 
12 months before the start of the screening/prospective observational phase. Subjects 
who have had a revascularization performed >12 months prior to screening and are 
clinically stable and symptom-free, per investigator's clinical judgment, can be 
included.

Hemodynamically significant valvular heart disease such as mitral regurgitation, aortic 
stenosis, or aortic regurgitation.

New York Heart Association (NYHA) Class III-IV heart failure of any etiology (refer 
to Attachment 2).
9.
Criterion modified per Amendment 2:
9.1. Subject has a history of uncontrolled hypertension despite diet, exercise, or 
antihypertensive therapy at the start of the screening/prospective observational phase or any 
past history of hypertensive crisis or ongoing evidence of uncontrolled hypertension defined 
as a supine systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) 
>90 mmHg during screening/prospective observational phase which continues to be above 
this range with repeated testing during this phase. Note: On Day 1 of the open-label
induction phase (prior to the first intranasal treatment session) a supine SBP >140 mmHg or 
DBP >90 mmHg is exclusionary.

A potential subject may have his/her current antihypertensive medication(s) adjusted 
during the screening/prospective observational phase and be re-evaluated to assess their 
blood pressure control. The subject must be on a stable regimen for at least 2 weeks 
before Day 1 of the open-label induction phase.
10. Subject has a current or past history of significant pulmonary insufficiency/condition or with 
an arterial blood oxygen saturation (SpO2) of <93% at the start of the screening/prospective 
observational phase or Day 1 of the open-label induction phase prior to the first intranasal 
treatment session.
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11. Criterion modified per Amendment 2:
11.1. Criterion modified per Amendment 3:
11.2. Subject has clinically significant ECG abnormalities at the start of the 
screening/prospective observational phase or on Day 1 of the open-label induction phase
prior to the first intranasal treatment session, defined as:

During screening, a QT interval corrected according to Fridericia's formula (QTcF): 
450 msec; if the QTcF is prolonged on the initial ECG, the average QTcF of three 
ECGs, recorded 4 minutes apart, must not be ≥450 msec.

On Day 1 (predose), a QT interval corrected according to Fridericia’s formula (QTcF): 
≥450 msec based on the site-evaluated ECG; if the QTcF is prolonged on the initial 
ECG, the average QTcF of three ECGs, recorded 4 minutes apart, must not be ≥450 
msec.

Evidence of 2nd and 3rd degree AV block, complete left bundle branch block (LBBB), or 
complete right bundle branch block (RBBB).

Features of new ischemia.

Arrhythmia (except premature atrial contractions [PACs] and premature ventricular 
contractions [PVCs]).
12. Criterion modified per Amendment 2:
12.1. Subject has a history of additional risk factors for torsades des pointes (eg, heart 
failure, hypokalemia, or family history of long QT syndrome).
13. Criterion modified per Amendment 2:
13.1. Subject has a history of, or symptoms and signs suggestive of, liver cirrhosis (eg, 
esophageal varices, ascites, and increased prothrombin time) OR alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) values 2x the upper limit of normal or total 
bilirubin >1.5 times the ULN in the screening/prospective observational phase.

Repeat of screening test for abnormal ALT and AST is permitted once during the 
screening period provided per investigator discretion and provide there is an alternative 
explanation for the out of range value.

For elevations in bilirubin if, in the opinion of the investigator and agreed upon by the 
sponsor’s medical officer, the elevation in bilirubin is consistent with Gilbert’s disease, 
the subject may participate in the study.
14. Criterion modified per Amendment 2:
14.1. Criterion modified per Amendment 3:
14.2. Subject has positive test result(s) for drugs of abuse (including barbiturates, 
methadone, opiates, cocaine, phencyclidine, and amphetamine/methamphetamine) at the 
start of the screening/prospective observational phase or Day 1 of the open-label induction 
phase prior to the first intranasal treatment session.

Subjects who have a positive test result at screening due to prescribed psychostimulants 
(eg, amphetamine, methylphenidate, etc.), taken for an indication other than MDD, are 
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permitted to continue to take this medication during the study in accordance with 
Attachment 1.

Otherwise, subjects who have a positive test result at screening due to prescribed/over-
the-counter opiates
or barbiturates
may be permitted to continue in the 
screening/prospective observational phase if the medication is discontinued at least 1 
week or 5 half-lives, whichever is longer, before Day 1 of the open-label induction 
phase prior to the first intranasal treatment session, in accordance with Attachment 1
restrictions. The result of the Day 1 (prior to the first intranasal treatment session) test
for drugs of abuse must be negative for the subject to have the first intranasal treatment 
session.
o
Retesting is not permitted for positive test result(s), except for reasons stated above.

Prior intermittent use of cannabinoids prior to the start of the screening/prospective 
observational phase is not exclusionary as long as the subject does not meet the criteria 
for substance use disorder. A positive test for cannabinoids at the start of the 
screening/prospective observational phase is not exclusionary; however, a positive test 
result for cannabinoids predose on Day 1 of the open-label induction phase is 
exclusionary.
15. Criterion modified per Amendment 2:
15.1. Subject has uncontrolled diabetes mellitus, as evidenced by HbA1c >9% in the 
screening/prospective observational phase or history in the prior 3 months prior to the start 
of the screening/prospective observational phase of diabetic ketoacidosis, hyperglycemic 
coma, or severe hypoglycemia with loss of consciousness.
16. Subject has untreated glaucoma, current penetrating or perforating eye injury, brain injury, 
hypertensive encephalopathy, intrathecal therapy with ventricular shunts, or any other 
condition associated with increased intracranial pressure or increased intraocular pressure or 
planned eye surgery.
17. Criterion modified per Amendment 2:
17.1. 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.
18. Criterion deleted per Amendment 2.
19. Subject has a history of malignancy within 5 years before the start of the 
screening/prospective observational phase (exceptions are squamous and basal cell 
carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that, in the 
opinion of the investigator, with concurrence with the sponsor's medical monitor, is 
considered cured with minimal risk of recurrence).
20. Subject has known allergies, hypersensitivity, intolerance, or contraindications to 
esketamine/ketamine and/or its excipients or all of the available oral antidepressant 
treatment options for the open-label induction phase.
21. Subject has taken any prohibited therapies that would not permit dosing on Day 1, as noted 
in Section 8 (Prestudy and Concomitant Therapy) and Attachment 1.
22. Subject is taking a total daily dose of benzodiazepines greater than the equivalent of 
6 mg/day of lorazepam at the start of the screening/prospective observational phase.
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23. Criterion modified per Amendment 2:
23.1. Subject has a score of 5 on the STOP-Bang questionnaire, in which case obstructive 
sleep apnea must be ruled out (eg, apnea-hypopnea index [AHI] must be <30). A subject 
with obstructive sleep apnea can be included if he or she is using a positive airway pressure 
device or other treatment/therapy that is effectively treating (ie, AHI <30) his or her sleep 
apnea.
24. Criterion modified per Amendment 2:
24.1. Subject has received an investigational drug (including investigational vaccines) or 
used an invasive investigational medical device within 60 days before the start of the 
screening/prospective observational phase, or has participated in 2 or more MDD or other 
psychiatric condition clinical interventional studies (with different investigational 
medication) in the previous 1 year before the start of the screening/prospective observational 
phase, or is currently enrolled in an investigational interventional study.
25. 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.
26. Subject has a diagnosis of acquired immunodeficiency syndrome (AIDS). Human 
immunodeficiency virus (HIV) testing is not required for this study.
27. 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.
28. Subject has had major surgery, (eg, requiring general anesthesia) within 12 weeks before the 
start of the screening/prospective observational phase, or will not have fully recovered from 
surgery, or has surgery planned during the time the subject is expected to participate in the 
study.

Note: Subjects with planned surgical procedures to be conducted under local anesthesia 
may participate.
29. 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 that the following criterion is intentionally not numbered sequentially:
31. Criterion added per Amendment 2: Subject has severe renal impairment (creatinine 
clearance <30 mL/min).
4.2.2.
Transferred-entry Subjects
The following exclusion criterion applies to transferred-entry subjects:
30. 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.
31. Criterion added per Amendment 2, in Section 4.2.1.
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32. Criterion added per Amendment 2: Transferred-entry subjects must meet the same criteria at 
the point of entry to this study as the direct-entry subjects at the same time point (ie,
beginning of optimization phase).
NOTE: Investigators should ensure that all relevant study enrollment criteria have been met 
prior to Day 1 of the open-label induction phase (direct entry) or the start of the optimization 
phase (transferred entry). If a subject's status changes (including laboratory results or receipt of 
additional medical records) before the first dose of intranasal study drug is given in this study 
such that he or she no longer meets applicable 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:

Refer to Section 4.1 (Inclusion Criteria) and Section 4.2 (Exclusion Criteria) for information 
regarding contraception requirements.

Refer to Section 4.3 (Prestudy and Concomitant Therapy) and Attachment 1 (Prohibited 
Concomitant Medications With Intranasal Study Medication [Esketamine or Placebo]) 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) during the screening/prospective observational phase can continue these 
medications during the induction phase. No dose increases beyond the equivalent of 
6 mg/day of lorazepam, or new benzodiazepine medications are permitted during the 
induction phase, with the exception of the use of permitted benzodiazepine rescue 
medication (post-dose on the dosing day only). 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 (PCP), or cocaine from Day 1 of the 
induction phase through the final visit in the final treatment phase (open-label induction, 
optimization, or maintenance phase) 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 must remain at the clinical study 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 study drug dosing.
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
Electroconvulsive therapy, DBS, transcranial magnetic stimulation (TMS), and VNS are 
prohibited from study entry through the end of the last treatment phase (open-label 
induction, optimization, or maintenance phase).

Subjects receiving psychotherapy (including cognitive behavioral therapy [CBT]) can 
continue receiving psychotherapy; however, CBT must have been ongoing for the last 
3 months prior to the start of the screening/prospective observational phase. With the 
exception of new CBT, which is prohibited, new psychotherapy is allowed during this study. 
Any change in existing therapy or new therapy must be documented on the concomitant 
therapies form.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation and Randomization
Intranasal Study Drug
Randomization is not applicable for the screening/prospective observational phase, open-label 
induction phase, or optimization phase of this study.
Central randomization will be implemented in the maintenance phase of this study. At the start of 
the maintenance phase, subjects in stable remission after treatment with intranasal esketamine 
plus an oral antidepressant will be randomly assigned to 1 of 2 treatment groups (intranasal 
esketamine or intranasal placebo) in a 1:1 ratio based on computer-generated randomization 
schedule prepared before the study by or under the supervision of the sponsor. The 
randomization will be balanced by using randomly permuted blocks and will be stratified by 
country. 
Although not part of the primary analysis, at the start of this phase, subjects in stable response 
(but who are not in stable remission) after treatment with intranasal esketamine plus an oral 
antidepressant will also be randomly assigned to 1 of 2 treatment groups in a 1:1 ratio based on a 
separate computer-generated randomization schedule (ie, different schedule from the subjects in 
stable remission) prepared before the study by or under the supervision of the sponsor. The 
randomization will be balanced by using randomly permuted blocks and will be stratified by 
country.
Transferred-entry subjects who achieved stable remission or stable response after treatment with 
intranasal placebo plus an oral antidepressant will continue to receive the same treatment in order 
to maintain the blinding for the ongoing short-term studies.
The Interactive Web Response System (IWRS) will assign a unique treatment code, which will 
dictate the treatment assignment and matching intranasal study drug kit for the subject. The 
requestor must use his or her own user identification and personal identification number when 
contacting the IWRS, and will then give the relevant subject details to uniquely identify the 
subject.
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Oral Antidepressant Medication
For direct-entry subjects, after the investigator assigns the oral antidepressant treatment for the 
open-label induction phase, the site will enter this information into IWRS and it will be 
dispensed throughout the study at the time points specified in the Time and Events Schedule.
For transferred-entry subjects, the IWRS will continue to dispense the same open-label oral 
antidepressant used in ESKETINTRD3001 and ESKETINTRD3002 throughout the study 
(optimization, maintenance, and follow-up phases) of this study at the time points specified in 
the Time and Events Schedule.
Blinding
To maintain the blinding of intranasal study medication, the esketamine and placebo intranasal 
devices will be indistinguishable. Please refer to Section 14 (Study Drug Information) for 
information on the physical characteristics of the intranasal study drug.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (ie, treatment allocation, biomarker 
or other specific lab data) will be handled with special care to ensure that the integrity of the 
blind is maintained and the potential for bias is minimized. This can include making special 
provisions, such as segregating the data in question from view by the investigators, clinical team, 
or others as appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until the maintenance and follow-up 
phases are completed and the database is finalized. Otherwise, the blind should be broken only if 
specific emergency treatment/course of action would be dictated by knowing the intranasal 
treatment status of the subject. In such cases, the investigator may in an emergency determine the 
identity of the intranasal treatment by contacting the IWRS. It is recommended that the 
investigator contact the sponsor or its designee if possible to discuss the particular situation, 
before breaking the blind. Telephone contact with the sponsor or its designee will be available 
24 hours per day, 7 days per week. In the event the blind is broken, the sponsor must be informed 
as soon as possible. The date and time of the unblinding will be documented by the IWRS, and 
reason for the unblinding must be documented in the appropriate section of the electronic case 
report form (eCRF) and in the source document. The documentation received from the IWRS 
indicating the code break must be retained with the subject's source documents in a secure 
manner.
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled early withdrawal and follow up visits.
In general, randomization codes will be disclosed fully only if the study is completed through the 
follow-up phase and the clinical database is closed. However, for the prespecified interim 
analysis, the randomization codes and, if required, the translation of randomization codes into 
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treatment and control groups will be disclosed to those authorized and only for those subjects 
included in the interim analysis. At the end of the follow-up phase, the database will be locked 
for the analysis and reporting of this study.
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, a basic life support course or equivalent course) that is up to date per local 
regulations, must be present with the subject during the intranasal treatment session and the 
postdose observation period. In addition, equipment for supportive ventilation and resuscitation 
needs to be present.
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 eCRF.
Prior to the first intranasal dose on Day 1, direct-entry subjects will practice spraying (into the 
air, not intranasally) a demonstration intranasal device that is filled with a placebo solution.
All subjects will self-administer the intranasal study drug (esketamine or placebo) at treatment 
sessions at the study site. Intranasal treatment sessions should not take place 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 can be delayed (per the permitted visit window; see the 
Time and Events Schedule). If an intranasal decongestant is used to reduce congestion, it cannot 
be used within 1 hour prior to intranasal study drug dosing.
On all intranasal dosing days, 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 site. Subjects must not drive a car or work 
with machines for 24 hours after receiving intranasal study drug.
Guidance for Blood Pressure Monitoring on Intranasal Treatment Session Days:
Given the potential for treatment-emergent transient elevation in systolic and diastolic blood 
pressure, the following guidance should be followed on intranasal dosing days:

If subsequent to fulfilling the inclusion and exclusion criteria on Day 1 (ie, applicable for all 
other intranasal treatment session days after Day 1), a subject’s pre-dose systolic blood 
pressure (SBP) is >140 mmHg and/or diastolic blood pressure (DBP) is >90 mmHg, it is 
recommended to repeat the blood pressure measurement after the subject rests in sitting or 
recumbent position. If after rest and repeated measurements, pre-dose SBP is >140 mmHg 
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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 primary care physician, prior to further dosing.

If at any postdose 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 primary care physician, if 
recommended by the referring doctor and considered appropriate according to the 
clinical judgment for the subject to continue in the study, then the subject may continue 
with intranasal dosing if the predose blood pressure at the next scheduled visit is within 
the acceptable range (see bullet point above).

If at any postdose 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 primary care physician for a follow-up 
assessment.

At 1.5 hours postdose, if the SBP is 160 mmHg and/or the DBP 100 mmHg, assessments 
should continue every 30 minutes until:

the blood pressure is <160 mmHg SBP and <100 mmHg 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.
6.1.1.
Open-label Induction Phase
All direct-entry subjects will self-administer open-label intranasal esketamine (56 mg or 84 mg) 
twice a week for 4 weeks as a flexible dose regimen at the study site. In addition, subjects will 
simultaneously initiate (switch to) a new, open-label oral antidepressant (duloxetine, 
escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of 
this phase.
On Day 1, subjects will start with a dose of 56 mg. On Day 4, the dose may be increased to 
84 mg or remain at 56 mg, as determined by the investigator based on efficacy and tolerability. 
On Day 8, the dose may be increased to 84 mg (if Day 4 dose was 56 mg), remain the same, or 
be reduced to 56 mg (if Day 4 dose was 84 mg), as determined by the investigator based on 
efficacy and tolerability. Similarly, on Days 11, 15, 18, and 22, the dose may be increased to 
84 mg, remain the same, or be reduced to 56 mg, if applicable as determined by the investigator 
based on efficacy and tolerability. On Day 25, a dose reduction from 84 mg to 56 mg is 
permitted if required for tolerability; no dose increase is permitted. 
The intranasal treatment sessions will be administered in this phase as described in Table 1.
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Table 1:
Intranasal Esketamine Treatment Sessions: Open-label Induction Phase
Intranasal Treatment
Time of Administration a
0a
5 minutes
10 minutes
Intranasal Device b
First
Second
Third
Esketamine 56 mg
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
No device required
Esketamine 84 mg
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
a
Time 0 is defined as the time of administration of the first intranasal spray to one nostril from the first intranasal 
device.
b
One device will be used at each time point. Each intranasal device contains 2 sprays. The intranasal devices 
containing esketamine deliver 14 mg per spray, for a total of 28 mg per individual device (ie, 2 sprays).
6.1.2.
Optimization Phase
6.1.2.1.
Transferred-entry Subjects
In the optimization phase, subjects will continue the same double-blind intranasal study drug 
(same 
dose) 
from 
the 
double-blind 
induction 
phase 
of 
ESKETINTRD3001 
or 
ESKETINTRD3002.
6.1.2.2.
Direct-entry Subjects
In the optimization phase, subjects will continue the same open-label intranasal esketamine 
treatment (same dose) from the open-label induction phase.
All subjects will continue their oral antidepressant medication (at the same dosage) during this 
phase.
6.1.2.3.
Intranasal Treatment Session Frequency (All Subjects)
During this phase, the MADRS will be performed weekly by an independent, remote rater, and 
this MADRS total score will be used for intranasal treatment session frequency decisions (if 
applicable) at that visit.
For all subjects, the frequency of intranasal treatment sessions will be reduced from the twice-
weekly frequency used in the induction phase to weekly for the first 4 weeks of the optimization 
phase (Week 5 to Week 8). 
During this phase, there are two fixed time points (Week 8 and Week 12) in which an adjustment 
to the frequency will be made, if applicable:
Week 8

Subjects with a MADRS total score >12 at Week 8 visit will continue to receive weekly 
intranasal treatment sessions for the remainder of the optimization phase. No further change 
to the treatment session frequency is permitted for the remainder of the optimization phase 
(through Week 16).
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
If the MADRS total score is 12 at Week 8, the subject will reduce the frequency to receive 
intranasal treatment sessions every other week for the next 4 weeks (ie, next treatment 
sessions will be at Week 10 and Week 12). 

This is the only time during the optimization phase that a subject will be permitted to 
change to a frequency of every other week.

If the MADRS assessment is missed at Week 8, the last MADRS total score available prior 
to Week 8 will be used to determine if a change in treatment session frequency is indicated 
at Week 8. In this case:

If the MADRS total score is ≤12, the subject will reduce the frequency to receive 
intranasal treatment sessions every other week for the next 4 weeks (ie, next treatment 
sessions will be at Weeks 10 and 12).

If the MADRS total score is >12, the subject will continue to receive weekly intranasal 
treatment sessions for the remainder of the optimization phase. No further change to the 
treatment session frequency is permitted for the remainder of the optimization phase 
(through Week 16).
Week 12 (only for those on an every other week treatment session frequency):

If the MADRS total score is >12 at Week 12, the frequency of intranasal treatment sessions 
will be increased to weekly for the remainder of the optimization phase; no further change to 
the treatment session frequency is permitted for the remainder of the optimization phase 
(through Week 16).

If the MADRS total score is ≤12 at Week 12, the subject will remain on the treatment 
session frequency of every other week for the next 4 weeks (ie, through to Week 16).

If the MADRS is missed at Week 12, the last MADRS total score available prior to Week 12 
will be used to determine if a change in treatment session frequency is indicated at Week 12. 
In this case:

If the MADRS total score is ≤12, the subject will remain on the treatment session 
frequency of every other week for the next 4 weeks (ie, through to Week 16).

If the MADRS total score is >12 at that week, the frequency of intranasal treatment 
sessions will be increased to weekly for the remainder of the optimization phase; no 
further change to the treatment session frequency is permitted for the remainder of the 
optimization phase (through Week 16).
Table 2 and Table 3 describe the administration of intranasal study drug during the optimization 
phase.
Table 2:
Intranasal Esketamine Treatment Sessions: Optimization Phase (Direct entry Subjects)
Time of Administration
0 a
5 minutes
10 minutes
Intranasal Device b
First
Second
Third
Esketamine 56 mg
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
No device required
Esketamine 84 mg
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
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a
Time 0 is defined as the time of administration of the first intranasal spray to one nostril from the first 
intranasal device.
b
One device will be used at each designated time point. Each intranasal device contains 2 sprays. The intranasal 
devices containing esketamine deliver 14 mg per spray, for a total of 28 mg per individual device (ie, 
2 sprays).
Table 3:
Intranasal Esketamine or Placebo Treatment Sessions: Optimization Phase
(Transferred-entry Subjects)
Time of Administration
0 a
5 minutes
10 minutes
Intranasal Device b
First
Second
Third
Placebo 
1 spray of placebo
to each nostril
1 spray of placebo
to each nostril
1 spray of placebo
to each nostril
Esketamine 56 mg
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
1 spray of placebo
to each nostril
Esketamine 84 mg
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
a
Time 0 is defined as the time of administration of the first intranasal spray to one nostril from the first 
intranasal device.
b
One device will be used at each designated time point. Each intranasal device contains 2 sprays. The intranasal 
devices containing esketamine deliver 14 mg per spray, for a total of 28 mg per individual device (ie, 
2 sprays). The intranasal devices for each intranasal treatment session should be administered in the 
medication kit order provided by the Interactive Web Response System (IWRS).
6.1.3.
Maintenance Phase
All subjects will receive double-blind intranasal study drug in this phase, as described above (see 
Section 3.1.1).
During this phase, the MADRS will continue to be assessed weekly by an independent, remote 
rater, and changes to the intranasal treatment session frequency will occur at 4-week intervals, if 
applicable, and be based on the MADRS total score (see below). 
At the start of this phase (Visit 4.1; Week 16):

Subjects who currently receive intranasal treatment sessions on a weekly basis will stay at 
the same weekly intranasal treatment session frequency for the first 4 weeks of this phase. 

For those on an every other week frequency:

If the MADRS total score is >12 at Week 16, the frequency of intranasal treatment 
sessions will be increased to weekly for the next 4 weeks.

If the MADRS total score is ≤12 at Week 16, the subject will stay at the same every 
other week intranasal treatment session frequency for the next 4 weeks. 
After the first 4 weeks of this phase (ie, starting at Week 20) the intranasal treatment session 
frequency will be adjusted (if applicable) at fixed, 4-week intervals (eg, Week 20, 24, 28, 32, 36, 
40, 44 and every 4 weeks until the end of the phase), based on the guidance below. 
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
If the MADRS total score is 12 at that week:

If the frequency is weekly, the frequency will be changed to every other week.

If the frequency is every other week, there will be no change in frequency.

If the MADRS total score is >12 at that week:

If the frequency is weekly, there will be no change in frequency.

If the frequency is every other week, the frequency will be changed to weekly.

If the MADRS is missed at that week, the last MADRS total score available prior to that 
week will be used to determine if a change in treatment session frequency is indicated at that 
week. In this case:

If the MADRS total score is ≤12, and the frequency is every other week, there will be 
no change in frequency.

If the MADRS total score is ≤12, and the frequency is weekly, the frequency will be 
changed to every other week.

If the MADRS total score is >12, and the frequency is weekly, there will be no change 
in frequency.

If the MADRS total score is >12, and the frequency is every other week, the frequency 
will be changed to weekly
A maximum of 3 changes in intranasal treatment session frequency from weekly to every other 
week is permitted during the maintenance phase. After this time, if a given subject is unable to 
sustain improvement on every other week dosing they will remain on a weekly dosing regimen 
for the duration of this phase.
Table 4 describes the administration of intranasal study drug in the maintenance phase.
Table 4:
Intranasal Esketamine or Placebo Treatment Sessions: Maintenance Phase
Time of Administration
0 a
5 minutes
10 minutes
Intranasal Device b
First
Second
Third
Placebo
1 spray of placebo
to each nostril
1 spray of placebo
to each nostril
1 spray of placebo
to each nostril 
Esketamine 56 mg
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
1 spray of placebo
to each nostril 
Esketamine 84 mg
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
a
Time 0 is defined as the time of administration of the first intranasal spray to one nostril from the first 
intranasal device. 
b
One device will be used at each designated time point. Each intranasal device contains 2 sprays. The intranasal 
devices containing esketamine deliver 14 mg per spray, for a total of 28 mg per individual device (ie, 2 sprays).
The 3 intranasal devices for each intranasal treatment session should be administered in the medication kit 
order provided by the Interactive Web Response System (IWRS).
6.1.4.
Follow-up Phase
No intranasal study medication will be administered during this phase.
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6.2.
Oral Antidepressants
Study-site personnel will instruct subjects on how to take/use and store the oral antidepressants 
supplied during this study for at-home use. A subject diary to capture oral antidepressant intake 
between clinic visits will be provided for use.
On intranasal dosing days, it is recommended that oral antidepressant treatment not be taken 
until at least 3 hours after the intranasal treatment session.
6.2.1.
Screening/Prospective Observational Phase (Direct-entry Subjects 
Only)
At the start of this phase, direct-entry subjects are to be taking a different oral antidepressant 
treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or above the minimum 
therapeutic dose. This antidepressant treatment, as well as any other ongoing medications being 
taken for depression at screening (including adjunctive/augmentation therapies), will continue 
from the start of Week 1 through the end of Week 4 of the screening/prospective observational 
phase, to confirm non-response. Dose adjustment is permitted per clinical judgment, but the oral 
antidepressant treatment is to remain at or above the minimum therapeutic dose (per the MGH-
ATRQ) through the end of Week 4. The sponsor will not supply these antidepressant 
medication(s).
During this phase, antidepressant treatment adherence will be assessed using the PAQ.
After 4 weeks subjects who are non-responders to their current oral antidepressant treatment may 
be eligible to proceed to the open-label induction phase. Non-response at the end of the 
screening/prospective observational phase is defined as ≤25% improvement in the MADRS total 
score from Week 1 to Week 4 and a MADRS total score of ≥28 on Week 2 and Week 4. 
After the completion of 4 weeks of prospective antidepressant treatment and assessment of the 
antidepressant treatment response, eligible subjects who are entering the open-label induction 
phase will discontinue all of their medication(s), including adjunctive/augmentation therapies. Of 
note, subjects 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) 
during the screening/prospective observational phase can continue these medications. No dose 
increases beyond the equivalent of 6 mg/day lorazepam or new benzodiazepine medications are 
permitted during the screening/prospective observational phase. If clinically indicated, the 
antidepressant medication may be tapered and discontinued over a period of up to 3 weeks per 
the local prescribing information or clinical judgment (eg, antidepressant treatments with short 
half lives, such as paroxetine and venlafaxine XR; or tolerability concerns). Eligible subjects 
who do not require a tapered discontinuation of their antidepressant treatment(s) can proceed 
immediately into the open-label induction phase.
6.2.2.
Open-label Induction Phase (Direct-entry Subjects Only)
Starting on Day 1 of the open-label induction phase, a new, open-label oral antidepressant 
treatment will be initiated for all direct-entry subjects, and continued for the duration of this 
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phase. The oral antidepressant will be 1 of 4 oral antidepressant medications (duloxetine, 
escitalopram, sertraline, or venlafaxine XR). The antidepressant medication will be assigned by 
the investigator based on review of the MGH-ATRQ and relevant prior antidepressant 
medication information, and will be one that the subject has not previously had a non-response to 
in the current episode (based on MGH-ATRQ), has not been previously intolerant to (lifetime), 
and is available in the participating country.
Dosing of the oral antidepressant will begin on Day 1. A mandatory titration schedule is 
provided in Attachment 3. Doses are not to exceed the maximum dose defined in the titration 
schedule. If higher doses are not tolerated, a down-titration is permitted based on clinical 
judgment. However, the subject’s dose should not be lower than the following minimum 
therapeutic doses at the end of the induction phase: sertraline (50 mg/day), venlafaxine XR 
(150 mg/day), escitalopram (10 mg/day), and duloxetine (60 mg/day). While subjects requiring 
lower doses can continue in the study and complete the induction phase, such subjects will not be 
eligible to participate in the optimization phase and will proceed to the follow-up phase after 
completion of the induction phase.
Study-site personnel will instruct subjects on how to take and store the oral antidepressant 
treatments supplied during this study for at-home use. A subject diary to capture oral 
antidepressant study medication use will be provided.
On intranasal dosing days, it is recommended the oral antidepressant medication not be taken 
until at least 3 hours after an intranasal treatment session.
6.2.3.
Optimization and Maintenance Phases (Direct-entry and Transferred-
entry Subjects)
For all subjects, the same oral antidepressant treatment (duloxetine, escitalopram, sertraline, or 
venlafaxine XR) started on Day 1 of the induction phase will be continued through the 
optimization and maintenance phases. The oral antidepressant dosage at the end of the induction 
phase will remain unchanged through the maintenance phase.
Subjects who miss 21 days of the oral antidepressant doses (total daily dose) in the optimization 
phase will not be eligible to continue into the maintenance phase.
6.2.4.
Follow-up Phase
At the start of the follow-up phase, further clinical/standard of care for the treatment of 
depression will be arranged by the study investigator and/or the subject’s treating physician.
No intranasal study medication will be administered during this phase. The decision to continue 
the oral antidepressant medication in this phase will be at the discretion of the investigator; 
however, in order to better assess potential withdrawal symptoms from the intranasal study 
medication, the oral antidepressant should be continued during the 2-week follow-up phase, 
unless determined as not clinically appropriate.
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All subjects will be provided with an additional 2-week supply of the oral antidepressant 
medication at the last clinic visit prior to entering the follow-up phase, to ensure there is no 
interruption of antidepressant therapy during the transition to further clinical/standard of care.
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.
Subjects will receive instructions on compliance with the oral antidepressant treatment. During 
the course of the study, the investigator or designated study-site personnel will be responsible for 
providing additional instruction to re-educate any subject to ensure compliance with taking the 
oral antidepressant. A subject diary will be provided to capture oral antidepressant intake 
between clinic visits.
The investigator or designated study-site personnel will maintain a log of all intranasal study 
drug and oral antidepressant medication dispensed and returned. Drug supplies for each subject 
will be inventoried and accounted for throughout the study (see Section 14.5, Drug 
Accountability).
During the screening/prospective observational phase, antidepressant treatment compliance will 
be assessed using the PAQ. Missing 4 days of antidepressant medication in the prior 2-week 
period will be considered as inadequate adherence.
For all other phases, antidepressant treatment compliance will be assessed by performing pill 
counts (ie, compliance check) and drug accountability at the time points specified in the Time 
and Events Schedule (see Section 14.5, Drug Accountability). 
Subjects who miss 21 days of the oral antidepressant doses (total daily dose) in the optimization 
phase will not be eligible to continue into the maintenance phase.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy non-antidepressant therapies administered up to 30 days before the start of the 
screening/prospective observational phase must be recorded at the start of this phase. 
All antidepressant treatment(s), including adjunctive treatment for MDD, taken during the 
current depressive episode (ie, including those taken more than 30 days prior to the start of the 
screening/prospective 
observational 
phase) 
will 
be 
recorded 
at 
the 
start 
of 
the 
screening/prospective observational phase. In addition, information will also be obtained 
regarding any history of intolerance to any of the 4 antidepressant choices (ie, duloxetine, 
escitalopram, sertraline, and venlafaxine XR). Antidepressant treatments which are not listed on 
the MGH-ATRQ but were used, or are currently being used, as antidepressant treatment in the 
current depressive episode must be recorded in "Concomitant Therapy" eCRF.
Any medication that is listed on the MGH-ATRQ and is being taken at the start of the 
screening/prospective observational phase for an indication other than depression (eg, insomnia) 
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should be continued during the screening/prospective observational phase but must be 
discontinued before the start of the double-blind induction phase.
Concomitant therapies 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.
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 on dosing days, the morning dose should be taken 
prior to intranasal dosing.
Subjects receiving psychotherapy (including cognitive behavioral therapy; CBT) can continue 
receiving psychotherapy; however, CBT must have been ongoing for the last 3 months prior to 
the start of the screening/prospective observational phase. With the exception of new CBT, 
which is prohibited, new psychotherapy is allowed during the study. Any change in existing 
therapy or any new therapy must be documented on the concomitant therapies form.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; nonpharmacologic therapies, such as psychotherapy, electrical stimulation, 
acupuncture, special diets, and exercise regimens) different from the study drug must be recorded 
in the eCRF. Modification of an effective preexisting therapy should not be made for the explicit 
purpose of entering a subject into the study, 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 intranasal 
esketamine/placebo, 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 (only permitted post-dose on the day of dosing).

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.
Prohibited Medications
A list of prohibited medications is provided in Attachment 1 as general guidance for the 
investigator (but is not all inclusive).
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The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, biomarker, 
pharmacogenomic, health economic, medical resource utilization, and safety measurements 
applicable to this study.
With the exception of postdose assessments,
visit-specific 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 eCRF.
The approximate total blood volume to be collected from each subject will depend on the 
number of study phases the subject participates in, but should not exceed 189 mL, as shown in 
Table 5. Note that the values listed in Table 5 represent the maximum total blood volume to be 
collected, based on the volume for direct-entry subjects; smaller amounts will be collected from 
the transferred-entry subjects, who will not participate in all study phases. 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.
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Table 5:
Volume of Blood to Be Collected From Each Subject
Type of Sample
Volume per 
Sample (mL)
No. of Samples 
per Subject
Total Volume 
of Blood (mL) a
Screening/Prospective Observational Phase
Serum chemistry b
5
1
5
TSH
3.5
1
3.5
Hematology c
2
1
2
Biomarker: protein
10
1
10
Biomarker: RNA
2.5
1
2.5
Biomarker: DNA
6
1
6
Tricyclic antidepressant blood level, if applicable d
6
1
6
FT4, if applicable e
3.5
1
3.5
Open-label Induction Phase
Serum chemistry
2.5
2
5
Hematology
2
2
4
Biomarker: protein
10
3
30
Biomarker: RNA
2.5
3
7.5
Biomarker: DNA
6
1
6
Optimization Phase
Serum chemistry
2.5
3
7.5
Hematology
2
3
6
Biomarker: protein
10
2
20
Biomarker: RNA
2.5
2
5
Biomarker: DNA
6
2
12
Maintenance Phase
Serum chemistry
2.5
2
5
Hematology
2
2
4
Biomarker: protein
13
1
13
Biomarker: RNA
2.5
1
2.5
Biomarker: DNA
6
1
6
Follow-up Phase
Serum chemistry
2.5
1
2.5
Hematology
2
1
2
Biomarker: protein
10
1
10
Biomarker: RNA
2.5
1
2.5
Approximate volume of blood collected during the study
189 mL
Key: DNA = deoxyribonucleic acid; FT4 = free thyroxine; RNA = ribonucleic acid; TSH = thyroid-stimulating hormone.
a
Calculated as number of samples multiplied by amount of blood per sample.
b
Serum chemistry includes highly sensitive serum β-human chorionic gonadotropin (β-hCG) pregnancy tests (for 
women of childbearing potential) and lipid panel.
c
As needed, glycated hemoglobin (HbA1c) will be measured from the sample collected for hematology.
d
During eligibility assessments, if a subject is taking a tricyclic antidepressant at a dose below the minimum therapeutic
dose recommended in the MGH-ATRQ, then the blood level of that antidepressant will be assessed to determine 
whether the therapeutic (antidepressant) range has been attained.
e
For any subject (regardless of thyroid history), if the TSH value is out of range, then the FT4 level will be assessed.
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.
Note: The values listed above represent the maximum total blood volume to be collected, based on the volume for direct-
entry subjects; smaller amounts will be collected from the transferred-entry subjects, who will not participate in all study 
phases.
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9.1.2.
Screening/Prospective Observational Phase
This phase is only for direct-entry subjects.
Prior to conducting any study procedure, the investigator (or designated study personnel) will 
review and explain the written ICF to each direct entry subject. After signing the ICF, subjects 
who are 18 years of age (or older if the minimum legal age of consent in the country in which the 
study is taking place is >18 years) to 64 years of age (inclusive) will begin to be screened to 
determine eligibility for study participation (please refer to the study entry criteria listed in 
Section 4).
Subjects must meet DSM-5 diagnostic criteria for single (if a single episode, duration of episode 
must be 2 years) or recurrent MDD, without psychotic features, based upon clinical assessment 
and confirmed by the MINI. In addition, at the start of the screening/prospective observational 
phase, the subject must have an IDS-C30 total score 34.
At the start of this phase, subjects must have had non-response (≤25% improvement) to 1 but 
5 (if current episode is >2 years, upper limit is applicable to only the last 2 years) oral 
antidepressant treatments taken at adequate dosage and for adequate duration, as assessed using 
the MGH-ATRQ and documented by records (eg, medical/pharmacy/prescription records or a 
letter from treating physician, etc.) for the current episode of depression. In addition, at the start 
of the screening/prospective observational phase, the subject is taking a different oral 
antidepressant treatment (on the MGH ATRQ) for at least the previous 2 weeks at or above the 
minimum therapeutic dose. This antidepressant treatment, as well as any other ongoing 
medications being taken for depression (including adjunctive/augmentation therapies), will 
continue from the start of Week 1 through the end of Week 4 of the screening/prospective 
observational phase to confirm non-response prospectively. Dose adjustment is permitted per 
clinical judgment, but the oral antidepressant treatment is to remain at or above the minimum 
therapeutic dose (per the MGH-ATRQ) through the end of Week 4.
Antidepressant treatment adherence will be assessed using the PAQ. Missing 4 days of 
antidepressant medication in the prior 2-week period will be considered as inadequate adherence.
The subject’s current major depressive episode, depression symptom severity (Week 1 MADRS 
total score ≥28 required), and antidepressant treatment response in the current depressive episode 
must be confirmed using the Site Independent Qualification Assessment.
An independent, remote, blinded rater will perform remote MADRS assessments to assess 
depressive symptoms during this phase. 
After 4 weeks, subjects who are non-responders to the current oral antidepressant treatment may 
be eligible to proceed to the open-label induction phase. Non-response at the end of the 
screening/prospective observational phase is defined as ≤25% improvement in the MADRS total 
score from Week 1 to Week 4 and a MADRS total score of ≥28 on Week 2 and Week 4. Eligible 
subjects (determined by remote blinded raters) who are entering the open-label induction phase 
will discontinue all of their current medication(s) being used for depression treatment, including 
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adjunctive/augmentative therapies, and any other prohibited psychotropic medications, including 
adjunctive atypical antipsychotics. Subjects who were taking benzodiazepines (at dosages equal 
to or less than the equivalent of 6 mg/day of lorazepam) and/or permitted nonbenzodiazepine 
sleep medications (eg, zolpidem, zaleplon) during the screening/prospective observational phase 
can continue these medications during the induction phase. No dose increases beyond the 
equivalent of 6 mg/day of lorazepam or new benzodiazepine medications are permitted during 
the induction phase, with the exception of the use of permitted benzodiazepine (post-dose on the 
dosing day only) rescue medication. Benzodiazepines and non-benzodiazepine sleeping 
medications (eg, zolpidem, zaleplon, eszopiclone, and ramelteon) are prohibited within 12 hours 
prior to the start of each intranasal treatment session or cognition testing.
All other subjects who do not participate in the open-label induction phase will end study 
participation at this time. No further study visits or follow-up is required.
Optional Antidepressant Taper Period
Since all non-responder subjects will be starting a new oral antidepressant during the open-label 
induction phase, no washout or drug-free period is required after discontinuing the current 
antidepressant treatment. However, an optional period of up to 3 weeks is permitted to taper and 
discontinue the current oral antidepressant medication per the local prescribing information or 
clinical judgment.
The taper period should not start until after the completion of 4 weeks of prospective 
antidepressant treatment and assessment of the antidepressant treatment response.
9.1.3.
Open-label Induction Phase
This phase is only for direct-entry subjects.
During this phase, subjects will self-administer open-label intranasal esketamine treatment 
(56 mg or 84 mg) twice a week for 4 weeks as a flexible dose regimen. In addition, subjects will 
simultaneously initiate (switch to) a new, open-label oral antidepressant (see Section 6, Dosage 
and Administration). A mandatory titration schedule is provided in Attachment 3. Doses are not 
to exceed the maximum dose defined in the titration schedule.
An independent, remote, blinded rater will perform all MADRS assessments during this phase. 
At the end of the open-label induction phase, subjects who are responders (as defined in 
Section 3.1.2) will be eligible to enter the optimization phase.
Those subjects who do not enter the optimization phase will have an Early Withdrawal Visit 
conducted and proceed to the follow-up phase (see Section 3.1.2).
Results for all assessments performed on Day 28 of the induction phase for direct-entry subjects 
(Visit 2.9) and transferred-entry subjects (Visit 2.10 of Study ESKETINTRD3001 or 
ESKETINTRD3002) will serve as the baseline values for the optimization phase and will not be 
repeated as part of Visit 3.1. The Day 28 visit should coincide with Day 28 (Visit 3.1) for this 
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study. All transferred-entry subjects must meet all of the transferred-entry subject-specific 
inclusion criteria and none of the exclusion criteria in order to be enrolled.
9.1.4.
Optimization Phase
Transferred-entry Subjects
Prior to conducting any study procedure for ESKETINTRD3003, the investigator (or designated 
study personnel) will review and explain the written ICF to each transferred entry subject. After 
signing the ICF, transferred-entry subjects will be evaluated to determine eligibility for study 
participation.
The ICF will be signed at the start of this phase (after completion of Day 28 study procedures of 
the double-blind induction phase for ESKETINTRD3001 or ESKETINTRD3002.
Results for all assessments performed on Day 28 of the induction phase for direct-entry subjects 
(Visit 2.9) and transferred-entry subjects (Visit 2.10 of Study ESKETINTRD3001 or 
ESKETINTRD3002) will serve as the baseline values for the optimization phase and will not be 
repeated as part of Visit 3.1. The Day 28 visit should coincide with Day 28 (Visit 3.1) for this 
study. All transferred-entry subjects must meet all of the transferred-entry subject-specific 
inclusion criteria and none of the exclusion criteria in order to be enrolled.
All Subjects
The intranasal treatment session frequency will be reduced from that in the induction phase 
(twice weekly) to weekly for the first 4 weeks of this phase. After the first 4 weeks, the 
frequency of intranasal treatment sessions will be individualized to once weekly or once every 
other week based on the severity of depression, as assessed by the MADRS total score. All 
subjects will continue taking the same oral antidepressant treatment from the induction phase.
An independent, remote, blinded rater will perform weekly MADRS assessments during this 
phase.
At the end of the optimization phase, subjects in stable remission and those with stable response 
(but who are not in stable remission), as defined in Section 3.1.2, may be eligible to continue into 
the maintenance phase; all other subjects will have an Early Withdrawal Visit conducted and 
proceed to the follow-up phase.
For subjects in stable remission and those with stable response at the end of this phase, the last 
visit of the optimization phase (Visit 3.13; Week 16) also serves as the baseline visit (Visit 4.1; 
Week 16) for the maintenance phase. Subjects eligible for the maintenance phase will be 
randomized and receive their first double-blind intranasal treatment session of the maintenance 
phase at this visit.
A subject will not be eligible to proceed into the maintenance phase if he or she:

Misses 21 days of the oral antidepressant doses (total daily dose) 
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9.1.5.
Maintenance Phase
Day of Randomization
At the next scheduled intranasal treatment session (Day 1 of this phase):

Approximately 211 subjects in stable remission at the end of the optimization phase (after 
treatment with intranasal esketamine plus an oral antidepressant) will be randomized in a 
1:1 ratio to either continue with intranasal esketamine (same dose) and the same oral 
antidepressant or to continue with the same oral antidepressant (active comparator) but 
switch to intranasal placebo. The primary efficacy analysis will be performed for these 
subjects only. 

Additionally, subjects with stable response (but who are not in stable remission) at the end 
of the optimization phase (after treatment with intranasal esketamine plus an oral 
antidepressant) will be randomized in a 1:1 ratio (using a separate randomization list) to 
either continue with intranasal esketamine (same dose) and the same oral antidepressant or 
to continue with the same oral antidepressant (active comparator) but switch to intranasal 
placebo (for a secondary efficacy analysis only). 

Transferred-entry subjects who achieve stable remission or stable response at the end of the 
optimization phase after treatment with an oral antidepressant plus intranasal placebo will 
and continue to receive the same treatment in order to maintain the blinding for the ongoing 
short-term studies. These subjects will not be included in the efficacy analyses, but will be 
included in safety analyses
The last MADRS assessment performed prior to the first intranasal treatment session of the 
maintenance phase will be the baseline value for this phase.
Assessment of Relapse
During this phase, depressive symptom severity will be assessed weekly by independent, remote,
blinded raters using the MADRS.
Time to relapse will be assessed by evaluating the time between randomization into the 
maintenance phase and the confirmation of a relapse, as defined in Section 3.1.2.
9.1.6.
Early Withdrawal/End of Maintenance Phase
Early Withdrawal
If a subject withdraws before the end of the induction, optimization, or maintenance phase for 
reasons other than withdrawal of consent, or has completed the induction or optimization phase 
but is not eligible to continue to the next treatment phase, an Early Withdrawal Visit should be 
conducted, followed by the follow up phase. If the Early Withdrawal Visit occurs on the same 
day as a scheduled visit, the Early Withdrawal Visit can be performed on the same day and 
duplicate assessments are not required.
A subject meeting relapse criteria during the maintenance phase is not considered an early 
withdrawal. These subjects, and subjects in the maintenance phase who remain relapse-free at 
study termination, will have an End of Maintenance Phase Visit conducted, followed by the 
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follow up phase. If clinically indicated, subjects who relapse in the Maintenance phase may 
proceed to the open-label safety extension study, 54135419TRD3008, without completing the 
follow up phase. If the End of Maintenance Phase Visit occurs on the same day as a scheduled 
visit, the End of Maintenance Phase Visit can be performed on the same day and duplicate 
assessments are not required.
Further clinical/standard of care for the treatment of depression will be arranged by the study 
investigator and/or the subject’s treating physician. The study investigator and/or treating 
physician will determine whether or not the current oral antidepressant medication will continue.
Subjects who withdraw early will receive additional oral antidepressant medication, if 
applicable, and it will be recommended that they continue taking the oral antidepressant 
medication for at least the 2-week follow-up phase unless determined as not clinically 
appropriate.
9.1.7.
Follow-up Phase
This phase will include all subjects who have received at least 1 dose of intranasal study 
medication in this study. For those subjects who relapse in the Maintenance phase, if clinically 
indicated based on investigator’s judgment, after completing the end of maintenance visit, the 
subject may proceed to the open-label safety extension study, 54135419TRD3008, without 
completing the follow up phase. Similarly, when the study is stopped, subjects in the Induction 
phase who are responders, after completing the early withdrawal visit, may proceed to the 
54135419TRD3008 study, without completing the follow up phase. 
Follow-up visits will be performed at 1 and 2 weeks after the last clinic visit.
At the start of the follow-up phase, further clinical/standard of care for the treatment of 
depression will be arranged by the study investigator and/or the subject’s treating physician. 
Refer to the Time and Events Schedule for a list of study evaluations that will be performed 
during the follow-up phase.
No intranasal study medication will be administered during this phase. Subjects will be provided 
with an additional 2-week supply of their oral antidepressant medication, to ensure there is no 
interruption of oral antidepressant therapy during the transition to further clinical/standard of 
care. The decision to continue the oral antidepressant in this phase will be at the discretion of the 
investigator; however, in order to better assess potential withdrawal symptoms from intranasal 
study drug, the oral antidepressant should be continued during the 2-week follow-up phase 
unless determined as not clinically appropriate.
An open-label safety extension study, 54135419TRD3008, may be available (pending country 
and site approval) for eligible subjects participating in the ESKETINTRD3003 study. Please 
refer to the 54135419TRD3008 protocol for full details of potential pathways for entry.
If information is obtained via telephone contact, written documentation of the communication 
must be available for review in the source documents.
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Investigators may recontact the subject to obtain long-term follow-up information to determine 
the subject's safety or survival status (refer to Section 16.2.3, Informed Consent).
Any clinically significant abnormalities persisting at the end of the study will be followed by the 
investigator until resolution or until a clinically stable endpoint is reached. All adverse events 
and special reporting situations, whether serious or non-serious, will be reported until completion 
of the subject's last study-related procedure.
9.2.
Efficacy
9.2.1.
Evaluations
9.2.1.1.
Primary Efficacy Evaluation: Montgomery-Asberg Depression Rating 
Scale (MADRS)
The primary efficacy evaluation will include the use of the MADRS total score as it pertains to 
relapses. The MADRS will be performed by independent remote raters during the study, using 
the Structured Interview Guide for the MADRS.138
The MADRS is a clinician-rated scale designed to measure depression severity and detects 
changes due to antidepressant treatment.83 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 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 interrater reliability. The MADRS will be administered with its typical recall period 
of 7 days. See Section 3.1.2 for the definition of relapses related to the MADRS total score.
The MADRS also will be used to measure the secondary objective of effects on depressive 
symptoms.
9.2.1.2.
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.50 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.
9.2.1.3.
Patient Health Questionnaire, 9-Item (PHQ-9)
The PHQ-9 is a 9-item, patient-reported outcome measure to assess depressive symptoms.128 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 
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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.
9.2.1.4.
Generalized Anxiety Disorder, 7-item (GAD-7)
The subject-reported Generalized Anxiety Disorder, 7-item (GAD-7) will be used to measure the 
secondary objective of symptoms of anxiety. The GAD-7 is brief and validated measure of 
overall anxiety.127 Each item is rated on a 4-point scale (0=not at all; 1=several days; 2=more 
than half the days; 3=nearly every day). Item responses are summed to yield a total score (range 
of 0 to 21), with higher scores indicating more anxiety. The recall period is 2 weeks.
9.2.1.5.
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).
The subject selects an answer for each of the 5 dimensions considering the response that best 
matches his or her health “today.” The descriptive system can be represented as a health state. 
The EQ-VAS self-rating records the respondent’s own assessment of his or her overall health 
status at the time of completion, on a scale of 0 to 100.
The time taken to complete the questionnaire varies with age, health status, and setting but is 
likely to be around 1 minute.
9.2.1.6.
Sheehan Disability Scale (SDS)
The Sheehan Disability Scale (SDS)74,117 will be used to assess the secondary objective of 
functional impairment and associated disability. The SDS, a patient-reported outcome measure, 
is a 5-item questionnaire that has been widely used and accepted for assessment of functional 
impairment and associated disability. The first 3 items cover (1) work/school, (2) social life, and 
(3) family life/home responsibilities using a rating scale from 0 to 10. The SDS also has 1 item 
assessing days lost from school or work and 1 item assessing days of underproductivity. The 
score for the first 3 items are summed to create a total score of 0 to 30, where higher score 
indicates greater impairment. The recall period for this study is 7 days.
9.2.2.
Endpoints
Primary Efficacy Evaluation/Endpoint
The primary efficacy evaluation will include the MADRS total score as it pertains to relapses.
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The primary efficacy endpoint includes only subjects who are in stable remission at the end of
the optimization phase after treatment with intranasal esketamine plus an oral antidepressant, and 
is defined as the time between subject randomization and the first documentation (earliest date) 
of a relapse in the maintenance phase. Relapse criteria are defined in Section 3.1.2, Definitions 
of Terms.
Secondary Efficacy Evaluations/Endpoints
Secondary efficacy evaluations/endpoints include the following:

The time between subject randomization and the first documentation (earliest date) of a 
relapse in the maintenance phase for subjects with stable response (not in remission) at the 
end of the optimization phase after treatment with intranasal esketamine plus an oral 
antidepressant. Relapse criteria are defined in Section 3.1.2, Definitions of Terms.

The change from baseline (of maintenance phase) to endpoint in:

Depressive symptoms, using the MADRS and the self-reported Patient Health 
Questionnaire 9-item (PHQ-9) scale

Overall severity of illness, using the Clinical Global Impression - Severity (CGI-S)

Symptoms of anxiety, using the Generalized Anxiety Disorder, 7-item (GAD-7) scale

Health-related quality of life and health status, using the European Quality of Life 
(EuroQol) Group, 5-Dimension, 5-Level (EQ-5D-5L) questionnaire

Functioning and associated disability, using the Sheehan Disability Scale (SDS)
9.3.
Medical Resource Utilization
Medical resource utilization data, associated with healthcare encounters, will be collected using 
the HRUQ during the optimization, maintenance, and follow-up phases. Protocol-mandated 
procedures, tests, and encounters will be excluded. The data collected may be used to conduct 
economic analyses and will include:

Number, duration, and type of healthcare encounters (inpatient and outpatient).

Duration of hospitalization (total days length of stay, including duration by wards).
9.4.
Safety Evaluations
Details regarding the IDMC are provided in Section 11.8.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached.
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Instances may occur where a subject has started a scheduled clinic visit in which an intranasal 
treatment session is planned, but then a predose observation (eg, blood pressure results or nasal 
congestion as described in Section 6.1 or intoxication as described in Section 4.3) prompts the 
site staff to postpone 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 signs (ie, blood pressure, pulse, 
respiratory rate, and temperature), 12-lead ECG, C-SSRS (since last visit), MOAA/S, pulse 
oximetry, BPRS+, and CADSS.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule:
Adverse Events
Treatment-emergent adverse events will be assessed.
TEAEs of special interest will be examined separately grouped in the following categories: drug 
abuse, dependence and withdrawal (SMQ), increased blood pressure, increased heart rate, 
transient dizziness/vertigo; impaired cognition; anxiety and cystitis.
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.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and urine samples for urinalysis will be 
collected. The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the adverse event section of the 
eCRF. The laboratory reports must be filed with the source documents.
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.
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
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
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 a subject's status as noted below:

Lipid panel: total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density 
lipoprotein (HDL) cholesterol, and triglycerides

Serum and urine pregnancy testing (for women of childbearing potential only)

Urine drug screen: barbiturates, methadone, opiates, cocaine, cannabinoids (cannabinoids 
are 
only 
exclusionary
at 
Day 
1 
predose), 
phencyclidine, 
and 
amphetamine/methamphetamine

Alcohol breath test

Thyroid-stimulating hormone (TSH)

Free thyroxine (FT4), only if required for abnormal TSH (refer to Inclusion Criteria).

Calculation of creatinine clearance.

HbA1c

A serum follicle stimulating hormone (FSH) level test, only if required for documentation 
that a female subject is not of childbearing potential (refer to Sec. 4.1, Inclusion Criteria).
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Single, 12-Lead ECGs
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 prior to dosing.
The subject must be discontinued at any time point after baseline (Day 1, predose), if:

QTcF change from baseline is ≥ 60 msec and QTcF > 480 msec, or 

QTcF > 500 msec.
Vital Signs (Temperature, Pulse/Heart Rate, Respiratory Rate, and Blood Pressure)
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, see Section 6.1 under the subheading entitled 
"Guidance for Blood Pressure Monitoring on Intranasal Treatment Session Days."
Tympanic temperature is recommended.
An automated device will be used for measurement of respiratory rate.
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 at prespecified 
timepoints. Any arterial oxygen saturation (SpO2) <93% should be confirmed by an additional 
measurement on another part of the body.
On intranasal treatment session days, pulse oximetry will be recorded every 15 minutes from 
predose to t=1.5 hours postdose. If oxygen saturation levels are <93% at any time during the 
1.5 hour postdose interval, pulse oximetry will be recorded every 5 minutes until levels return to 
93% or until the subject is referred for appropriate medical care, if clinically indicated.
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Physical Examination, Height, Body Weight, and Neck Circumference
Physical examinations, body weight, and height will be performed/measured as per the Time and 
Events Schedule.
In addition, body mass index (BMI) will be calculated and neck circumference measured as part 
of the information required for the STOP-Bang questionnaire.
Nasal Examinations
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 will be graded as follows: absent, mild, moderate, or severe. 
Nasal Symptom Questionnaire
Subjects will complete a nasal symptom questionnaire. The nasal symptom questionnaire was 
developed by the sponsor to assess nasal tolerability following intranasal administration of study 
drug. The questionnaire asks about nasal symptoms, which are rated by the subject as none, mild, 
moderate, or severe, based on how he or she feels at the time of the assessment.
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 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.106 It is a 
clinical interview providing a summary of both 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.
Two versions of the C-SSRS will be used in this study, the Baseline/Screening version, and the 
Since Last Visit version. The Baseline/Screening version of the C-SSRS will be used in the 
screening/prospective observational phase. In this version, suicidal ideation will be assessed at 
2 timepoints: “lifetime” and “in the past 6 months,” and suicidal behavior will be assessed at 
2 timepoints: “lifetime” and “in the past year.” All subsequent 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.
Clinician Administered Dissociative States Scale (CADSS)
The CADSS is an instrument for the measurement of present-state dissociative symptoms,8 and 
will be administered to assess treatment-emergent dissociative symptoms.
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The CADSS consists of 23 subjective items, divided into 3 components: depersonalization 
(Items 3 to 7, 20, and 23), derealization (Items 1, 2, 8 to 13, 16 to 19, and 21) and amnesia 
(Items 14, 15, and 22). Participant’s responses are coded on a 5-point scale (0=not at all through 
to 4=extremely). CADSS has excellent inter-rater reliability and internal consistency. 
Positive-symptom Subscale of the Brief Psychiatric Rating Scale (BPRS+)
Four items of the BPRS will be administered to assess potential treatment-emergent psychotic 
symptoms. 
The BPRS is an 18-item rating scale that is used to assess a range of psychotic and affective 
symptoms, rated from both observation of the subject and the subject's own report.97,98 It 
reportedly provides a rapid and efficient evaluation of treatment response in clinic drug studies 
and in clinical settings.111
Only the 4-item positive symptom subscale BPRS+ (ie, suspiciousness, hallucinations, unusual 
thought content, and conceptual disorganization) will be used in this study. It is highly sensitive
to change, and excellent inter-rater reliability can be achieved with training and a standard 
interview procedure.
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 continuum.
The MOAA/S scores range from 0=no response to painful stimulus (corresponds to ASA 
continuum for general anesthesia) to 5=readily responds to name spoken in normal tone (awake; 
corresponds to ASA continuum for minimal sedation).
On each intranasal dosing day, the MOAA/S will be performed every 15 minutes from predose 
to t=+1.5 hours postdose.

If the score is 3 at any time during the 1.5 hour postdose interval, the MOAA/S will be 
performed every 5 minutes until a score of 4 is reached (at which point a frequency of every 
15 minutes can be resumed until t=+1.5 hours post dose). 

If a subject does not have a score of at least 5 at t=+1.5 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 each intranasal dosing day, the CGADR will be performed at 1 hour and 1.5 hours postdose; 
if the response is not "Yes" at 1.5 hours postdose, 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. A subject should not be discharged prior to the 1.5 hour time 
point.
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.
Physician Withdrawal Checklist, 20-item (PWC-20)
The PWC-20 will be administered to assess potential withdrawal symptoms following cessation 
of intranasal esketamine treatment. An assessment will be performed for all subjects on Day 25 
to establish a baseline prior to discontinuation of intranasal esketamine treatment – although only 
relevant for those subjects not continuing to the optimization phase. For those subjects who 
proceed to the optimization and maintenance phases, the PWC-20 is conducted at the End of 
Study Visit. If subjects withdraw early from the study during any phase, the PWC-20 will be 
conducted at the Early Withdrawal Visit. In order to better assess potential withdrawal symptoms 
from the intranasal medication, the oral antidepressant medication should be continued for the 2-
week 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.109 Discontinuation symptoms occur 
early and disappear rather swiftly, depending upon speed of taper, daily medication dose, and 
drug elimination half-life.
Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS)
The BPIC-SS will be used to monitor subjects for potential symptoms of cystitis, bladder pain, 
and interstitial cystitis. 
The BPIC-SS a patient-reported outcome measure that was developed to identify an appropriate 
bladder pain syndrome/interstitial cystitis population for clinical studies to evaluate new 
treatments for bladder pain syndrome.55
The BPIC-SS contains 8 questions with a recall period of the past 7 days and addresses key 
symptoms identified by subjects with bladder pain syndrome (BPS) including symptom concepts 
of pain and/or pressure of the bladder and urinary frequency. Subjects respond to items using a 
5-point scale (0=never, 1=rarely, 2=sometimes, 3=most of the time, 4=always for frequency-
based questions, and 0=not at all, 1=a little, 2=somewhat, 3=moderately, and 4=a great deal for 
items related to bother associated with symptoms). Question 8 records the worst bladder pain in 
the last 7 days using a 0-10 numerical rating scale. A total score is calculated by adding up the 
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numbers beside the response options chosen by the subject. A total score of 19 or more has 
demonstrated good sensitivity/specificity and is considered a relevant cut-off to distinguish those 
with significant bladder symptoms or cystitis.55 If any items are missing, a total score cannot be 
calculated.
In the current study, if a subject has a score greater than 18 on the BPIC-SS scale and urinalysis 
and microscopy indicate no evidence of urinary tract infection, then the subject will be referred 
to a specialist for further evaluation. If a subject is determined to have a diagnosis of ulcerative 
cystitis, then the subject must be discontinued from the study and followed up with appropriate 
medical care. As such, in addition to urinalysis, a urine culture should also be obtain if BPIC-SS 
on applicable study day is >18.
Cognition Testing
The tests described below should be administered in the following order: HVLT-R, 
computerized cognitive battery, and HVLT-R Delayed. All subjects will complete a practice 
session for the computerized cognitive battery during the screening/prospective observational 
phase. There is no practice session for the HVLT-R.
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).5 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.
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University of Pennsylvania Smell Identification Test (UPSIT) and Smell Threshold Test
To assess any potential treatment-emergent effects on the sense of smell, olfactory function will 
be qualitatively and quantitatively assessed using validated standardized olfactory tests prior to 
and at specified time points during the study. The 2 tests to be administered are: 

The UPSIT assesses a subject’s ability to identify odors. This standardized test, the most 
widely used olfactory test in the world, is derived from basic psychological test 
measurement theory and focuses on the comparative ability of subjects to identify odorants 
at the suprathreshold level. The UPSIT consists of 4 envelope-sized booklets, each 
containing 10 “scratch and sniff” odorants embedded in 10- to 50-µm polymer 
microcapsules positioned on brown strips at the bottom of the pages of the booklets. The 
internal consistency and test-retest reliability coefficients of this instrument are >0.90.27,28,29
Numerous studies have shown this and related tests to be sensitive to subtle changes in smell 
function associated with multiple etiologies, including those due to viruses, head trauma, 
and a number of neurodegenerative diseases.

The Smell Threshold Test will assess the smell threshold using a forced-choice single 
staircase threshold procedure. This test quantifies a detection threshold for the rose-like 
smelling odorant phenyl ethyl alcohol (PEA). This odorant is used because it has little 
propensity to stimulate the trigeminal nerve within the nose. This test is sensitive to 
olfactory deficits from a wide range of disorders. 
These tests will be administered bilaterally (ie, both nostrils at the same time). Testing will occur 
during the screening/prospective observational phase to establish a subject’s baseline sensitivity. 
The degree of change from this baseline will be determined subsequently over time. The percent 
change from baseline will serve as the dependent measure for each subject for each test.
If the subject has significant nasal congestion on the day of a scheduled UPSIT and/or Smell 
Threshold Test, the site should consider postponing the smell test assessment(s) to the next 
scheduled clinic visit.
9.5.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations
During the study, blood will be collected for the assessment of biomarkers (protein, metabolite, 
and RNA) at the time points indicated in the Time and Events Schedule. The biomarker blood 
samples should be collected prior to dosing. It is preferred that subjects adhere to a low fat diet 
the day of collection.
In blood, biomarkers (protein, metabolite, and RNA) related to (but not limited to) the immune 
system activity, hypothalamus pituitary adrenal (HPA) axis activation, neurotrophic factors and 
metabolic factors will be investigated. Biomarkers may be added or deleted based on scientific 
information or technical innovations under the condition that the total volume of blood collected 
will not be increased.
The biomarker data obtained from this study may also be included in an ongoing cross-study 
analysis to investigate the relationship between depression severity and phenotypes and 
biomarkers.
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Blood samples for DNA analyses will be collected at the time points indicated in the Time and 
Events Schedule for the assessment of genetic and epigenetic variation in genes in pathways 
relevant to depression (eg, HPA axis, inflammation, growth factors, monoamine transporters, ion 
channels, and circadian rhythm, etc).
Genotyping will be conducted only on the screening/baseline sample; pharmacogenomic and 
epigenetic evaluations may be performed on any/all collected samples.
DNA samples will be used for research related to esketamine, oral antidepressants, TRD, or 
MDD. They may also be used to develop tests/assays related to esketamine, oral antidepressants, 
TRD, or MDD. Pharmacogenomic research may consist of the analysis of 1 or more candidate 
genes or of the analysis of genetic markers throughout the genome (as appropriate) in relation to 
esketamine, oral antidepressants, TRD, or MDD clinical endpoints.
Further information regarding handling, shipment, and labeling of biological samples will be 
provided in a separate laboratory manual.
9.6.
Other Evaluations
Massachusetts General Hospital Female Reproductive Lifecycle and Hormones 
Questionnaire (MGH-FRLHQ): Module I and Menstrual Cycle Tracking
The MGH-FRLHQ: Module I (childbearing potential, menopausal status, and menstrual cycle) is 
a brief questionnaire aimed at standardizing the minimal collection of relevant information about 
reproductive hormones and status. It will be completed by a clinician. This information will not 
only assist with assessing eligibility criteria, but also may facilitate exploratory analyses of the 
impact of endogenous and exogenous reproductive hormones on the course of treatment of MDD 
and potentially inform care of women with MDD in the future.48
Menstrual cycle tracking (start date of last menstrual period) is captured as part of MGH-FRLHQ 
at Week 1 of the screening/prospective observational phase, and then is tracked separately 
thereafter only for women with a menstrual cycle at the study visits specified in the Time and 
Events Schedule.
Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire 
(MGH-ATRQ)
The MGH-ATRQ is used to determine treatment resistance in MDD.25
The MGH-ATRQ evaluates the adequacy of duration and dose of all antidepressant medications 
used for the current major depressive episode. In addition, the MGH-ATRQ assesses the degree 
of improvement on a scale from 0% (not improved at all) to 100% (completely improved). The 
MGH-ATRQ will be completed by the clinician in collaboration with the subject.
Inventory of Depressive Symptomatology - Clinician-rated, 30-item (IDS-C30)
The 30-item IDS-C30 was designed to assess all the criterion symptom domains designated by 
Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) to diagnose a 
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major depressive episode112; these criteria have not changed in the DSM-5.2 These assessments 
can be used to screen for depression, although they have been used predominantly as measures of 
symptom severity. The 7-day period prior to assessment is the usual time frame for assessing 
symptom severity. The psychometric properties of the IDS-C30 have been established in various 
study samples.131
Snoring, Tiredness, Observed Apnea, High Blood Pressure, Body Mass Index, Age, Neck 
Size, Gender (STOP-Bang) Questionnaire 
The STOP-Bang Questionnaire129 is a concise, easy-to-use, validated, and sensitive screening 
tool for obstructive sleep apnea (OSA). This questionnaire has 8 items which address key risk 
factors for obstructive sleep apnea: snoring, tiredness, observed breathing interruption during 
sleep, high blood pressure, body mass index, age, neck size, and gender. The STOP-Bang 
questions do not specify a recall period. Subjects will answer yes or no to questions about 
snoring, tiredness, observed breathing interruption, and high blood pressure (these are the 
“STOP” items in the STOP-Bang acronym); this takes approximately 1 minute.
Study site staff will answer yes or no to questions about body mass index (more than 35 kg/m²?), 
age (older than 50 years?), neck circumference (larger than 17 inches [43 cm] in men, or larger 
than 16 inches [41 cm] in women?), and gender (male?).
The total STOP-Bang score is calculated by summing the number of positive responses, yielding 
a score range of 0 to 8. A score of 5 on the STOP-Bang indicates a moderate to severe risk for 
obstructive sleep apnea (apnea hypopnea index of >30).
Site Independent Qualification Assessment
Independent psychiatrists/psychologists will perform the Site Independent Qualification 
Assessment in the screening/prospective observational phase for all subjects to confirm the 
subject's current major depressive episode, depression symptom severity (including by MADRS, 
required at Week 1 to be total score ≥28), and antidepressant treatment response in the current 
depressive episode, in terms of eligibility for the study.130
Further information regarding this assessment will be provided to sites in a separate document.
PAQ
Subjects’ 
adherence 
to 
their 
oral 
antidepressant 
treatment 
regimen 
during 
the 
screening/prospective observational phase will be assessed using the PAQ. It is a brief, 2-item 
self-report scale that was developed at the University of Texas Southwestern Medical Center to 
assess how often the subject has taken, and whether he or she has made any changes to his/her 
antidepressant treatment regimen in the last 2 weeks. The total score is based on the response 
selected to Question 1, and is interpreted as 0-1 = adherent and 2 or more = nonadherent.
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9.7.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. If blood samples are collected via an indwelling cannula, an appropriate 
amount (1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock 
will be removed from the cannula and discarded before each blood sample is taken. After blood 
sample collection, the cannula will be flushed with 0.9% sodium chloride, United States 
Pharmacopeia (USP) (or equivalent) and charged with a volume equal to the dead space volume 
of the lock.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections. 
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Criteria for Completion
A subject will be considered as having completed the study if he or she either:

Has had a relapse during the maintenance phase

Has remained relapse-free during the maintenance phase up to the time that the study is 
terminated
Subjects in the Screening Prospective Observational phase at the time of study termination may 
be eligible to proceed to the 54135419TRD3008 study. Subjects in the induction phase of the 
study at the time of study termination will be allowed to complete the induction phase. These 
subjects, after completing the Early Withdrawal visit, may proceed to the 54135419TRD3008 
study, but will not be considered completers for this study. Subjects in the optimization phase at 
time of study termination will not need to complete this phase, and will complete an Early 
Withdrawal Visit, and continue into the follow up phase, but they will not be considered 
completers.
10.2.
Withdrawal From the Study
During any phase of the study, a subject will be withdrawn from the study for any of the 
following reasons:

The investigator believes that for safety reasons (eg, an adverse event) it is in the best 
interest of the subject to stop treatment.

See also guidance on blood pressure monitoring on intranasal dosing days in 
Section 6.1.

The subject becomes pregnant.

The blind is broken by the investigator (where applicable).
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
Lack of efficacy (induction and optimization phases only)

The subject does not meet response criteria for continuing into the optimization phase at the 
end of the open-label induction phase (direct-entry subjects only).

The subject does not meet criteria for continuing into the maintenance phase at the end of 
the optimization phase.

The subject does not meet criteria for stable remission or stable response.

Subject misses 21 days of the oral antidepressant doses (total daily dose) in the 
optimization phase.

Lost to follow-up

Withdrawal of consent (Note: See the "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 participating in the Early 
Withdrawal Visit and the follow-up phase, another reason for withdrawal should be 
selected.)

Violation of protocol procedures (determined on a case-by-case basis)

The subject is unwilling or unable to adhere to the intranasal treatment schedule.

At any time point after baseline (Day 1, predose), the subject has a:

QTcF change from baseline ≥60 msec and QTcF >480 msec, or 

QTcF >500 msec.

The sponsor terminates the study.

Death
If a subject withdraws before the end of the induction, optimization, or maintenance phase for 
reasons other than withdrawal of consent, or has completed the induction or optimization phase 
but is not eligible to continue to the next treatment phase, an Early Withdrawal Visit should be 
conducted, followed by the follow up phase. If the Early Withdrawal Visit occurs on the same 
day as a scheduled visit, the Early Withdrawal Visit can be performed on the same day and 
duplicate assessments are not required.
A subject meeting relapse criteria during the maintenance phase is not considered an early 
withdrawal. If clinically indicated, after completing the end of maintenance visit, subjects who 
have met relapse criteria may proceed to the open-label safety extension study, 
54135419TRD3008, without completing the follow up phase. Subjects who remain relapse-free 
at study termination, will have an End of Maintenance Phase Visit conducted, followed by the 
follow up phase. If the End of Maintenance Phase Visit occurs on the same day as a scheduled 
visit, the End of Maintenance Phase Visit can be performed on the same day and duplicate 
assessments are not required.
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. This should 
include at least 3 telephone calls, certified letters, email requests, etc. To ensure access to follow-
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up subjects, the study sites should attempt to obtain both primary and secondary telephone 
contact numbers (eg, home, work, and mobile phone numbers), as well as other contact 
information (eg, email addresses) from subjects before the first dose of study drug is 
administered. In addition, the study site should emphasize the importance of follow-up 
information to the subject before the first dose of study drug is administered. The attempted 
follow-up measures must be documented.
When a subject withdraws, the reason for withdrawal is to be documented in the eCRF and in the 
source document. Subjects who withdraw will not be replaced.
Withdrawal of Consent
Every effort will be made in the study to ensure withdrawal of consent is not selected as a reason 
for discontinuation when in fact the subject withdrew for an identifiable reason (eg, due to an 
adverse event or lack of efficacy).
Subjects who wish to withdraw from the study should be asked if they are agreeable to continue 
to an Early Withdrawal Visit (if withdrawing from the induction, optimization or maintenance 
phase) and the follow up phase, or to be contacted to collect follow-up information. 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 agree to provide follow-up 
information will be withdrawn 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).
10.3.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, Long-
term Retention of Samples for Additional Future Research). In such a case, samples will be 
destroyed after they are no longer needed for the clinical study. Details of the sample retention 
for research are presented in the main ICF.
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).
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11.1.
Subject Information
The following analysis sets will be analyzed:

Full Analysis Sets for Primary Efficacy Evaluation:

At Interim Analysis: All subjects who are in stable remission at the end of the 
optimization phase and who receive at least 1 dose of intranasal study drug and 1 dose 
of oral antidepressant during the maintenance phase at the time of the interim analysis 
data cutoff

At Final Analysis: All subjects who are in stable remission at the end of the 
optimization phase and who receive at least 1 dose of intranasal study drug and 1 dose 
of oral antidepressant during the maintenance phase

Safety Analysis Sets:

For open-label induction phase: All subjects who receive at least 1 dose of intranasal 
study drug or 1 dose of oral antidepressant in the open-label induction phase

For optimization phase: All subjects who receive at least 1 dose of intranasal study drug 
or 1 dose of oral antidepressant in the optimization phase

For maintenance phase: All randomized subjects who receive at least 1 dose of 
intranasal study drug or 1 dose of oral antidepressant during the maintenance phase
Transferred-entry subjects who continue to receive an oral antidepressant plus intranasal placebo 
will be summarized separately in both optimization and maintenance phases.
11.2.
Sample Size Determination
The maximum number of relapses (in the subjects with stable remission) required for this study 
is 84, which provides 90% power to detect a hazard ratio of 0.493 at the 1-sided significance 
level of 0.025, when a fixed-sample design is implemented, to detect superiority of esketamine 
plus oral antidepressant over antidepressant alone in delaying relapse of depressive symptoms in 
subjects with TRD who are in stable remission. The calculation of sample size assumed that the 
time to the first relapse follows an exponential distribution with a median time of 6 months for 
oral antidepressant alone and 12.17 months for intranasal esketamine plus oral antidepressant 
(hazard ratio = 0.493). The corresponding 6-month relapse rates are 50% for oral antidepressant 
alone and 28.95% for oral antidepressant plus intranasal esketamine. 
Based on the subsequent assumptions, a total of approximately 211 subjects in stable remission 
need to be randomized (in a 1:1 ratio) in order to obtain 84 relapses:

A maximum accrual period of 18 months and a maximum study duration of 20 months (this 
is the maximum duration for the full study, not for each subject);

Accrual rate of approximately 11.7 subjects/month during the accrual period;

Subjects are followed until relapse, dropout, or end of study;

35% dropout rate in each group over 6 months.
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In addition to the 1:1 randomization of the 211 subjects in stable remission described above, 
subjects with stable response (but who are not in stable remission) also will be randomized 1:1. 
The actual number of subjects randomized (which includes both those in stable remission and 
those with stable response ) will depend on the time it takes to obtain the necessary number of 
relapses. Blinded surveillance of the total number of relapses in the maintenance phase will be 
performed during the study to assess the appropriateness of the assumptions regarding accrual 
and dropout rates. The number of subjects enrolled and the number of subjects who discontinue 
before entering the maintenance phase will be closely monitored. A sample size re-estimation 
rule will be provided in the SAP.
11.3.
Efficacy Analyses
To evaluate the assumptions used in sample size calculation, relapse rates will be monitored 
sequentially during the maintenance phase. In particular, a 2-stage group-sequential design will 
be adopted, with 1 interim analysis to be performed when a total of 30 relapses are observed. 
Early termination of the maintenance phase for efficacy will be based on interim analysis results. 
If the interim analysis results show that the study should proceed to the second stage (ie, 
continue to record more relapses after the interim cutoff), sample size re-estimation will be 
performed based on the interim analysis results to determine how many additional relapses 
should be obtained. 
The primary analysis for efficacy will be carried out on the Full Analysis Set and only for 
subjects who are in stable remission at the end of the optimization phase. The primary efficacy 
endpoint will be the time between subject randomization into the maintenance phase and the first 
documentation of a relapse event. Subjects who meet at least 1 of the relapse criteria for the 
primary analysis while receiving treatment in the maintenance phase at the time that the study is 
stopped are considered to have had a relapse. All other randomized subjects with stable 
remission who had entered the maintenance phase but do not have a relapse by the time that the 
study is stopped will be considered censored.
The cumulative distribution function of the time to relapse will be estimated by the Kaplan-
Meier method. Time to relapse will be summarized (number of relapses, number of censored 
subjects, median, 25th and 75th percentile of time to relapse, if estimable) by treatment group. 
Treatment differences will be compared using a 2-sided log-rank test as the primary analysis. 
The estimate of the hazards ratio and its 95% confidence interval will be based on the Cox 
proportional hazards model with treatment as a factor.
Treatment comparison between intranasal esketamine plus oral antidepressant and oral 
antidepressant (active comparator) plus intranasal placebo in the changes from baseline to 
endpoint of MADRS total score, PHQ-9, CGI-S, SDS, and GAD-7 during the maintenance phase
will be performed using an analysis of covariance model with treatment and country as factors 
and baseline (maintenance phase) value as a covariate. Least-squares estimates of the treatment 
differences and 95% confidence intervals will be presented. Dimension scores of EQ-5D-5L 
data, health status index, and the overall health status score will be summarized over time. These 
analyses will be provided separately for stable remitters and stable responders (not in remission).
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Additionally, the time between the randomization of a subject with stable response (but who are 
not in stable remission) and the first documentation of a relapse for that subject in the 
maintenance phase will be analyzed using the log-rank test as described above for the primary 
efficacy endpoint.
11.4.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Analyses
Baseline biomarker values and changes from baseline biomarker values to the time points 
specified in the Time and Events Schedule will be summarized. Exploratory analyses may 
include comparison of biomarker measures between the treatment groups and correlation with 
baseline and change from baseline biomarker values in the efficacy and other measures. 
Additional exploratory analyses may also include relationship of baseline and change from 
baseline in biomarker measures to clinical response, maintenance/stabilization of response, 
relapse, and non-response.
Pharmacogenomic analyses may include candidate gene analyses or genome-wide association 
analyses in relation to treatment response, maintenance/stabilization of response, relapse, and 
non-response and MDD/TRD. Expression analyses may include testing of known 
mRNA/miRNA transcripts or transcriptome-wide analysis in relation to antidepressant treatment 
and MDD/TRD.
Details of the analysis plan and summary of results from both biomarker and pharmacogenomics 
analyses will be reported separately.
11.5.
Medical Resource Utilization Analyses
Medical resource utilization data (including HRUQ results) will be descriptively summarized by 
treatment group.
11.6.
Safety Analyses
All safety data will be analyzed separately for each phase.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events 
with onset during 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 by treatment group.
TEAEs of special interest will be examined separately grouped in the following categories: drug 
abuse, dependence and withdrawal (SMQ), increased blood pressure, increased heart rate, 
transient dizziness/vertigo; impaired cognition; anxiety and cystitis.
Adverse events occurring during the follow-up phase will be summarized separately. For 
transferred-entry subjects, adverse events ongoing at the time of entry into the study will be 
summarized separately.
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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.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the SAP) will be used in the summary of laboratory data. 
Descriptive statistics will be calculated for each laboratory analyte at baseline and at each 
scheduled time point in each phase of the study. Changes from baseline results will be presented 
in pre- versus posttreatment cross-tabulations (with classes for below, within, and above normal 
ranges). Frequency tabulations of the abnormalities will be provided. Listings of subjects with 
laboratory results outside the reference ranges and markedly abnormal results will be provided.
Electrocardiogram (ECG)
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. These tables will include observed values and changes from baseline 
values.
Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will be 
calculated at baseline and for observed values and changes from baseline at each scheduled time 
point. Frequency tabulations of the abnormalities will be made.
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, 
and QT interval corrected (QTc) according to Bazett's formula (QTcB) and Fridericia's formula 
(QTcF).4,117
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.
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, pulse oximetry, and supine 
blood pressure (systolic and diastolic) values and changes from baseline will be summarized at 
each scheduled time point. The percentage of subjects with values beyond clinically important 
limits will be summarized.
Nasal Examination and Nasal Symptom Questionnaire
Changes in findings from the baseline nasal examination (including the upper respiratory 
tract/throat) will be listed by treatment group. Examinations will provide ratings (none, mild, 
moderate, or severe) that are based on a visual inspection of the nostrils, nasal mucosa, and 
throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption and epistaxis. A 
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shift table for changes from baseline in ratings for each examination will be presented by 
treatment group.
In addition, scoring from the nasal tolerability questionnaire will be summarized descriptively 
for each scheduled time point by treatment group.
Other Safety and Tolerability Questionnaires and Assessments

C-SSRS: Suicide-related thoughts and behaviors based on the C-SSRS will be summarized 
by treatment group in incidence and shift tables. Separate endpoints for suicidal ideation and 
suicidal behavior will be defined and summarized descriptively by treatment group.

BPIC-SS, BPRS+, CADSS, CGADR, MOAA/S, Smell Threshold Test, PWC-20, and 
UPSIT: Descriptive statistics of scores and their changes (and/or percent changes) from 
predose or baseline will be summarized at each scheduled time point.

Computerized cognitive battery and HVLT-R: Descriptive statistics of each of the cognitive 
domain scores and changes from baseline will be summarized at each scheduled time point.
11.7.
Interim Analysis
See Section 11.1 for a description of the interim analysis population, Section 11.3 for efficacy 
analyses to be conducted at interim, and Section 11.8 for a description of the involvement of the 
IDMC with the interim analysis. As described in those sections, a 2-stage group-sequential 
design will be adopted, with 1 interim analysis to be performed when a total of 30 events (of the 
84 maximum) are observed. At the interim analysis, if the study is not stopped for efficacy and a 
sample size re-estimation is performed, none of the esketamine team members or staff members 
at the investigational sites conducting the clinical study will be informed of the specific sample 
size adjustment resulting from this interim analysis. However, the Clinical Supplies group will 
be informed of the decision made at interim analysis so that only the required amount of study 
medication will be packaged.
11.8.
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. In addition, the committee will review 1 interim analysis. 
The committee will meet every 6 months to review safety data and will meet once to review 
efficacy data after the interim analysis has been completed. After the reviews, the IDMC will 
make recommendations regarding the continuation of the study, or in the case of the interim 
analysis for efficacy, to stop the study due to efficacy or to adjust the sample size (ie, number of 
relapses) to achieve the desired power while maintaining control of the overall Type I error. 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.
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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.
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*
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*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For , the 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.
For oral antidepressants with marketing authorizations (duloxetine, escitalopram, sertraline, and 
venlafaxine XR), the expectedness of an adverse event will be determined by whether or not it is 
listed in the SmPC/ US Prescribing Information.
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).
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Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
An assessment of severity grade will be made using the following general categorical
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
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.

Inadvertent or accidental 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)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure (which may include contact for follow-up of safety) , with the exception 
of pregnancy which will be reported up to 6 weeks after the last dose of study medication 
(females) or 90 days after the last dose of study medication (partners of male participants). 
Serious adverse events, including those spontaneously reported to the investigator, must be 
reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 
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information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. Anticipated events will be 
recorded and reported as described in Attachment 4.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the eCRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
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. A SUSAR will be reported to regulatory
authorities unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR 
summary, unless otherwise specified.
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number.

Statement, in the local language(s), that the subject is participating in a clinical study.

Investigator's name and 24-hour contact telephone number.

Local sponsor's name and 24-hour contact telephone number (for medical staff only).

Site number.

Subject number.

Any other information that is required to do an emergency breaking of the blind.
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
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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 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 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.

For convenience the investigator may choose to hospitalize the subject at times during 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.
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Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported by the study-site personnel within 24 hours of their 
knowledge of the event using the appropriate pregnancy notification form.
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 on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drugs
Intranasal Study Drug
Esketamine will be supplied 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 
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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-L 
spray. Each individual nasal spray pump (device) contains a total of 28 mg (ie, 2 sprays). 
The placebo solution will be provided as a clear, colorless intranasal solution of water for 
injection, with a bittering agent (denatonium benzoate [Bitrex®] at a final concentration of 
0.001mg/mL) added to simulate the taste of the intranasal solution with active drug, in a nasal 
spray pump. Benzalkonium chloride is added as a preservative at a concentration of 0.3 mg/mL.
Each individual nasal spray pump (device) contains 2 sprays.
Esketamine and placebo will be manufactured and provided under the responsibility of the 
sponsor. Refer to the Investigator’s Brochure for a list of excipients.
Oral Antidepressant Medications
Duloxetine
Duloxetine 30 mg will be obtained from commercial stock and provided under the responsibility 
of the sponsor. Refer to the Summary of Product Characteristics (SmPC)/Package Insert (PI) for 
the physical description and a list of excipients.
Escitalopram
Escitalopram 10 mg will be obtained from commercial stock and provided under the 
responsibility of the sponsor. Refer to the Summary of Product Characteristics (SmPC)/Package 
Insert (PI) for the physical description and a list of excipients.
Sertraline
Sertraline 50 mg and 25mg (as applicable) will be obtained from commercial stock and provided 
under the responsibility of the sponsor. Refer to the Summary of Product Characteristics 
(SmPC)/Package Insert (PI) for the physical description and a list of excipients.
Venlafaxine XR
Venlafaxine XR 75 mg and 37.5mg (as applicable) will be obtained from commercial stock and 
provided under the responsibility of the sponsor. Refer to the Summary of Product 
Characteristics (SmPC) /Package Insert (PI) for the physical description and a list of excipients.
14.2.
Packaging
Intranasal Study Drug
Study drug (ie, intranasal esketamine and placebo solution) will be supplied by the sponsor in a 
bi-dose nasal spray device. The devices will contain 200 µL. Each device delivers 16.14 mg 
esketamine hydrochloride (14 mg esketamine base) or 0.1 µg of denatonium benzoate per 
100-µL spray. 
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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.
Device for Practicing Intranasal Study Drug Administration
The demonstration intranasal device will also be supplied by the sponsor and will contain 
placebo solution. Subjects will practice spraying (into the air, not intranasal).
Oral Antidepressant Medication
Oral antidepressant tablets or capsules will remain in their commercial packaging. If blisters are 
supplied, each blister will be packaged into a child-resistant dose pack to constitute a subject kit,
labeled with a unique medication kit number. These will be labeled according to applicable 
regulatory requirements.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
Study drug will be stored at the study site in a secure area with restricted access until dispensed to 
the subjects. 
All study drugs must be stored at controlled temperatures as indicated on the product-specific 
labeling.
Refer to the pharmacy manual/study site investigational product manual for additional guidance on 
study drug preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study.
The dispensing of study drug to the subject, and the return of study drug from the subject (if 
applicable), must be documented on the drug accountability form. Subjects must be instructed to 
return all original containers, whether empty or containing study drug.
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 supplies are destroyed on-site, this must also be documented on 
the investigational product destruction form.
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Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes.
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. 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.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Practice intranasal devices

Investigator’s Brochure for esketamine

SmPC/USPI and local prescribing information for oral antidepressant study medication

Investigational Product (IP)Binder, including the investigational product procedures manual

Laboratory manual and materials

Clinician-administered and subject-completed outcomes assessments

Paper versions, as applicable

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

Subject diary

Rater qualifications/requirements for select clinician-administered assessments

Computerized cognitive battery and HVLT-R, and all associated equipment and materials

Device to measure respiratory rate

Procedural documents for Site -Independent Qualification Assessment.

Procedural documents for independent, remote rater interviews

Guidance on recommended order of study procedures

MGH-ATRQ guidance document
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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 the efficacy of intranasal esketamine plus an oral 
antidepressant for delaying relapse in patients with TRD. Thus, the study cannot be completed 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. 
For eligibility, direct entry subjects must have had non-response to at least 1 prior antidepressant 
treatment and
be currently taking an antidepressant treatment at the start of the 
screening/prospective observational phase that will be continued as prospective treatment in the 
screening/prospective observational phase. Only subjects with non-response to their current 
antidepressant treatment after 4 weeks of prospectively observed treatment (total duration of at 
least 6 weeks by the end of the screening/prospective observational phase), will be eligible to 
proceed to the open-label induction phase, when all subjects will receive a new oral 
antidepressant in addition to intranasal esketamine. 
Direct-entry subjects will receive 4 weeks of esketamine treatment in the open-label induction 
phase; at the end of this phase, those who are responders will be eligible to participate in the 
12-week optimization phase. At the end of the optimization phase, subjects who are stable 
responders or stable remitters may be eligible to enter the maintenance phase. At any time during 
the study, subjects may discontinue and proceed to the 2-week follow-up phase; they will be 
provided with an additional 2-week supply of oral antidepressant and appropriate follow-up care 
will be arranged.
At the start of the maintenance phase, eligible subjects in stable remission, or with stable 
response, will be randomized to either continue intranasal treatment with esketamine or switch to 
intranasal placebo. All subjects will continue to take the same oral antidepressant.
The study will be stopped once 84 relapses (in the subjects with stable remission) occur during 
the maintenance phase, or earlier based on the results of the interim analysis for efficacy. At the 
time the study is stopped, subjects in the induction phase will be able to complete the Induction
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phase. Those subjects who are responders after completing an Early Withdrawal Visit may 
proceed to the 54135419TRD3008 study without completing the follow up phase. Those who are 
not responders will have an Early Withdrawal Visit and proceed directly to the follow-up phase. 
Subjects who are in the optimization or maintenance phase at the time the study is terminated 
will have an Early Withdrawal Visit/End of Maintenance Phase Visit conducted and proceed 
directly to the follow-up phase.
Subjects will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
Justification for Using Placebo
Intranasal placebo is being used as a double-blind for esketamine to maintain study blinding for 
transferred-entry subjects from 1 of the short-term double-blind studies. All subjects will also 
receive a newly initiated oral antidepressant during the induction phase. Subjects will not be on 
placebo alone. Assessment of the potential efficacy of a new compound for the treatment of 
treatment-resistant major depression requires adequate and well-controlled clinical studies. This 
study will compare intranasal esketamine plus an oral antidepressant to switching to an oral 
antidepressant as an active comparator. Recent analyses have shown response to placebo varies 
considerably, from 10% to 55%. Therefore, there is a concern that randomized, controlled 
studies that rely on comparison with standard antidepressants alone will generate unreliable 
results with limited assay sensitivity. However, some have considered it unethical to do placebo-
controlled studies in major depression due to the potential risk of irreversible harm.110 In a meta-
analysis of drug studies conducted in MDD, it was reported that adult subjects did not have 
higher rates of suicide behaviors or attempts in the placebo group compared with those receiving 
an active antidepressant.67 These studies showed annual suicide rates of 0.8% on the 
investigational drug, 0.7% on the active comparator, and 0.4% on placebo. Thus, the risk of 
irreversible harm was not higher in the placebo arm compared with the active control arms. 
Some subjects may decide not to participate in a placebo-controlled study due to the potential for 
increased distress and dysfunction from prolonged depression. 
Therefore, the use of an active-controlled study allows for assessment of efficacy of a new 
compound to allow for scientifically meaningful results. 
Subjects will visit the study site at least every other week during the study, and their symptoms 
will be carefully monitored during each study visit. Safety evaluations will include evaluation of 
suicidal ideation/behavior at each clinic visit. At any point in the study, the subject may 
withdraw consent or be removed from the study by the investigator if there are any clinical 
concerns.
Intranasal esketamine may or may not be available for subjects after the study. However, 
following completion of the study, subjects can be treated according to standard of care. 
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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. 
The probability of receiving placebo and the concept of random assignment will be explained to 
the subject. Potential disadvantages and adverse events of participating in the study and 
alternative treatment options will be discussed. 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.
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).
Only subjects who had non-response to their current oral antidepressant treatment, where a 
clinician would consider changing it in the future due to lack of response, will be enrolled (direct 
entry).
Only qualified and trained investigators will participate in the study.
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 is 
approximately 189 mL, which 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):
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
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.
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), 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.
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
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. The reapproval should be documented in writing (excluding the ones that are purely 
administrative, with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
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, and 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.
Where local regulations require, a separate ICF may be used for the required DNA component of 
the study.
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16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory DNA and biomarker research is not conducted under standards appropriate for the 
return of data to subjects. In addition, the sponsor cannot make decisions as to the significance of 
any findings resulting from exploratory research. Therefore, exploratory research data will not be 
returned to subjects or investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.
16.2.5.
Long-term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand oral 
antidepressants, to understand depression, to understand differential drug responders, and to 
develop tests/assays related to oral antidepressants, and depression. The research may begin at 
any time during the study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3 [Withdrawal From the Use of Samples in Future 
Research)]).
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16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, 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 (and 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 (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the eCRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.
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
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.
17.4.
Source Documentation
At a minimum, source documentations 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 
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date of signed informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol; record of all adverse events and follow-up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; study drug administration 
information; and date of study completion and reason for early discontinuation of study drug or 
withdrawal from the study, if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
The minimum source documentation requirements for inclusion and exclusion criteria (in 
Section 4) 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, and 
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.
17.5.
Case Report Form Completion
Case report forms are provided 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.
Electronic data capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an eCRF, and transmitted in a secure 
manner to the sponsor within the timeframe agreed upon between the sponsor and the study site. 
The electronic file will be considered to be the eCRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documents. All data relating to the study 
must be recorded in eCRFs prepared by the sponsor. Data must be entered into eCRFs in English.
Study site personnel must complete the eCRF as soon as possible after a subject visit, and the 
forms should be available for review at the next scheduled monitoring visit.
The investigator must verify that all data entries in the eCRFs are accurate and correct.
All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. If necessary, queries will be generated in the eDC tool. The 
investigator or study-site personnel must adjust the eCRF (if applicable) and complete the query. 
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If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 
either of the following ways:

Investigator and study site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, and 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 eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRFs 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 eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
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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 eCRFs with the hospital or clinic records (source 
documents); a sample may be reviewed. The nature and location of all source documents will be 
identified to ensure that all sources of original data required to complete the eCRF are known to 
the sponsor and study-site personnel and are accessible for verification by the sponsor study-site 
contact. If electronic records are maintained at the study site, the method of verification must be 
discussed with the study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents 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 documentation 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 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.
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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.

Study is terminated by sponsor due to interim analysis results
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 and comparison with the eCRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding or the sponsor's operations 
(eg, patent application, formulas, manufacturing processes, basic scientific data, prior clinical 
data, formulation information) supplied by the sponsor to the investigator and not previously 
published, and any data, including pharmacogenomic or exploratory biomarker research data, 
generated as a result of this study, are considered confidential and remain the sole property of the 
sponsor. The investigator agrees to maintain this information in confidence and use this 
information only to accomplish this study, and will not use it for other purposes without the 
sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of esketamine, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information 
derived from the clinical studies to be used, the investigator is obligated to provide the sponsor 
with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain eCRF data from all study sites that participated in the study and will represent 
uploaded data transfers from external service providers into the sponsor’s database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
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study will be used to determine a coordinating investigator. Results of pharmacogenomic or 
exploratory biomarker analyses performed after the Clinical Study Report has been issued will 
be reported in a separate report and will not require a revision of the Clinical Study Report. 
Study subject identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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ATTACHMENTS
Attachment 1:
Prohibited Concomitant Medications With Intranasal Study Medication 
(Esketamine or Placebo)
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 oral antidepressant treatment 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: If a medication is part of the antidepressant 
treatment regimen being taken at the time of signing the ICF (ie, start of screening/prospective 
observational phase), per protocol, the medication is continued until the end of Week 4 of the 
screening/prospective observational phase, therefore this requirement is not applicable. In such cases the 
investigator may choose to taper the relevant medication during the up to 3-week taper period based on 
their clinical judgment.
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
N
N
Subjects with seizures are excluded. 
Use as adjunctive treatment for major 
depressive disorder (MDD) is 
prohibited.
- Note: Anticonvulsants used for 
indications other than seizures may 
be allowed (eg, valproate for 
migraine; pregabalin).
Safety and PD 
interaction
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Drug Class
Episodic 
Use (As 
Needed)
Continuous 
Use
Comments
Reason for 
Prohibition
Antidepressants 
(other than the specific 
antidepressant started in the 
induction phase of the study)
N
N
-Only 1 of the 4 predefined oral 
antidepressant treatment options are 
permitted.
-If a subject is taking a monoamine 
oxidase inhibitor (MAOI) during the 
screening/prospective observational 
phase, there must be a minimum 
washout interval of 2 weeks prior to 
the first dose of intranasal study 
medication.
- Even if used for indications other 
than MDD (eg, trazodone for sleep), 
the use of any medication listed on 
the ATRQ is not permitted during 
study phases that include intranasal 
treatment.
Safety and PD 
interaction
Antipsychotics
N
N
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
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 oral 
products should not be used within 
12 hours prior to an intranasal 
treatment session.
Safety and PD 
interaction
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Status: Approved, Date: 4 April 2017
Drug Class
Episodic 
Use (As 
Needed)
Continuous 
Use
Comments
Reason for 
Prohibition
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
Lithium
N
N
PD interaction
Memantine
N
N
PD interaction
Methyldopa
N
N
Safety and PD 
Interaction
Metyrosine
N
N
Safety and PD 
interaction
Non-vitamin K antagonist 
oral anticoagulation agents 
(eg, dabigatran, rivaroxaban, 
apixaban)
N
N
Safety
Opioids
N
N
Note: With Sponsor approval, brief 
treatment with opiates may be allowed 
for treatment of acute injuries etc.
PD interaction
Psychostimulants 
(eg, amphetamines, 
methylphenidate, modafinil, 
armodafinil)
N
Y
Prescribed psychostimulants taken for 
indications other than MDD 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.
Cardiovascular 
safety
Reserpine
N
N
PD interaction
Scopolamine
N
N
PD interaction
St. John’s wort
N
N
PD interaction 
and PK
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: N, Prohibited; PD, pharmacodynamics; PK, pharmacokinetics; Y, permitted, with restrictions (please 
refer to the column labeled “Comments” for additional guidance).
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Attachment 2:
New York Heart Association Classification of Cardiac Disease
Category
Description
Functional Capacity
Class I
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
Class II
Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
Class III
Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable 
at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any 
physical activity is undertaken, discomfort is increased.
Objective Assessment
A
No objective evidence of cardiovascular disease.
B
Objective evidence of minimal cardiovascular disease.
C
Objective evidence of moderately severe cardiovascular disease.
D
Objective evidence of severe cardiovascular disease.
Source: Reference 21
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Attachment 3:
Oral Antidepressant Titration Schedules for Open-label Induction Phase
Below is the titration schedule for the 4 oral antidepressants to be used in the current study. Adjustments 
to the titration schedules may be required in some countries in order to conform to local labeling.
Global Titration Schedule:
Oral Antidepressant 
(Active Comparator)
Titration Schedule
Week 1
(Starting Day 1)
Week 2
(Starting Day 8)
Week 3
(Starting Day 15)
Week 4
(Starting Day 22)
Duloxetine
60 mga
60 mg
60 mg
60 mg
Escitalopram
10 mg
20 mg
20 mg
20 mg
Sertraline
50 mg
100 mg
150 mg
200 mg
Venlafaxine XR
75 mg
150 mg
225 mg
225 mg
aSubjects should be initiated with 60 mg/day. Subjects that have in the past shown increased sensitivity towards 
serotonin reuptake inhibitors (SSRI) /norepinephrine reuptake inhibitors (SNRI) can, at the discretion of the treating 
physician, be started on a 30 mg dose and up-titrated to the therapeutic range of 60 mg by the start of Week 2.
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Attachment 4:
Anticipated Events
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease related) or background regimen. For 
the purposes of this study the following events will be considered anticipated events.31,32,36,37,60,119,120,132,133  
For esketamine and major depressive disorder (MDD) (including treatment-resistant depression [TRD];
based on DSM-5):

Suicidal thinking, ideation, and behavior

Sleep changes, difficulty sleeping, reduced sleep, abnormal sleep, abnormal sleep, tiredness, fatigue, 
and reduced energy

Difficulty in sexual desire, performance or satisfaction

Reduced appetite and weight changes (loss or increase)

Activation or hypomania/ mania

Excessive happiness

Irritability, anger, and impulsive behavior

Agitation, feeling anxious/anxiety, tension, panic attacks, and phobia
For esketamine, regarding events related to concomitant therapy with oral antidepressants (from the 
product’s reference safety information/US prescribing information):

Duloxetine

Most commonly observed adverse reactions from pooled studies of all indications (incidence of 
at least 5% and at least twice the incidence in placebo subjects) were nausea, dry mouth, 
somnolence, fatigue, constipation, decreased appetite, and hyperhidrosis (sweating). Duloxetine 
treatment worsens glycemic control in some subjects with diabetes.

Increased the risk compared with placebo of suicidal thinking and behavior; serotonin 
syndrome; hepatotoxicity; hepatic failure; orthostatic hypotension, syncope; abnormal bleeding; 
severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS); 
activation of mania or hypomania; hyponatremia.

Venlafaxine XR

According to the US prescribing information, adverse events in short-term studies occurring in 
at least 5% of subjects receiving venlafaxine XR and at a rate twice the incidence in placebo 
subjects: abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), 
central nervous system complaints (dizziness, somnolence, and abnormal dreams), and 
sweating. Sustained hypertension is noted within Warnings and Precautions section.

Increased the risk compared with placebo of suicidal thinking and behavior, treatment-emergent 
insomnia and nervousness, activation of mania/hypomania, hyponatremia, mydriasis, abnormal 
bleeding, sustained hypertension, and serotonin syndrome.

Escitalopram

Most commonly observed adverse reactions (incidence of approximately 5% or greater and 
approximately twice the incidence in placebo subjects) were insomnia, ejaculation disorder 
(primarily ejaculatory delay), nausea, sweating increased, fatigue, and somnolence.

Increased the risk compared with placebo of suicidal thinking and behavior, serotonin 
syndrome, activation of mania/hypomania, hyponatremia and abnormal bleeding
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
Sertraline

Most common treatment-emergent AEs associated with sertraline (incidence of at least 5% for
sertraline or at least twice the incidence in placebo subjects) were ejaculation failure, dry mouth, 
increased sweating, somnolence, tremor, dizziness, fatigue, pain, malaise, abdominal pain, 
anorexia, constipation, diarrhea/loose stools, dyspepsia, nausea, agitation, insomnia, and 
decreased libido, and serotonin syndrome. 

Increased the risk compared with placebo of suicidal thinking and behavior, activation/mania; 
bleeding events related to SSRI use (have ranged from ecchymosis, hematomas, epistaxis, and
petechiae to life-threatening hemorrhages), hyponatremia (appears to be the result of the 
syndrome of inappropriate antidiuretic hormone secretion [SIADH]); serotonin syndrome
Reporting of Anticipated Events
These events will be captured on the eCRF and in the database, and will be reported to the sponsor as 
described in Section 12.3.1, All Adverse Events. Any event that meets serious adverse event criteria will 
be reported to the sponsor within the appropriate timeline as described in Section 12.3.2, Serious Adverse 
Events. These anticipated events are exempt from expedited reporting as individual single cases to health 
authorities. However, if based on an aggregate review, it is determined that an anticipated event is 
possibly related to study drug, the sponsor will report these events in an expedited manner.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of pre-specified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug. 
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).
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INVESTIGATOR AGREEMENT
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