Clinical trial NCT04338321
Conditions: Depressive Disorder, Major
Sponsor: Janssen-Cilag International NV
Start date: 2020-08-21; Completion date: 2022-07-15
Enrollment: 676 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to evaluate the efficacy of flexibly dosed esketamine nasal spray compared with quetiapine extended-release (XR), both in combination with a continuing selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI), in achieving remission in participants who have treatment-resistant major depressive disorder (MDD) with a current moderate to severe depressive episode.

Detailed description:
A depressive state with classical symptoms such as low (depressive/sad) mood, markedly diminished interest in activities, significant weight loss/gain, insomnia or hypersomnia, psychomotor agitation/retardation, excessive fatigue, inappropriate guilt, diminished concentration, and recurrent thoughts of death, persisting for more than 2 weeks is classified as major depressive disorder (MDD). The mechanism of action of ketamine is distinct from conventional antidepressants (ADs), which target the monoamines (serotonin, norepinephrine, and/or dopamine). Esketamine, the S-enantiomer of ketamine, is approved and widely used for the induction and maintenance of anesthesia via intramuscular or intravenous (IV) administration. There is a significant unmet need to develop novel AD treatments based on the relevant psychophysiological pathways underlying MDD. The goal of any novel treatment would be the rapid and long-lasting relief of depressive symptoms, especially in participants with treatment-resistant depression (TRD), who lack a sufficient response to the currently available treatment strategies. The study consists of a Screening Phase (up to 14 days), an Acute Phase (8 Weeks), a Maintenance Phase (24 Weeks) and a Safety Follow-up Phase (2 Weeks). Safety assessment includes adverse event, serious adverse events, physical examination, vital signs, electrocardiogram, clinical safety laboratory assessments, suicidal risk monitoring. The total duration of the study is approximately 36 Weeks for all participants.

Arms: arm 1: Participants will receive treatment with esketamine nasal spray (28 milligram \[mg\] \[initial dose for elderly participants 65 to 74 years of age and adults of Japanese ancestry; may be used throughout the study in these populations; may be uptitrated in 28 mg increments\], 56 mg \[initial dose for adult participants aged 18 to 64 years and may be used for all age groups throughout the study\], or 84 mg \[maximum dose esketamine nasal spray may be uptitrated to\]) twice-weekly with a flexible dose regimen from Day 1 until Week 4, once weekly from Week 5 to Week 8 and once-weekly or once every 2 weeks from Week 9 to Week 32 in combination with continuing serotonin-norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (SSRI/SNRI). arm 2: Participants will continue to take their current SSRI/SNRI augmented with quetiapine extended release (XR) as per the Summary of Product Characteristics (SmPC) (or local equivalent, if applicable). In adult participants aged 18 to 64 years, the initial dose is 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 \[lowest effective dose\]; a further dose increase to 300 mg/day on Day 5 and onward will be based on individual participant evaluation. In elderly participants aged 65 to 74 years, the initial dose is 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day will be based on individual participant evaluation no earlier than Day 22.
Interventions: intervention 1: Esketamine 28 mg intervention 2: Esketamine 56 mg intervention 3: Esketamine 84 mg intervention 4: Quetiapine XR 50 mg intervention 5: Quetiapine XR 100 mg intervention 6: Quetiapine XR 150 mg intervention 7: SSRI/SNRI
Intervention descriptions: intervention 1: Esketamine will be self-administered at a dose of 28 mg as nasal spray. intervention 2: Esketamine will be self-administered at a dose of 56 mg as nasal spray. intervention 3: Esketamine will be self-administered at a dose of 84 mg (maximum uptitrated dose) as nasal spray. intervention 4: Quetiapine XR will be administered at an initial dose of 50 mg/day and may be further increased to 300 mg/day based on individual participant evaluation. intervention 5: Quetiapine XR will be administered at a dose of 100 mg/day and may be further increased to 300 mg/day based on individual participant evaluation. intervention 6: Quetiapine XR will be administered at a dose of 150 mg/day and may be further increased to 300 mg/day based on individual participant evaluation. intervention 7: Participants will continue to take SSRI/SNRI that is approved for use in depression in their country of participation; off-label use of any SSRI/SNRI is not permitted. The continuing SSRI/SNRI dosage may be optimized throughout the study, at the investigator's discretion and based on the SmPC (or local equivalent, if applicable).

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 8 October 2020
Janssen EMEA *
Clinical Protocol
A Randomized, Open-label, Rater-Blinded, Active-Controlled, International, Multicenter 
Study to Evaluate the Efficacy, Safety, and Tolerability of Flexibly Dosed Esketamine 
Nasal Spray Compared With Quetiapine Extended-Release in Adult and Elderly 
Participants With Treatment-Resistant Major Depressive Disorder Who are Continuing a 
Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor
ESCAPE-TRD
A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine 
Extended-Release, Both in Combination With a Selective Serotonin Reuptake 
Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With 
Treatment-Resistant Major Depressive Disorder 
Protocol 54135419TRD3013; Phase 3b
AMENDMENT 1
JNJ-54135419 (esketamine)
* Janssen EMEA is an organization that operates through different legal entities in various countries. The
legal entity acting as the sponsor for Janssen EMEA studies may vary, such as, but not limited to Janssen-
Cilag International NV or Janssen Pharmaceutica NV. 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.
EudraCT NUMBER: 2019-002992-33
Status:
Approved  
Date:
8 October 2020
Prepared by:
Janssen-Cilag Limited
EDMS number:
EDMS-ERI-192877595, 2.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04338321


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3013 Amendment 1
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 8 October 2020
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
8 October 2020
Original Protocol
13 January 2020
Amendment 1 (8 October 2020)
Overall Rationale for the Amendment:  To address the impact that the Coronavirus Disease 2019 
(COVID-19) pandemic may have had on the conduct of this study and to address comments made by 
regional health authorities on the protocol.
Section Number
and Name
Description of Change
Brief Rationale
10.8. Appendix 8, 
Guidance on Study 
Conduct During a
COVID-19 Pandemic.
Added guidance on study conduct during a 
COVID-19 pandemic.
To provide guidance to 
investigators and participants on 
options for study assessments and 
procedures in the event of further 
restrictions/limitation to a 
COVID-19 pandemic.
1.3.1. Schedule of 
Activities (Weeks 1 to 
8);
5.2. Exclusion 
Criteria;
10.2. Appendix 2: 
Clinical Laboratory 
Tests.
Added Exclusion criteria 30 to exclude patients 
with a pre-existing thyroid disease/disorder 
treated with thyroid hormones not on a stable 
dosage for 3 months prior to the start of the 
screening phase, and ensure patients with TSH 
value out of range are tested for free thyroxine 
(FT4) and, if out of range, are excluded.
To ensure pre-existing thyroid 
disease/disorder is sufficiently 
treated as esketamine should be 
used with caution in these patients, 
per SPRAVATO Summary of 
Product Characteristics (SmPC).
5.2. Exclusion 
Criteria.
Modified Exclusion criterion 6 to exclude current 
diagnosis of obsessive compulsive disorder; 
current or prior diagnosis of histrionic personality 
disorder or narcissistic personality disorder, and 
add DSM-5 diagnostic codes for intellectual 
disability.
For consistency with other clinical 
studies of esketamine.
5.2. Exclusion 
Criteria.
Modified Exclusion criterion 13 to exclude 
patients with confirmed or suspected 
cardiomyopathy or myocarditis.
Cardiomyopathy and myocarditis 
are advised for reassessment of 
quetiapine treatment in the 
Seroquel XR SmPC.28
5.2. Exclusion 
Criteria.
Added Exclusion criterion 31 to exclude patients 
with a white blood cell count ≤2.0 × 103/µL at 
screening or history of drug induced neutropenia.
To address possible risk factors for 
neutropenia associated with 
quetiapine treatment in the 
Seroquel XR SmPC.28
1.3.1. Schedule of 
Activities (Weeks 1 to 
8).
Added weekly assessments of C-SSRS during the 
first 4 weeks of the study and at the safety 
follow-up visit.
Sponsor’s decision and health 
authority requests to monitor 
suicidality more intensively during 
the study.
1.3. Schedule of 
Activities.
Increased frequency of body weight monitoring 
throughout the study.
To address the metabolic risk 
associated with quetiapine 
(including body weight), per 
Seroquel XR SmPC.28
1.2. Schema;
1.3 Schedule of 
Activities;
Added treatment discontinuation of quetiapine by 
gradual dose reduction over 1 to 2 weeks.
Acute withdrawal symptoms have 
been described after sudden 
discontinuation of quetiapine.


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3013 Amendment 1
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 8 October 2020
Section Number
and Name
Description of Change
Brief Rationale
6.1.2. Quetiapine 
Extended-release in 
Combination With a 
Continuing 
SSRI/SNRI.
10.2 Appendix 2: 
Clinical Laboratory 
Tests.
Added magnesium to the clinical chemistry panel 
assessed during the study.
The Seroquel XR SmPC28 indicates 
that caution should be exercised 
when quetiapine is prescribed in 
patients with hypomagnesaemia.
10.4. Appendix 4: 
Prohibited 
Concomitant 
Medications.
Updated concomitant medications table to 
include anti-cholinergic medications, medications 
that cause electrolyte imbalance or QT-
prolongation, and revised use of antipsychotics.
To address health authority 
requests.
1.1. Synopsis;
8.3.7. Adverse Events 
of Special Interest.
Added events suggestive of abuse potential, 
cystitis, and hepatic impairment to AEs of special 
interest. Clarified that suicidality includes 
suicidal ideation and suicidal behavior.
To expand the list of AEs of 
special interest due to the evolving 
regulatory environment and 
company commitments.
8.2.3.
Electrocardiograms.
Removed instructions for conducting triplicate 
ECGs.
To prevent confusion as no 
triplicate ECGs are required for the 
study.
1.1. Synopsis;
4.1. Overall Design;
4.2.1. Selection of 
Participant Population;
5.1. Inclusion Criteria.
Reworded inclusion criteria 4, 5 and 6.
To add clarification to existing 
wording.
7.1. Discontinuation of 
Study Intervention.
Added discontinuation of participants where the 
investigator believes there is no evidence of 
clinical improvement and further continuation of 
study intervention would not be in the best 
interest of the participant.
For consistency with existing 
wording in the protocol and to add 
it as a specific reason for 
discontinuation of study 
intervention.
10.7. Appendix 7: List 
of Acceptable 
Previous 
Antidepressive 
Treatments.
Added table of acceptable previous 
antidepressive treatments.
To specify which treatments are 
allowed including minimal doses 
and substance classes.
8.1.2.4. 36-Item Short-
Form Health Survey 
(SF-36v2).
Clarified scoring and scales used in SF-36 
questionnaire.
To add clarification to existing 
wording.
1.1. Synopsis;
9.4.3. Other 
Secondary/Exploratory 
Endpoints.
Stated that subgroup analyses will be performed 
for age (18 to 64 years [inclusive]; 65 to 74 
years[inclusive]) and total number of treatment 
failures (2; 3 or more), as well as sex and severity 
of depression. Analysis by geographical region
may also be provided.
To add clarification to existing 
wording and allow analysis by 
geographical region if required.
2. Introduction;
8.3. Adverse Events 
and Serious Adverse 
Events;
8.3.8. Medical Device 
Deficiencies;
10.5. Appendix 5: 
Adverse Events: 
Definitions and 
Procedures for 
Added text to state that for combination 
products 
with 
a 
device 
constituent, 
malfunctions or deficiencies will be reported as 
PQC.
Clarified procedures for reporting of adverse 
events and serious adverse events 
for 
combination 
products 
with 
a 
device 
constituent. 
Removed Section 8.3.8. Medical Device 
Deficiencies.
To align with the most recent
guidance and protocol procedures 
within Janssen regarding reporting 
of combination products with a 
device constituent. To clarify that 
combination products with a device 
constituent will have malfunctions 
or deficiencies reported as PQCs 
and not as adverse device effects.


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3013 Amendment 1
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 8 October 2020
Section Number
and Name
Description of Change
Brief Rationale
Evaluating, Follow-up, 
and Reporting;
10.7. Appendix 7: 
Medical Device 
Adverse Events, 
Adverse Device 
Effects, Serious 
Adverse Events, and 
Device Deficiencies: 
Definition and 
Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting.
Removed Appendix 7: Medical Device 
Adverse Events, Adverse Device Effects, 
Serious 
Adverse 
Events, 
and 
Device 
Deficiencies: Definition and Procedures for 
Recording, 
Evaluating, 
Follow-up, 
and 
Reporting
Throughout the 
protocol
Changed source data so it may be recorded 
directly into the eCRF.
Added collection of height at Screening.
Updated Work Productivity and Activity 
Impairment 
Questionnaire 
from 
Specific 
Health Problem (WPAI:SHP) to Depression 
(WPAI:D).
Minor 
grammatical, 
formatting, 
spelling, 
editorial clarifications or consistency changes 
were made.
Revised confidentiality statement to comply 
with an update from the legal department.
To clarify scientific and 
operational aspects of the study 
design and correct or clarify minor 
errors that were noted.


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3013 Amendment 1
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved,  Date: 8 October 2020
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 7
1.
PROTOCOL SUMMARY ..................................................................................................................... 9
1.1.
Synopsis........................................................................................................................................... 9
1.2.
Schema .......................................................................................................................................... 18
1.3.
Schedule of Activities..................................................................................................................... 20
1.3.1.
Schedule of Activities (Weeks 1 to 8)......................................................................................... 20
1.3.2.
Schedule of Activities (Weeks 9 to 32)....................................................................................... 24
2.
INTRODUCTION................................................................................................................................ 28
2.1.
Study Rationale.............................................................................................................................. 29
2.2.
Background .................................................................................................................................... 30
2.2.1.
Pharmacologic Profile................................................................................................................. 30
2.2.2.
Nonclinical Studies ..................................................................................................................... 30
2.2.3.
Clinical Studies ........................................................................................................................... 31
2.2.3.1.
Metabolism and Excretion ....................................................................................................... 31
2.2.3.2.
Pharmacokinetics .................................................................................................................... 31
2.2.3.3.
Pharmacodynamics and Efficacy ............................................................................................ 33
2.2.3.4.
Safety Studies.......................................................................................................................... 35
2.2.4.
Comparator................................................................................................................................. 37
2.3.
Benefit-Risk Assessment ............................................................................................................... 40
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 41
4.
STUDY DESIGN ................................................................................................................................ 43
4.1.
Overall Design................................................................................................................................ 43
4.2.
Scientific Rationale for Study Design............................................................................................. 47
4.2.1.
Selection of Participant Population............................................................................................. 47
4.2.2.
Selection of Active Comparator .................................................................................................. 48
4.2.3.
Selection of SSRI/SNRI as the Classes of Concomitant Oral Antidepressants......................... 48
4.2.4.
Screening.................................................................................................................................... 48
4.2.5.
Follow-up .................................................................................................................................... 49
4.2.6.
Blinding, Control, Study Phase, Intervention Groups ................................................................. 49
4.2.7.
Clinician and Participant-reported Efficacy Assessments .......................................................... 49
4.2.8.
Safety Evaluations...................................................................................................................... 49
4.2.9.
Biomarker and Pharmacogenomic (DNA/RNA) Collection......................................................... 50
4.2.10.
Study-Specific Ethical Design Considerations ........................................................................... 50
4.3.
Justification for Dose...................................................................................................................... 51
4.4.
End of Study Definition................................................................................................................... 52
5.
STUDY POPULATION ...................................................................................................................... 52
5.1.
Inclusion Criteria ............................................................................................................................ 53
5.2.
Exclusion Criteria ........................................................................................................................... 55
5.3.
Lifestyle Considerations................................................................................................................. 59
5.4.
Screen Failures .............................................................................................................................. 60
6.
STUDY INTERVENTION................................................................................................................... 61
6.1.
Study Interventions Administered .................................................................................................. 61
6.1.1.
Esketamine Nasal Spray in Combination With a Continuing SSRI/SNRI .................................. 61
6.1.1.1.
Esketamine Nasal Spray ......................................................................................................... 62
6.1.1.2.
Esketamine Nasal Spray Dosing Recommendations.............................................................. 63
6.1.1.3.
Nasal Treatment Sessions ...................................................................................................... 64
6.1.1.4.
Acute (Weeks 1 to 8) and Maintenance (Weeks 9 to 32) Phases........................................... 65


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3013 Amendment 1
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Status: Approved,  Date: 8 October 2020
6.1.2.
Quetiapine Extended-Release in Combination With a Continuing SSRI/SNRI.......................... 65
6.1.2.1.
Quetiapine Extended-Release................................................................................................. 66
6.1.3.
Continuing SSRI/SNRI................................................................................................................ 67
6.1.4.
Medical Devices.......................................................................................................................... 67
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 68
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 69
6.4.
Study Intervention Compliance...................................................................................................... 69
6.5.
Concomitant Therapy..................................................................................................................... 70
6.5.1.
Psychotherapy............................................................................................................................ 71
6.6.
Dose Modification........................................................................................................................... 72
6.6.1.
Esketamine Nasal Spray ............................................................................................................ 72
6.6.2.
Quetiapine Extended-Release.................................................................................................... 75
6.6.3.
Continuing SSRI/SNRI................................................................................................................ 75
6.7.
Intervention After the End of the Study.......................................................................................... 75
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 75
7.1.
Discontinuation of Study Intervention ............................................................................................ 75
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 76
7.2.1.
Withdrawal From the Use of Research Samples ....................................................................... 76
7.3.
Lost to Follow-up............................................................................................................................ 77
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 77
8.1.
Efficacy Assessments .................................................................................................................... 79
8.1.1.
Clinician-Rated ........................................................................................................................... 79
8.1.1.1.
Screening Evaluations............................................................................................................. 79
8.1.1.2.
Montgomery-Asberg Depression Rating Scale (MADRS)....................................................... 81
8.1.1.3.
Clinical Global Impression – Severity (CGI-S) and Change (CGI-C)...................................... 81
8.1.2.
Patient-Reported Outcomes ....................................................................................................... 82
8.1.2.1.
Patient Health Questionnaire, 9-Item (PHQ-9)........................................................................ 82
8.1.2.2.
Quality of Life in Depression Scale (QLDS) ............................................................................ 82
8.1.2.3.
European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level (EQ-5D-5L) ...................... 82
8.1.2.4.
36-Item Short-Form Health Survey (SF-36v2) ........................................................................ 83
8.1.2.5.
Sheehan Disability Scale (SDS).............................................................................................. 83
8.1.2.6.
Work Productivity and Activity Impairment (WPAI): Depression (D)....................................... 83
8.2.
Safety Assessments....................................................................................................................... 83
8.2.1.
Physical Examinations................................................................................................................ 84
8.2.2.
Vital Signs................................................................................................................................... 84
8.2.3.
Electrocardiograms..................................................................................................................... 85
8.2.4.
Clinical Safety Laboratory Assessments .................................................................................... 85
8.2.5.
Suicidal Risk Monitoring ............................................................................................................. 86
8.3.
Adverse Events and Serious Adverse Events ............................................................................... 87
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 87
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 88
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 88
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 88
8.3.5.
Pregnancy................................................................................................................................... 89
8.3.6.
Disease-Related Events and Disease-Related Outcomes not Qualifying as Adverse 
Events or Serious Adverse Events ............................................................................................. 90
8.3.7.
Adverse Events of Special Interest............................................................................................. 90
8.4.
Treatment of Overdose .................................................................................................................. 90
8.5.
Pharmacokinetics........................................................................................................................... 91
8.6.
Pharmacodynamics........................................................................................................................ 91
8.7.
Biomarker and Pharmacogenomic (DNA and RNA) Evaluations .................................................. 91
8.8.
Medical Resource Utilization and Health Economics .................................................................... 92
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 92


JNJ-54135419 (esketamine)
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Status: Approved,  Date: 8 October 2020
9.1.
Statistical Hypotheses.................................................................................................................... 92
9.2.
Sample Size Determination ........................................................................................................... 93
9.3.
Populations for Analyses................................................................................................................ 93
9.4.
Statistical Analyses ........................................................................................................................ 93
9.4.1.
General Considerations.............................................................................................................. 94
9.4.2.
Efficacy Endpoints ...................................................................................................................... 94
9.4.3.
Other Secondary/Exploratory Endpoints .................................................................................... 95
9.4.4.
Safety Analyses .......................................................................................................................... 95
9.4.5.
Other Analyses ........................................................................................................................... 96
9.5.
Interim Analysis.............................................................................................................................. 96
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 97
10.1.
Appendix 1: Abbreviations ............................................................................................................. 98
10.2.
Appendix 2: Clinical Laboratory Tests ......................................................................................... 100
10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations....................................... 101
REGULATORY AND ETHICAL CONSIDERATIONS ........................................................................ 101
FINANCIAL DISCLOSURE ................................................................................................................ 104
INFORMED CONSENT PROCESS ................................................................................................... 104
DATA PROTECTION ......................................................................................................................... 105
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH.................... 106
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA......................................... 106
DATA QUALITY ASSURANCE .......................................................................................................... 107
CASE REPORT FORM COMPLETION ............................................................................................. 108
SOURCE DOCUMENTS .................................................................................................................... 108
MONITORING .................................................................................................................................... 109
ON-SITE AUDITS............................................................................................................................... 110
RECORD RETENTION ...................................................................................................................... 110
STUDY AND SITE START AND CLOSURE...................................................................................... 111
10.4.
Appendix 4: Prohibited Concomitant Medications ....................................................................... 112
10.5.
Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................................................. 117
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS............................................................ 117
ATTRIBUTION DEFINITIONS............................................................................................................ 118
SEVERITY CRITERIA ........................................................................................................................ 118
SPECIAL REPORTING SITUATIONS ............................................................................................... 119
PROCEDURES .................................................................................................................................. 119
CONTACTING SPONSOR REGARDING SAFETY........................................................................... 120
PRODUCT QUALITY COMPLAINT HANDLING................................................................................ 120
10.6.
Appendix 6: Contraceptive and Barrier Guidance and Collection of Pregnancy Information...... 122
10.7.
Appendix 7: List of Previous Antidepressive Treatments ............................................................ 124
10.8.
Appendix 8: Guidance on Study Conduct During a COVID-19 Pandemic .................................. 126
10.9.
Appendix 9: Protocol Amendment History ................................................................................... 129
11.
REFERENCES................................................................................................................................. 130
INVESTIGATOR AGREEMENT ............................................................................................................... 132
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:  
Treatment Continuation Assessment of Study Intervention ..................................................... 46
Table 2:
Recommended Dosing for Esketamine Nasal Spray in Adults <65 Years of Age ................... 63
Table 3:
Recommended Dosing for Esketamine Nasal Spray in Elderly Participants 
65 to 74 Years of Age, Inclusive, and Adults of Japanese Ancestry........................................ 64
Table 4:
Nasal Treatment (Esketamine) Sessions ................................................................................. 64
Table 5:
Recommended Uptitration Schedule for Quetiapine Extended-Release ................................. 67


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3013 Amendment 1
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Status: Approved,  Date: 8 October 2020
FIGURES
Figure 1:
Adults: Recommendations for Dose Modification of Esketamine Nasal Spray to 
Optimize Efficacy During the Acute and Maintenance Phases ................................................ 73
Figure 2:
Adults: Recommendations for Dose Modification of Esketamine Nasal Spray to 
Handle Decreased Tolerability During the Acute and Maintenance Phases............................ 73
Figure 3:
Elderly and Adults of Japanese Descent: Recommendations for Dose Modification of 
Esketamine Nasal Spray to Optimize Efficacy During the Acute and Maintenance 
Phases ...................................................................................................................................... 74
Figure 4:
Elderly and Adults of Japanese Descent: Recommendations for Dose Modification of 
Esketamine Nasal Spray to Handle Decreased Tolerability During the Acute and 
Maintenance Phases ................................................................................................................ 74


JNJ-54135419 (esketamine)
Clinical Protocol 54135419TRD3013 Amendment 1
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 8 October 2020
1.
PROTOCOL SUMMARY
1.1.
Synopsis
A Randomized, Open-label, Rater-Blinded, Active-Controlled, International, Multicenter Study to Evaluate 
the Efficacy, Safety, and Tolerability of Flexibly Dosed Esketamine Nasal Spray Compared With 
Quetiapine Extended-Release in Adult and Elderly Participants With Treatment-Resistant Major 
Depressive Disorder Who are Continuing a Selective Serotonin Reuptake Inhibitor/Serotonin-
Norepinephrine Reuptake Inhibitor
A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended-Release, Both in 
Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor,
in Participants With Treatment-Resistant Major Depressive Disorder 
Depression is a major cause of morbidity and mortality, with global estimates of 300 million treated and 
untreated individuals worldwide. A depressive state with classical symptoms such as low (depressive/sad) 
mood, markedly diminished interest in activities, significant weight loss/gain, insomnia or hypersomnia, 
psychomotor agitation/retardation, excessive fatigue, inappropriate guilt, diminished concentration, and 
recurrent thoughts of death, persisting for more than 2 weeks is classified as major depressive disorder 
(MDD).
Ketamine affects fast excitatory glutamate transmission. Antidepressant (AD) effects may relate to 
increased brain-derived neurotrophic factor release and synaptogenesis. Esketamine, the S-enantiomer of 
ketamine, is approved and widely used for the induction and maintenance of anesthesia via intramuscular 
or intravenous (IV) administration. Because of the higher N-methyl-D-aspartate receptor affinity of 
esketamine over arketamine (R-enantiomer of ketamine), Janssen Research & Development is developing 
esketamine (not the racemate) for AD therapy. Moreover, intranasal administration was investigated instead 
of IV administration, since intranasal administration can offer better convenience for patients and fewer 
errors in dosing, and esketamine can be rapidly and well absorbed via the intranasal route.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
The primary objective of this study is to evaluate 
the efficacy of flexibly dosed esketamine nasal 
spray compared with quetiapine extended-release 
(XR), both in combination with a continuing 
selective serotonin reuptake inhibitor 
(SSRI)/serotonin-norepinephrine reuptake inhibitor 
(SNRI), in achieving remission in participants who 
have treatment-resistant MDD with a current 
moderate to severe depressive episode. 
Remission at the Week 8 visit, defined as a 
Montgomery-Asberg Depression Rating Scale 
(MADRS) total score of ≤10.
Key Secondary
To assess the efficacy of esketamine nasal spray 
compared with quetiapine XR, both in combination 
with a continuing SSRI/SNRI, in the proportion of 
participants being relapse-free at Week 32 after 
remission at Week 8.
Remission at Week 8 visit (ie, MADRS total score 
of ≤10 at the end of Week 8) and no relapse within 
the consecutive 24 weeks until the end of the 
prospective observation period at Week 32 visit.


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Objectives
Endpoints
Note: A relapse is defined by any of the following:
a)
Worsening of depressive symptoms as 
indicated by MADRS total score 
≥22 confirmed by 1 additional assessment of 
MADRS total score ≥22 within the next 5 to 
15 days. The date of the second MADRS 
assessment will be used for the date of 
relapse.
b)
Any psychiatric hospitalization for

worsening of depression

suicide prevention or due to a suicide 
attempt
for any of these events, the start date of 
hospitalization will be used for the date of 
relapse.
c)
Suicide attempt, completed suicide, or any 
other clinically relevant event determined per 
the investigator’s clinical judgment to be 
indicative of a relapse of depressive illness, 
but for which the participant was not 
hospitalized. The onset of the event will be 
used for the date of relapse.
In case more than 1 of the relapse criteria are met, 
the earliest date will be defined as the date of 
relapse for that participant.
Other Secondary
To assess the effect of esketamine nasal spray 
compared with quetiapine XR, both in combination 
with a continuing SSRI/SNRI, in:
Change from baseline at all visits for the following 
scale scores:

Clinician-rated overall severity of depressive 
illness 

Clinician-rated MADRS:

Overall severity of depressive illness 
(total score)

Early onset of action

Early onset of action (change in total 
score from baseline at Day 8 visit) 

Depressive symptoms (individual items)

Clinician-rated depressive symptoms

Clinician-rated overall severity of depressive 
illness: 

Clinical Global Impression – Severity 
(CGI-S)

Clinical Global Impression – Change 
(CGI-C), is a measure of change, 


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Objectives
Endpoints
analyzed as a score not as change from 
baseline

Participant-reported depressive symptoms

Participant-reported functional impairment 
and associated disability

Participant-reported health-related quality of 
life and health status

Participant-reported work productivity 

Participant-reported depressive symptoms: 
Patient Health Questionnaire 9-item (PHQ-9) 

Participant-reported functional impairment 
and associated disability: Sheehan Disability 
Scale (SDS)

Participant-reported health-related quality of 
life and health status: 36-item Short-Form 
Health Survey (SF-36)

Participant-reported Quality of Life in 
Depression Scale (QLDS)

Participant-reported European Quality of Life 
(EuroQoL) Group, 5-Dimension, 5-Level 
(EQ-5D-5L) questionnaire

Participant-reported work productivity: Work 
Productivity and Activity Impairment 
(WPAI): Depression (D) questionnaire
To assess the safety and tolerability of esketamine 
nasal spray compared with quetiapine XR, both in 
combination with a continuing SSRI/SNRI.
Intervention-emergent adverse events (AEs), 
including intervention-emergent AEs of special 
interest
Suicidal ideation and behavior: Columbia-Suicide 
Severity Rating Scale (C-SSRS)
Exploratory
To assess the potential relationship of biomarkers 
with response/nonresponse to study intervention in 
participants with treatment-resistant MDD.
-
Hypotheses
The primary hypothesis of this study is that among participants who have treatment-resistant MDD with a 
current moderate to severe depressive episode, the proportion of participants achieving remission at the 
Week 8 visit is greater in participants treated with flexibly dosed esketamine nasal spray than in participants 
treated with quetiapine XR, both administered in combination with a continuing SSRI/SNRI.
The major secondary hypothesis of this study is that among participants who have treatment-resistant MDD 
with a current moderate to severe depressive episode, the proportion of participants who achieved remission 
at the Week 8 visit and remain relapse-free through the Week 32 visit is greater in participants treated with 
esketamine nasal spray than in participants treated with quetiapine XR, both administered in combination 
with a continuing SSRI/SNRI.
OVERALL DESIGN
This is a randomized, open-label, rater-blinded, active-controlled, international, multicenter study to 
evaluate the efficacy, safety, and tolerability of flexibly dosed esketamine nasal spray compared with 
quetiapine XR, both in combination with a continuing SSRI/SNRI, in participants 18 to 74 years of age, 


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inclusive, with treatment-resistant MDD. A psychiatrist should determine eligibility of participants for 
inclusion in the study. 
To be eligible for enrollment in the study:

Participant must be on a current antidepressive treatment that includes an SSRI/SNRI at screening that 
resulted in nonresponse (less than 25% improvement of symptoms) after having been given at an 
adequate dosage (based on antidepressive dosages from Summary of Product Characteristics [SmPC; 
or local equivalent, if applicable]) for an adequate duration of at least 6 weeks and having been 
uptitrated to the maximum tolerated dose; however, at screening the participant must show signs of 
minimal clinical improvement to be eligible for the study. 

In addition the current antidepressive treatment must have been immediately preceded by nonresponse 
to at least 1 but not more than 5 different consecutive treatments (all within the current moderate to 
severe depressive episode) with ADs taken at an adequate dosage for an adequate duration of at least 
6 weeks 

“At least 1 but not more than 5” means that participants may be screened and enrolled while 
receiving treatment with their second to sixth consecutive treatment with oral ADs taken at 
adequate dosage for an adequate duration of at least 6 weeks to which they are having a 
nonresponse. 
o
If a participant was receiving an oral AD at an adequate dosage for an adequate duration of 
at least 6 weeks and then had an augmentation therapy added or had combination AD therapy 
initiated, it would then be considered the next consecutive treatment with AD if taken at an 
adequate dosage for an adequate duration of at least 6 weeks. 

For treatments with AD(s) to be counted as consecutive, there may have been interspersed 
insufficient treatments (ie, insufficient duration and/or at insufficient dosage). These insufficient 
treatments are allowed but will not be considered when documenting participant nonresponse.

Participant must have been treated with at least 2 different antidepressive substance classes among the 
treatments taken at an adequate dosage for an adequate duration of at least 6 weeks resulting in 
nonresponse in the current moderate to severe depressive episode (including the current treatment with 
an SSRI/SNRI).

Participant must be on a single oral SSRI/SNRI on Day 1 prior to randomization.

Participants who are taking combination ADs and/or augmentation (other than quetiapine XR 
which is exclusionary at doses >50 mg/day) for the current moderate to severe depressive episode 
at screening are eligible for the study. All AD treatments, including any augmenting substances, 
must be stopped prior to randomization on Day 1 according to applicable SmPCs (or local 
equivalents, if applicable), except the SSRI/SNRI to be continued.
The study has 4 phases: an up-to-14-day screening phase, an 8-week acute phase, a 24-week maintenance 
phase, and a 2-week safety follow-up phase. During the acute phase, participants in the esketamine arm 
will have twice-weekly visits from Week 1 to Week 4 and once weekly visits from Week 5 to Week 8; 
during the maintenance phase from Week 9 to Week 32, visits will be once weekly or every 2 weeks (even 
weeks) based on dosing. Participants in the comparator arm will have weekly visits from Week 1 to Week 4, 
and then every 2 weeks for the remainder of the acute phase (Week 6 and Week 8) and the maintenance 
phase (Week 10, Week 12, etc) through Week 32. All participants have a safety follow-up visit 2 weeks 
following the last dose of study intervention. Participants who discontinue the study intervention early 
(ie, discontinue either component of the randomized combination therapy) will remain in the study and 
continue to return for all follow-up visits through Week 32, according to the Schedule of Activities. The 
total duration of the study is approximately 36 weeks for all participants. The end of study is considered as 
the last visit for the last participant in the study.


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For participants in the esketamine arm:

At the Week 4 visit, evidence of therapeutic benefit of the study intervention (ie, esketamine nasal 
spray in combination with a continuing SSRI/SNRI) will be evaluated clinically by the investigator. 
In the evaluation of therapeutic benefit, the full scope of clinical improvement should be evaluated 
including any improvement in depressive symptoms, general functioning, social functioning, and 
self-care. If there is no evidence of therapeutic benefit, the investigator and the participant should 
discuss the treatment strategy and mutually agree on whether to continue or discontinue esketamine 
nasal spray.
Treatment Continuation Assessment of Study Intervention: Beginning at the Week 8 visit, all participants
in both study intervention arms will undergo regular assessments of symptom changes from baseline 
(ie, treatment continuation assessment) to ensure that study intervention continuation is appropriate. This 
will be operationalized using the CGI-C clinician-rated scale (referring to study baseline [Day 1]) every 
4 weeks, and treatment decisions will be made using cut-off values below. 
Treatment Continuation Assessment of Study Intervention
CGI-C ≥4 (“no change” or worse) 
at 2 consecutive visits
Recommendation to reconsider appropriateness of study 
intervention and to switch to an alternative standard-of-care 
treatment.
CGI-C <4 (“Minimally improved” or better) at 
any visit
Study intervention may be continued at the discretion of the 
investigator.
CGI-C= Clinical Global Impression – Change
Note: After early discontinuation of study intervention, the CGI-C will still be performed at follow-up visits according to the 
Schedule of Activities; however, treatment decisions will be at the discretion of the investigator and not based on the criteria for 
the treatment continuation assessment.
Participants who complete the study will have a safety follow-up visit performed 2 weeks after their last 
dose of study intervention.
Participants who discontinue the study intervention early (ie, discontinue either component of the 
randomized combination therapy) will remain in the study and continue to return for follow-up visits every 
2 weeks through Week 32. For these participants, all safety follow-up visit assessments will be performed 
in addition to the assessments scheduled at their first 2-week follow-up visit, or if study intervention is 
discontinued after the Week 30 visit, the safety follow-up visit will be performed 2 weeks after their last 
dose. Refer to Safety Evaluations for details of AE reporting for participants who discontinue study 
intervention early.
If a participant withdraws from the study, an early study withdrawal visit should be conducted within 
1 week of the date of withdrawal unless they withdraw consent, are lost to follow-up, or have died.
Participants who are taking study intervention at the time of early withdrawal from the study should return 
for the safety follow-up visit 2 weeks after their last dose unless they withdraw consent, are lost to 
follow-up, or have died.
All procedures, assessments, follow-up visits for participants who discontinue study intervention before 
Week 32, early withdrawal visits, and safety follow-up visits will be performed according to the Schedule 
of Activities. 
NUMBER OF PARTICIPANTS
A total of 622 participants will be randomly assigned on Day 1 (baseline) in a 1:1 ratio to 1 of 2 open-label 
study intervention arms (311 participants per arm). The randomization will be balanced by using randomly 
permuted blocks and will be stratified by age (18 to 64 years [inclusive]; 65 to 74 years [inclusive]) and 
total number of treatment failures (2; 3 or more [inclusive of current antidepressive treatment at screening 
used to determine eligibility]).


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Status: Approved,  Date: 8 October 2020
INTERVENTION GROUPS AND DURATION

Esketamine Arm: Participants will continue to take their current SSRI/SNRI in combination with 
esketamine nasal spray.
On Day 1, participants will have their first nasal treatment session. Adult participants aged 18 to 
64 years will start with a dose of 56 mg. Elderly participants aged 65 to 74 years and adults of Japanese 
ancestry will start with a dose of 28 mg. As of Day 4, the dose may be increased from 56 mg to 84 mg 
in adult participants, from 28 mg to 56 mg in elderly participants and adults of Japanese ancestry, or 
participants may remain at the starting dose, as determined by the investigator based on efficacy and 
tolerability. Elderly participants and adults of Japanese ancestry may be uptitrated in 28 mg increments 
at subsequent visits. The highest dose that may be used in all participants is 84 mg. Nasal treatment 
sessions will occur twice weekly during Week 1 to Week 4, once weekly during Week 5 to Week 8, 
and once weekly or every 2 weeks, as determined by the investigator based on efficacy and tolerability, 
during the maintenance phase (Week 9 to Week 32). Dosing may be increased at any visit, may remain 
the same, or may be reduced as determined by the investigator based on efficacy and tolerability. Nasal 
treatment sessions should not take place on 2 consecutive days. Esketamine nasal spray dosing and 
related safety-monitoring procedures MUST be performed LAST at all visits. Esketamine nasal spray 
must NOT be administered before all other visit assessments are completed. Food will be restricted 
for at least 2 hours before each administration of esketamine nasal spray. Drinking of any fluids will 
be restricted for at least 30 minutes before the first nasal spray at each session.

Comparator Arm: Participants will continue to take their current SSRI/SNRI which will be 
augmented with quetiapine XR as per the SmPC (or local equivalent, if applicable) starting on Day 1 
and will continue through Week 32. In adult participants aged 18 to 64 years, the initial dose of 
quetiapine XR is 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 [lowest effective dose]; a further 
dose increase to 300 mg/day as of Day 5 will be based on individual participant evaluation. In elderly 
participants aged 65 to 74 years, the initial dose is 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, 
and 150 mg/day on Day 8; a further dose increase to 300 mg/day will be based on individual participant 
evaluation no earlier than Day 22. If participants cannot tolerate at least 150 mg/day of quetiapine XR 
by the end of Week 2 (or at any subsequent time during the study), they must have quetiapine XR 
discontinued.

Continuing SSRI/SNRI: The continuing SSRI/SNRI being taken by a participant must be labeled for 
treatment of depression/MDD in their country of participation and the dosage being taken should be 
according to the respective SmPC (or local equivalent, if applicable). Off-label use of an SSRI/SNRI 
is not permitted.
The investigator may optimize the dose of the continuing SSRI/SNRI, up to the maximum tolerated 
dose as per the respective SmPC (or local equivalent, if applicable). Once optimized, a stable dose 
should be maintained; however, dose modifications may be made, if necessary, at the investigator’s 
discretion.  
The study intervention will be considered discontinued if either component of the randomized combination 
therapy (ie, esketamine nasal spray, quetiapine XR, or continuing SSRI/SNRI) is stopped. 

If esketamine nasal spray or quetiapine XR is discontinued at any time during the acute or maintenance 
phase, the participant will be switched to an alternative standard of care treatment, which may or may 
not include the continuing SSRI/SNRI, at the discretion of the investigator and continue follow-up 
visits through Week 32. If determined by the investigator that the alternative standard of care will 
include esketamine nasal spray (when commercially available in country of participation) or quetiapine 
XR for a participant, it will not be provided to the participant, rather, the investigator must prescribe 
the medication to the participant.


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
If the SSRI/SNRI is discontinued at any time during the acute or maintenance phase, the esketamine 
nasal spray or quetiapine XR must also be discontinued. The participant will be switched to an 
alternative standard of care treatment at the discretion of the investigator and continue follow-up visits 
through Week 32.
After participants have completed study intervention (Week 32), they should return to their primary 
physician to determine standard of care. In exceptional situations, where participants would not have access 
to commercially available esketamine nasal spray, those participants who, at the discretion of the 
investigator, could benefit from continuing treatment with esketamine nasal spray following their Week 32 
visit, will be advised on how continuation of treatment can be assured. Country-specific details on 
accessibility will be evaluated by the sponsor on a case-by-case basis considering, among others, regulatory 
and operational requirements.
Standard of care treatment after completion of the study is at the discretion of the investigator or primary 
physician; there is no requirement to change a participant’s standard of care treatment when they complete 
the study at Week 32.
EFFICACY EVALUATIONS
Efficacy will be assessed using clinician-rated scales (MADRS, CGI-S, and CGI-C) and patient-reported 
outcomes (PROs). As the MADRS is used to assess the primary and major secondary endpoints in the study, 
it must be performed by a qualified independent blinded rater.
All visit-specific PRO assessments (PHQ-9, QLDS, EQ-5D-5L, SF-36, SDS, and WPAI:D) should be 
conducted/completed before clinician-rated assessments, any tests (other than the urine drug screen at 
baseline visit [Day 1]; see Schedule of Activities), procedures, other consultations, or administration of 
esketamine nasal spray (in applicable participants) to prevent influencing participant perceptions.
BIOMARKERS AND PHARMACOGENOMIC (DNA AND RNA) EVALUATIONS
Blood samples will be collected for exploratory analysis of biomarkers (protein and metabolites) related to 
immune system activity, hypothalamic–pituitary–adrenal axis activation, neurotrophic and metabolic 
factors. Exploratory analyses may be performed for additional biomarkers as well. A pharmacogenomic 
blood sample will be collected to allow for pharmacogenomic (DNA and RNA) research (where local 
regulations permit). Biomarker and pharmacogenomic blood samples will only be collected at select study 
sites. Participation in the biomarker and pharmacogenomic research is optional for participants.
Details of the analysis plan and summary of results from both biomarker and pharmacogenomic analyses 
will be reported separately.
SAFETY EVALUATIONS
Safety assessments include the monitoring of AEs, physical/nasal examinations, measurement of body 
weight, vital sign measurements, clinical laboratory tests, electrocardiograms, and pregnancy testing. 
Suicide risk will also be assessed throughout the study using the C-SSRS.
For participants who discontinue study intervention early: (1) if their alternative standard of care treatment 
includes commercial esketamine or another Janssen medicinal product for depression, AEs will continue to 
be collected after completion of the safety follow-up visit; (2) if their alternative standard of care treatment 
does not include commercial esketamine or another Janssen medication for depression, AEs will not be 
systemically collected after completion of the safety follow-up visit. For AEs that are not systematically
collected (including AEs for Janssen medicinal products not indicated for depression) and where the 
participating physician considers there is at least a reasonable possibility of a causal relationship to a 
medicinal product (ie, spontaneous adverse drug reactions), the participating physician is requested to notify 
the manufacturer (ie, Janssen or other manufacturer) of the medicinal product or the appropriate 
regulatory/competent authority through the national spontaneous reporting system as soon as possible.


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STATISTICAL METHODS
Sample Size Calculation
For the primary endpoint, the assumptions are that the rate of remission for completers at the Week 8 visit 
is 50% in the esketamine arm and 35% in the comparator arm, and that the rate for participants who
discontinue study intervention between baseline and the Week 8 visit is 17.5% in both treatment arms (to 
be imputed as non-remitters). Combining these assumptions leads to an estimated remission rate at the 
Week 8 visit in non-responder imputation (NRI) analysis of 41.25% in the esketamine arm and 28.88% in 
the comparator arm. With a power of 90%, a 2-sided significance level of 0.05 and using chi-square test, a 
sample size of 311 participants per arm (622 participants in total) is needed to detect the difference between 
the study intervention arms.
For the key secondary endpoint, among participants who achieve remission at the Week 8 visit, a relapse 
rate of 30% is assumed for both study intervention arms and rates for participants who discontinue study 
intervention between the Week 8 and Week 32 visits (to be imputed as non-relapse-free after remission) is 
assumed to be 10% for the esketamine arm and 20% for the comparator arm. Combining these assumptions 
leads to an estimated rate of relapse-free after remission at the Week 32 visit in NRI analysis of 25.99% in 
the esketamine arm and 16.17% in the comparator arm. With a power of 80%, a 2-sided significance level 
of 0.05 and using a chi-square test, a sample size of 270 randomized participants per arm (540 participants 
in total) is needed to detect a difference between the study intervention arms.
When combining the 2 calculations above, a sample size of 311 participants per study intervention arm 
(622 participants in total) is needed to detect the difference between the study intervention arms with both 
a power of at least 90% on the primary endpoint and a power of 80% on the key secondary endpoint.
Efficacy Analyses
The efficacy analyses of data will be based on the full analysis set (ie, all participants who are randomized 
in the study). The rate of remission at the Week 8 visit (primary endpoint) and the rate of remission at the 
Week 8 visit without relapse up to the Week 32 visit (key secondary endpoint) will be tested between study 
intervention arms using a Cochran-Mantel-Haenszel (CMH) chi-square test adjusting for age (18 to 
64 years [inclusive]; 65 to 74 years [inclusive]) and total number of treatment failures (2; 3 or more). 
Participants will be considered as having a positive outcome on relapse-free after remission if they are in 
remission at the Week 8 visit and do not experience any relapse between the Week 8 and Week 32 visits. 
All other cases (participants not achieving remission at the Week 8 visit, or participants achieving remission 
at the Week 8 visit but experiencing a relapse between the Week 8 and Week 32 visits) will be considered 
as having a negative outcome. Both the primary and key secondary endpoints will be analyzed using a NRI 
approach, meaning that participants discontinuing study intervention will be considered as having a 
negative outcome (non-remission for the primary endpoint, non-relapse-free-remission for the key 
secondary endpoint). In sensitivity analyses, for participants who stopped study intervention, but are still 
followed in the study, no imputation will be performed, and their observed status will be used for the 
analyses.
For continuous/ordinal parameters (eg, MADRS, CGI-S, PHQ-9, EQ-5D-5L, SF-36, SDS, WPAI:D) 
descriptive statistics of the score or values and change from baseline will be provided for each study visit 
during the study for the full analysis set. For CGI-C descriptive statistics of the score will be provided for 
each study visit during the study for the full analysis set. Summaries of both observed and last observation 
carried forward (LOCF) data will be presented. The change from baseline at each visit will be analyzed 
using a mixed model for repeated measurements based on observed cases. The model will include 
baseline score as a covariate, and study intervention, stratification factors (age [18 to 64 years (inclusive); 
65 to 74 years (inclusive)] and total number of treatment failures [2; 3 or more]), visit, and visit-by-study-
intervention interaction as fixed effects. The change from baseline at each visit will also be analyzed using 
an analysis of covariance model including LOCF data with factors for treatment, stratification factors (age 
[18 to 64 years (inclusive); 65 to 74 years (inclusive)] and total number of treatment failures [2; 3 or more]) 


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and baseline score as a covariate. For all model approaches, least squares estimates of the treatment 
differences and 95% confidence intervals will be presented.
Additionally, for scales that have a minimum clinically important difference (MCID), the proportion of 
participants having improved by at least the MCID will be described at each visit and compared between 
study interventions using CMH chi-square test adjusting for age (18 to 64 years [inclusive]; 65 to 74 years 
[inclusive]) and total number of treatment failures (2; 3 or more). The same analysis will be conducted for 
the proportion of participants who deteriorate by at least the MCID. The MCIDs used in the analysis will 
be documented in the Statistical Analysis Plan.
Time to event parameters (eg, time to improvement by at least MCID) will be analyzed by the Kaplan-Meier 
method and study interventions will be compared using a 2-sided log-rank test for the full analysis set. Time 
to event will be summarized with median, 25th and 75th percentile (if estimable). Confidence intervals of 
25th, 50th, and 75th percentile of time to event will also be provided. Hazard ratios and their confidence 
intervals will be estimated using Cox proportional hazard models stratified by age (18 to 64 years 
[inclusive]; 65 to 74 years [inclusive]) and number of previous treatment failures (2; 3 or more).
Subgroup analyses will be performed for age (18 to 64 years [inclusive]; 65 to 74 years [inclusive]) and 
total number of treatment failures (2; 3 or more), as well as sex and severity of depression. Analysis by 
geographical region may also be provided.  
Safety Analyses
All safety analyses will be made on the Safety Population (ie, all randomized participants who take at least 
1 dose of study intervention).
Intervention-emergent AEs are AEs occurring or worsening in severity after the start of study intervention. 
All reported intervention-emergent AEs will be included in the analysis. For each AE, the percentage of 
participants who experience at least 1 occurrence of the given event will be summarized by intervention 
group. In addition, comparisons between intervention groups will be provided if appropriate.
Intervention-emergent AEs of special interest will be summarized separately grouped in the following 
Medical Dictionary for Regulatory Activities (MedDRA) based categories: sedation, dissociation, events 
suggestive of abuse potential, cystitis, hepatic impairment and suicidality (including suicidal ideation and 
behavior).


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1.2.
Schema
Abbreviations: CGI-C=Clinical Global Impression – Change; ESK=esketamine nasal spray; MDD=major depressive disorder; QTP XR=quetiapine extended-release; R=randomization; 
SmPC=Summary of Product Characteristics; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; W=week.
a
On Day 1, adult participants aged 18 to 64 years will start with a dose of 56 mg; elderly participants aged 65 to 74 years and adults of Japanese ancestry will start with a dose of 28 mg. 
As of Day 4, the dose may be increased from 56 mg to 84 mg in adult participants, from 28 mg to 56 mg in elderly participants and adults of Japanese ancestry, or participants may 
remain at the starting dose, as determined by the investigator based on efficacy and tolerability. Elderly participants and adults of Japanese ancestry may be uptitrated in 28 mg 
increments at subsequent visits. Dosing may be increased at any visit, may remain the same, or may be reduced as determined by the investigator based on efficacy and tolerability. 


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The highest dose that may be used in all participants is 84 mg. Based on the dosing frequency in the maintenance phase, the last nasal treatment session will occur at Week 30 (every 
2 weeks frequency) or Week 31 (once-weekly frequency).
b
The investigator may optimize the dose of the continuing SSRI/SNRI, up to the maximum tolerated dose as per the respective SmPC (or local equivalent, if applicable). Once 
optimized, a stable dose should be maintained; however, dose modifications may be made, if necessary, at the investigator’s discretion.
c
The treatment continuation assessment will be performed on all participants who are taking study intervention (ie, both components of the randomized combination therapy) and will 
be the basis for the decision to continue study intervention. If the study intervention is discontinued early, the CGI-C (ie, the basis of the treatment continuation assessment for the 
study interventions) will still be performed at time points noted in the Schedule of Activities; however, treatment decisions will be at the discretion of the investigator and not based on 
the criteria for the treatment continuation assessment.
d
Participants who discontinue the study intervention early (ie, discontinue either component of the randomized combination therapy) will remain in the study and continue to return for 
follow-up visits (every 2 weeks) through Week 32 unless study intervention is discontinued after the Week 30 visit, in which case participants must have the safety follow-up visit 
2 weeks after their last dose. 
e
If the SSRI/SNRI is discontinued at any time during the acute or maintenance phase, the esketamine nasal spray or quetiapine XR must also be discontinued. The participant will be 
switched to an alternative standard of care treatment at the discretion of the investigator. If esketamine nasal spray or quetiapine XR is discontinued at any time during the acute or 
maintenance phase, the participant will be switched to an alternative standard of care treatment, which may or may not include the continuing SSRI/SNRI, at the discretion of the 
investigator. If determined by the investigator that the alternative standard of care will include esketamine nasal spray (when commercially available in country of participation) or 
QTP XR, it will not be provided to the participant, rather, the investigator must prescribe the medication to the participant. Standard of care treatment after completion of the study is at 
the discretion of the investigator or treating physician; there is no requirement to change a participant's standard of care treatment when they complete the study at Week 32.
f
Quetiapine XR will be uptitrated (starting at 50 mg/day) as per the SmPC (or local equivalent, if applicable); dosing may be adapted as determined by the investigator based on 
efficacy and tolerability. Participants should be uptitrated to at least 150 mg/day according to the recommended uptitration schedule and based on individual tolerability no later than 
the Week 2 visit (ie, end of Week 2). If participants cannot tolerate at least 150 mg/day of QTP XR by the end of Week 2 (or at any subsequent time during the study), they must have 
QTP XR discontinued. Treatment discontinuation by gradual dose reduction over 1 to 2 weeks is recommended.






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Abbreviations: AD=antidepressant; C-SSRS=Columbia-Suicide Severity Rating Scale; CGI-C=Clinical Global Impression – Change; CGI-S=Clinical Global Impression – Severity; 
D=day; ECG=electrocardiogram; EQ-5D-5L=European Quality of Life Group, 5 Dimension, 5-Level (questionnaire); FT4=free thyroxine; IDS-C30=Inventory of Depressive 
Symptomatology Clinician-rated, 30-item scale; NSAIDs=non-steroidal anti-inflammatory drugs; MADRS=Montgomery-Asberg Depression Rating Scale; MINI=Mini International 
Neuropsychiatric Interview; PHQ-9=Patient Health Questionnaire, 9-item; PRO=patient-reported outcome; QLDS=Quality of Life in Depression Scale; QTP XR=quetiapine extended-
release; SDS=Sheehan Disability Scale; SF-36=36-item Short-Form Health Survey; SmPC=Summary of Product Characteristics; SNRI=serotonin-norepinephrine reuptake inhibitor; 
SSRI=selective serotonin reuptake inhibitor; TSH=thyroid stimulating hormone; W=week; WPAI:D=Work Productivity and Activity Impairment: Depression.
a
At the screening visit, all participants will be asked by the study staff to abstain from alcohol consumption for 24 hours before their baseline visit. All participants must restrict food 
and water intake from the time they arrive at the site for the baseline visit. Once eligibility is confirmed and participants are randomly assigned to a study intervention arm, only those 
participants randomly assigned to the esketamine arm will be required to continue to restrict food and water intake (until after dosing). If a participant is randomly assigned to the 
esketamine arm, the nasal treatment session must not be started until food has been restricted for at least 2 hours and water has been restricted for at least 30 minutes.
b
The investigator will evaluate any changes in the participants signs/symptoms of depression since the screening assessment and confirm that the inclusion criteria for the current AD 
treatment are still met (ie, nonresponse and minimal clinical improvement).
c
For women of childbearing potential, serum pregnancy test (central laboratory) only at screening; urine pregnancy test (at site/local) from baseline onwards. Counseling on pregnancy 
prevention will be provided at all visits, as applicable. 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 participation in the study.
d
The ECG does not need to be repeated at baseline if the screening ECG was performed within 1 week before the Day 1 visit.
e
Full nasal examination (including upper respiratory tract/throat) will be conducted at screening in all participants.
f
This test will be performed first on Day 1. If the urine drug screen is positive, the participant may have their Day 1 visit rescheduled 1 time, if negative on retest then the participant 
will be allowed to continue.
g
To minimize bias, psychotherapy has to be discussed with the participant prior to randomization.
h
Visit-specific PRO assessments should be conducted/completed before clinician-rated assessments, any tests, procedures, other consultations, or esketamine nasal spray administration 
(in applicable participants) to prevent influencing participant perceptions.
i
Must be performed prior to esketamine dosing in applicable participants (ie, randomly assigned to the esketamine arm).
j
The treatment continuation assessment will be performed on all participants who are taking study intervention (ie, both components of the randomized combination therapy) (see 
Section 4.1) and will be the basis for the decision to continue study intervention. If the study intervention is discontinued early, the CGI-C (ie, the basis of the treatment continuation 
assessment for the study interventions) will still be performed at follow-up visits (refer to the Maintenance Phase Schedule of Activities); however, treatment decisions will be at the 
discretion of the investigator and not based on the criteria for the treatment continuation assessment.
k
Blood samples should be collected in fasting condition (at least 8 hours fasting, water is permitted). If clinically relevant abnormal results are found in hematology, chemistry, or 
urinalysis tests, tests should be repeated more frequently at the discretion of the investigator. Additionally, required laboratory tests as recommended in the respective SSRI/SNRI
SmPC (or local equivalent, if applicable) should be performed.
l
Hematology, chemistry, and urinalysis tests do not need to be repeated at baseline if screening tests were performed within 1 week before the Day 1 visit.
m
Vital signs: blood pressure, pulse/heart rate, respiratory rate.
n
Vital signs will be measured at approximately 40 minutes after esketamine nasal spray dose and subsequently as clinically warranted until blood pressure values decline. Participants 
must be monitored by a healthcare professional until the participant is considered clinically stable and ready to leave the study site. If blood pressure remains elevated for a prolonged 
period of time, assistance should promptly be sought from practitioners experienced in blood pressure management. Participants who experience symptoms of a hypertensive crisis 
should be referred immediately for emergency care.
o
Visual inspection of nostrils, nasal mucosa, and throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption, and epistaxis.
p
If participants cannot tolerate at least 150 mg/day of QTP XR by the end of Week 2 (or at any subsequent time during the study), they must have QTP XR discontinued. Treatment 
discontinuation by gradual dose reduction over 1 to 2 weeks is recommended.
q
Quetiapine XR will be dispensed at the Day 1 visit and then as necessary at subsequent visits based on a participant’s dose. If necessary, participants may need to return for an 
unscheduled visit to allow for dispensing of a new supply of quetiapine XR to accommodate changes in dosing.
r
Nasal treatment sessions should not take place on 2 consecutive days. If the participant has nasal congestion on the dosing day, a nasal decongestant can be used (but not within 1 hour 
before esketamine dosing) to reduce congestion or the dosing day can be delayed (per the permitted visit window).
s
Esketamine nasal spray dosing and related safety-monitoring procedures MUST be performed LAST at all visits. Esketamine nasal spray must NOT be administered before all other 
visit assessments are completed.
t
The frequency of nasal treatment sessions may be individualized from once weekly to every 2 weeks based on severity of depressive symptoms and at the discretion of the investigator. 
The next visit (ie, in the maintenance phase) will be at Week 9 if frequency remains once weekly or at Week 10 for participants who have their frequency changed to every 2 weeks at 
Week 8.


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u
If possible, blood samples should be collected under fasting conditions (minimum 8 hours prior to biomarker sample collection, water is permitted). Participants should refrain from 
exercise/strenuous physical activity and the use of NSAIDs for 24 hours prior to blood collection. Not following these recommendations will not constitute a protocol violation.
v
If a participant is switched to an alternative standard of care treatment prior to Week 8, the blood sample for biomarker evaluation and menstrual cycle information should be collected 
at the visit when the switch is made.
w
Prestudy non-AD therapies administered up to 30 days before screening must be recorded.






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Abbreviations: C-SSRS=Columbia-Suicide Severity Rating Scale; CGI-C=Clinical Global Impression – Change; CGI-S=Clinical Global Impression – Severity; ECG=electrocardiogram;
EQ-5D-5L=European Quality of Life Group, 5 dimension, 5-level (questionnaire); MADRS=Montgomery-Asberg Depression Rating Scale; NSAIDs=non-steroidal anti-inflammatory 
drugs; PHQ-9=Patient Health Questionnaire – 9; PRO=patient-reported outcome; QLDS=Quality of Life in Depression Scale; QTP XR=quetiapine extended-release; SDS=Sheehan 
Disability Scale; SF-36=36-item Short-Form Health Survey; SmPC=Summary of Product Characteristics; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotonin 
reuptake inhibitor; WPAI:D=Work Productivity and Activity Impairment: Depression.
a
Participants who discontinue the study intervention early (ie, discontinue either component of the randomized combination therapy) will remain in the study and continue to return for 
all follow-up visits after early study intervention discontinuation. For these participants, the first 2-week follow-up visit must include any additional assessments listed for the safety 
follow-up visit that are not included in this column. The last visit for these participants will be Week 32.
b
Participants who withdraw early from the study must have the early study withdrawal visit performed within 1 week of the date of withdrawal and then return for the safety follow-up 
visit 2 weeks after their last dose of study intervention, unless they withdraw consent. If the early study withdrawal visit is conducted on the same day as a scheduled visit, duplicate 
assessments are not required. 
c
For participants in the esketamine arm, the safety follow-up visit will be performed 2 weeks after the last nasal treatment session. In participants with a dosing frequency of every 
2 weeks, this visit will be at Week 32, and for participants with a dosing frequency of once weekly, this visit will be at Week 33.
d
For participants in the comparator arm who complete the study through Week 32, the safety follow-up visit will be performed 2 weeks after the last dose of study intervention 
(ie, QTP XR in combination with a continuing SSRI/SNRI) was taken during the study.
e
Visit-specific PRO assessments should be conducted/completed before clinician-rated assessments, any tests, procedures, other consultations, or esketamine nasal spray administration 
(in applicable participants) to prevent influencing participant perceptions.
f
Must be performed prior to esketamine dosing in applicable participants (ie, randomly assigned to the esketamine arm).
g
The treatment continuation assessment will be performed on all participants who are taking study intervention (ie, both components of the randomized combination therapy) (see 
Section 4.1) and will be the basis for the decision to continue study intervention. If the study intervention is discontinued early, the CGI-C (ie, the basis of the treatment continuation
assessment for the study interventions) will still be performed at follow-up visits; however, treatment decisions will be at the discretion of the investigator and not based on the criteria 
for the treatment continuation assessment.
h
Blood samples should be collected in fasting condition (at least 8 hours fasting, water is permitted). If clinically relevant abnormal results are found in hematology, chemistry, or 
urinalysis tests, tests should be repeated more frequently at the discretion of the investigator. Additionally, required laboratory tests as recommended in the respective SSRI/SNRI
SmPC (or local equivalent, if applicable) should be performed.
i
Urine pregnancy testing (at site/local) for women of childbearing potential. Counseling on pregnancy prevention will be provided at all visits, if applicable. 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 
participation in the study.
j
Vital signs: blood pressure, pulse/heart rate, respiratory rate.
k
At Week 32 and at the safety follow-up visit (no esketamine nasal spray dose), vital signs will be performed according to usual practice and nasal examination as described below will
be performed.
l
Visual inspection of nostrils, nasal mucosa, and throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption, and epistaxis.
m
Vital signs will be measured at approximately 40 minutes after esketamine nasal spray dose and subsequently as clinically warranted until blood pressure values decline. Participants 
must be monitored by a healthcare professional until the participant is considered clinically stable and ready to leave the study site. If blood pressure remains elevated for a prolonged 
period of time, assistance should promptly be sought from practitioners experienced in blood pressure management. Participants who experience symptoms of a hypertensive crisis 
should be referred immediately for emergency care.
n
If participants cannot tolerate at least 150 mg/day of QTP XR during the maintenance phase, they must have QTP XR discontinued. Treatment discontinuation by gradual dose 
reduction over 1 to 2 weeks is recommended.
o
Quetiapine XR will be dispensed as necessary at visits based on a participant’s dose. If necessary, participants may need to return for an unscheduled visit to allow for dispensing of a 
new supply of quetiapine XR to accommodate changes in dosing.
p
If the participant has nasal congestion on the dosing day, a nasal decongestant can be used to reduce congestion (but not within 1 hour before esketamine dosing) or the dosing day can 
be delayed (per the permitted visit window). 
q
Esketamine nasal spray dosing and related safety-monitoring procedures MUST be performed LAST at all visits. Esketamine nasal spray must NOT be administered before all other 
visit assessments are completed.


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r
The frequency of nasal treatment sessions may be individualized on even week visits from once weekly to every 2 weeks based on severity of depressive symptoms and at the 
discretion of the investigator. If participants show early signs of worsening of depressive symptoms after reduced treatment frequency, the treatment frequency can be changed back to 
once weekly at any visit.
s
If possible, blood samples should be collected under fasting conditions (minimum 8 hours prior to biomarker sample collection, water is permitted). Participants should refrain from 
exercise/strenuous physical activity and the use of NSAIDs for 24 hours prior to blood collection. Not following these recommendations will not constitute a protocol violation.
t
Only if a participant withdraws from the study at or prior to Week 8.
u
For participants who discontinue study intervention early: (1) if their alternative standard of care treatment includes commercial esketamine or another Janssen medicinal product for 
depression, AEs will continue to be collected after completion of the safety follow-up visit; (2) if their alternative standard of care treatment does not include commercial esketamine 
or another Janssen medication for depression, AEs will not be systemically collected after completion of the safety follow-up visit. For AEs that are not systematically collected 
(including AEs for Janssen medicinal products not indicated for depression) and where the participating physician considers there is at least a reasonable possibility of a causal 
relationship to a medicinal product (ie, spontaneous adverse drug reactions), the participating physician is requested to notify the manufacturer (ie, Janssen or other manufacturer) of 
the medicinal product or the appropriate regulatory/competent authority through the national spontaneous reporting system as soon as possible.


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2.
INTRODUCTION
The mechanism of action of ketamine is distinct from conventional antidepressants (ADs), which 
target the monoamines (serotonin, norepinephrine, and/or dopamine). Ketamine affects fast 
excitatory glutamate transmission.8 Antidepressant effects may relate to increased brain-derived 
neurotrophic factor release and synaptogenesis.
Esketamine, the S-enantiomer of ketamine, is approved and widely used for the induction and 
maintenance of anesthesia via intramuscular or intravenous (IV) administration.
Because of the higher N-methyl-D-aspartate (NMDA) receptor affinity of esketamine over 
arketamine (R-enantiomer of ketamine), Janssen Research & Development is developing 
esketamine (not the racemate) for AD therapy. Moreover, intranasal administration was 
investigated instead of IV administration, since intranasal administration can offer better 
convenience for patients and fewer errors in dosing, and esketamine can be rapidly and well 
absorbed via the intranasal route.4,23 Esketamine nasal spray was approved by the United States 
Food and Drug Administration (FDA) on 5 March 2019 for use in conjunction with an oral AD to 
treat adults with treatment-resistant depression (TRD); and is under development in other countries 
for patients with TRD and with major depressive disorder (MDD) with current suicidal ideation 
with intent. A Marketing Authorisation Application was approved by European Medicines Agency 
in December 2019 for esketamine nasal spray in adults with treatment-resistant MDD (also 
referred to as TRD) who have not responded to at least 2 different treatments with ADs in the 
current moderate to severe depressive episode. It must be administered in combination with an oral
AD from the selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake 
inhibitor (SNRI) classes.
For the most comprehensive nonclinical and clinical information regarding esketamine 
(JNJ-54135419), refer to the latest edition of the Investigator’s Brochure (IB).15
The term “sponsor” used throughout this document refers to the Janssen entities listed in the 
Contact Information page(s), which will be provided as a separate document.
The term “participant” throughout the protocol refers to the common term “subject”.
The term “study intervention” throughout the protocol refers to the combination product: 
esketamine nasal spray in combination with a continuing SSRI/SNRI or a continuing SSRI/SNRI
augmented with quetiapine extended-release (XR), as defined in Section 6.1, Study Interventions 
Administered. The study intervention will be considered discontinued if either component of the 
randomized combination therapy is stopped.
In the text of this document, Studies ESKETINTRDxxxx (eg, ESKETINTRD3001) and 
54135419TRDxxxx (eg, 54135419TRD3008) are abbreviated as TRDxxxx.


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2.1.
Study Rationale 
Depression is a major cause of morbidity and mortality, with global estimates of 300 million 
treated and untreated individuals worldwide. In its severe forms, depression is the most common 
diagnosis associated with suicide, a leading cause of death among 15- to 29-year-olds, and is one 
of the top 10 causes of disability and years lost to disability in young and middle-aged adults.1 A 
depressive state with classical symptoms such as low (depressive/sad) mood, markedly diminished 
interest in activities, significant weight loss/gain, insomnia or hypersomnia, psychomotor 
agitation/retardation, excessive fatigue, inappropriate guilt, diminished concentration, and 
recurrent thoughts of death, persisting for more than 2 weeks is classified as MDD.
Despite the years of research in depressive disorders, it remains a heterogenous disease with a host 
of genetic and physiological mechanisms warranting individualized treatment.1 It is estimated that 
10% to 15% of patients suffering from depression will have insufficient or no response to clinical 
intervention and retain a significant mortality risk by suicide. This is a part of a larger problem of 
partial or relative response to intervention in 50% to 70% of patients undergoing antidepressive 
treatment. Different definitions and staging exist for patients with TRD.3,5,9
There is a significant unmet need to develop novel AD treatments based on the relevant 
psychophysiological pathways underlying MDD. The goal of any novel treatment would be the 
rapid and long-lasting relief of depressive symptoms, especially in patients with TRD, who lack a 
sufficient response to the currently available treatment strategies. These patients are primarily 
treated by dose optimization, augmentation/combination therapies, and switching therapies.
Data from a Phase 3 study (TRD3004) of esketamine nasal spray in combination with a newly 
initiated SSRI/SNRI in participants with TRD showed improvements in depressive symptoms over 
the 4-week induction phase that appeared to be sustained in those participants who continued 
treatment for up to 1 year. The improvements with esketamine nasal spray in combination with a
newly initiated SSRI/SNRI were in the range of the previous Phase 2 and Phase 3 short-term 
studies (TRD2003, TRD3001, and TRD3002). Additionally, in a relapse prevention study
(TRD3003) that used a randomized withdrawal design in the context of continuing SSRI/SNRI
treatment, a statistically significantly longer time to relapse was observed with continued 
esketamine treatment relative to discontinuation of esketamine in adult participants with TRD who 
had achieved stable remission (or stable response) of their depression symptoms during 16 weeks 
of treatment with esketamine in combination with an SSRI/SNRI.
The evaluation of esketamine in an elderly population (aged 65 to 74 years) is important as TRD 
in this population is more severe5 and less responsive to treatment. Furthermore, treatment of 
depression in the elderly is challenging as patients not only commonly suffer from disability, 
functional decline, and diminished quality of life from TRD, but also as a consequence of comorbid 
medical conditions.17 In a study in elderly patients (TRD3005), there was an estimated treatment 
difference in the Montgomery-Asberg Depression Rating Scale (MADRS) change from baseline 
of -3.6. Although this change was not statistically significant, it suggests a clinically meaningful 
benefit in this vulnerable and difficult-to-treat elderly population with TRD who were started at 
28 mg and could be titrated to 56 or 84 mg as clinically appropriate. Additionally, results showed 


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a clinically meaningful treatment difference (a difference of -4.9 in the change from baseline in 
MADRS total score at Day 28) for participants aged 65 to 74 years favoring esketamine in 
combination with a newly initiated SSRI/SNRI. Treatment differences observed in the 65 to 74 
years subgroup were comparable to MADRS results observed in the adult populations (18 to 64 
years) in other Phase 3 studies of esketamine. 
In the current study, participants will be included who are aged 18 to 74 years (inclusive). To 
complement the Phase 3 program and to generate clinical data for esketamine nasal spray taken by 
patients who are continuing their current SSRI/SNRI following the esketamine nasal spray label 
for the indication of TRD, this study will evaluate the efficacy, safety, and tolerability of flexibly 
dosed esketamine nasal spray compared with quetiapine XR, both in combination with a 
continuing SSRI/SNRI, in adult and elderly participants who have treatment-resistant MDD with 
a current moderate to severe depressive episode. This study has both a short-term (8-week primary 
efficacy endpoint) and long-term (24-week post primary efficacy endpoint) treatment period.
2.2.
Background
The following sections detail the nonclinical and clinical profile of esketamine. Further details on 
pharmacologic profile and safety of racemic ketamine can be found in the IB.15
2.2.1.
Pharmacologic Profile
Excitatory synaptic transmission in the central nervous system is primarily mediated by ionotropic 
glutamate receptors such as NMDA which require glutamate and D-serine and membrane 
depolarization for opening and allowing influx of calcium. Ketamine acts as a non-competitive, 
subtype nonselective, activity-dependent NMDA receptor antagonist functioning at the 
phencyclidine (PCP) binding site and enters the channel, blocking further calcium influx. Among 
ketamine enantiomers and their metabolites (including norketamine, hydroxynorketamine, and 
dehydronorketamine), esketamine is the most potent NMDA receptor antagonist.
2.2.2.
Nonclinical Studies
In repeat-dose toxicity studies, no adverse effects were noted with nasal esketamine up to the 
highest dose tested in rats (9 mg/day) and in dogs (72 mg/day). Although heart rate was slightly 
increased in dogs, no relevant electrocardiogram (ECG) changes were observed. Minor, 
non-adverse histologic findings were noted in the nasal cavity. Following nasal administration, a 
fraction of the dose is orally absorbed. Two in vivo assays (rat bone marrow and liver cells), 
conducted with esketamine HCl at dose levels up to the maximum tolerated dose, showed no 
evidence of genotoxic potential. The potential formation of N-nitroso-esketamine in simulated 
gastric fluid was evaluated. The equivalent of a full human dose orally ingested did not lead to the 
formation of N-nitroso-esketamine. Consequently, the (partial) oral absorption of esketamine 
following intranasal dosing does not pose a genotoxic risk. Repeated-dose neurotoxicity studies in 
juvenile rats and dogs did not cause brain lesions even at high exposures, consequently, the risk of 
neurotoxicity associated with nasal administration of esketamine to juvenile and adult patients is 
low. Intranasally administered ketamine or esketamine did not affect fertility, early embryonic 
development, and pre- and postnatal development in rats. When pregnant rabbits were treated with 
ketamine at maternally toxic dose levels, skeletal malformations were noted in the offspring. There 


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may be a relationship to ketamine treatment. Considering the published evidence on the 
developmental neurotoxicity potential of ketamine in animals during pregnancy and in early 
postnatal rodent pups, a similar risk with esketamine to humans cannot be excluded.
In summary, currently available nonclinical safety studies support chronic nasal administration of 
esketamine in human participants up to a dosage of 84 mg/day. Further details on the nonclinical 
profile of esketamine and nasal esketamine can be found in the IB.15
2.2.3.
Clinical Studies
The clinical program for esketamine includes: a comprehensive clinical pharmacology program in 
healthy volunteers and special populations to fully characterize the product’s pharmacokinetic and 
pharmacodynamic activity, including Phase 2 studies with IV esketamine and ketamine; a Phase 2 
dose response study in adults with TRD; a Phase 2 proof-of-concept study in the related condition 
of MDD with imminent risk for suicide; and data from 5 completed Phase 3 studies establishing 
efficacy and safety in adults with TRD, including those 65 years and older. Results from 1 ongoing 
Phase 2 study and 2 ongoing Phase 3 studies in adults with TRD are not available at the time of 
finalization of this protocol.
2.2.3.1.
Metabolism and Excretion
Esketamine undergoes extensive metabolism by human hepatic cytochrome P450 (CYP). 
Demethylation of esketamine to noresketamine (M10) is the initial, but not the primary metabolite, 
as multiple downstream metabolites are formed. Minor secondary pathways are produced by 
oxidation of the cyclohexanone moiety (M2, M4, and M5), oxidative deamination (M11), and 
keto-reduction of M10 (M12). In addition, traces of oxidation of the cyclohexanone moiety of 
esketamine (M6) has been observed. The major human hepatic cytochromes that catalyze 
esketamine N-demethylation in vitro were CYP2B6 and CYP3A4. The cytochrome enzymes 
responsible for the formation of norketamine metabolites include CYP2A6 and CYP2B6.
Following oral administration of radiolabeled esketamine, approximately 86% and 2% of 
administered radioactivity was recovered in urine and feces, respectively. The recovered 
radioactivity consisted primarily of esketamine metabolites. For the IV and oral routes of 
administration, <1% of the dose was excreted in the urine as unchanged drug.
2.2.3.2.
Pharmacokinetics
The mean absolute bioavailability of nasally administered esketamine is approximately 48%. 
Esketamine is rapidly absorbed through the nasal mucosa following administration as a nasal spray 
with measurable concentrations in plasma at 7 minutes after the first spray. The maximum plasma 
concentration (Cmax) of esketamine is typically observed at approximately 20 to 40 minutes after 
the last nasal spray of a given dose. Mean Cmax and area under the plasma concentration-time curve 
(AUC) values increase with dose from 28 mg to 84 mg. The increases were less than dose 
proportional between 28 mg and 56 mg or 84 mg, but nearly dose proportional between 56 mg and 
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The pharmacokinetic results of Janssen sponsored clinical studies for nasally administered 
esketamine are summarized below:

Studies in Asian populations: In Study TRD1008, mean plasma esketamine Cmax and area 
under the plasma concentration-time curve from time 0 to infinity (AUCvalues produced 
by a 56-mg dose administered as a nasal spray were approximately 14% and 33% higher, 
respectively, in Chinese participants compared with white participants. Both parameters were 
approximately 40% higher in Japanese participants, compared with white participants. On 
average, esketamine Cmax was 10% lower and AUCwas 17% higher in Korean participants, 
relative to white participants. In Study TRD1002, the mean plasma esketamine Cmax and 
AUCvalues produced by 28 mg, 56 mg, and 84 mg of intranasal esketamine were higher in 
Japanese participants as compared with white participants, consistent with results from 
Study TRD1008. The mean plasma esketamine concentrations at 40 minutes to 6 hours 
postdose in Japanese participants in Study TRD2003 were higher relative to the corresponding 
concentrations following the same esketamine dose self-administered by non-Japanese 
participants from the United States and Belgium, consistent with results from the Phase 1 
studies.

Elderly (65 years of age) and younger adults (18 to ≤55 years of age): In single, 
self-administered dose studies using 28 mg (TRD1003) and 84 mg (TRD1012) of esketamine, 
the geometric means of Cmax and AUCwere up to 21% and 18% higher, respectively, for the 
28 mg dose and up to 67% and 38% higher, respectively, for the 84 mg dose, in the elderly 
compared with the younger adult participants. In both studies, the decline in the esketamine 
concentrations was similar in the elderly and young adult participants. Mean plasma 
esketamine Cmax and AUCvalues following 28 to 84 mg of intranasal esketamine were 
higher in elderly Japanese participants as compared with younger adult Japanese participants
(TRD1018).

Hepatic impairment: In Study TRD1011, the mean Cmax and AUCof esketamine following 
a 28-mg nasal dose were 8% and 14% higher, respectively, in participants with mild hepatic 
impairment (Child-Pugh score 5 and 6, Class A), compared with healthy participants. In 
moderately hepatically impaired participants (Child-Pugh score 7 to 9, Class B), the Cmax and 
AUCof esketamine were 8% and 103% higher, respectively, compared to healthy 
participants. Small differences with no clear trend were observed in the apparent terminal 
half-life of esketamine across the 3 cohorts (13.1 to 18.7 hours). The pharmacokinetics of 
esketamine in participants with severe hepatic impairment was not investigated.

Renal Impairment: In Study TRD1014, no clinically meaningful effect on pharmacokinetics 
of esketamine (28-mg nasal dose) was observed in participants with mild to severe renal 
impairment relative to the participants with normal renal function (creatinine clearance 
[CLCR], 88 to 140 mL/min). The Cmax of esketamine was on average 20% to 26% higher 
following administration of a 28-mg dose of esketamine in participants with mild (CLCR, 58 to 
77 mL/min), moderate (CLCR, 30 to 47 mL/min), or severe (CLCR, 5 to 28 mL/min, not on 
dialysis) renal impairment. The AUCwas 13% to 36% higher in the participants with mild 
to severe renal impairment. The half-life of esketamine ranged between 11.0 and 16.3 hours 
and did not appear to be related to renal function.

Allergic rhinitis: The pharmacokinetic profiles of nasal esketamine in participants with 
allergic rhinitis who were exposed to grass pollen prior to dosing and in healthy participants
are similar.


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
Participants with TRD: At corresponding intranasal esketamine doses and timepoints, the 
mean plasma esketamine concentrations in samples collected in the Phase 2 and 3 studies were 
similar to the range of mean plasma esketamine concentrations in samples collected in the 
Phase 1 studies.

Effects of potent inducers and inhibitors of hepatic CYP: On average, the Cmax and AUC
of an intranasal dose of esketamine were approximately 17% and 28% lower, respectively, 
when participants were pretreated with rifampin (an inducer of CYP3A4 and CYP2B6 
activity). On average, the Cmax and AUCof an intranasal dose of esketamine were increased 
by <11% when participants were pretreated with clarithromycin (a potent inhibitor of hepatic 
CYP3A activity), and the decline in plasma concentrations (ie, half-life) of esketamine was 
not affected by clarithromycin pretreatment. Pretreatment with oral ticlopidine, an inhibitor 
of hepatic CYP2B6 activity, had no effect on the Cmax of nasally administered esketamine, the 
AUCof esketamine was increased by approximately 29%, and there was no effect on 
terminal half-life of esketamine.

Intranasal drug-drug interactions: Daily administration of intranasal mometasone furoate 
(with the last dose given 1 hour prior to intranasal esketamine) did not affect the 
pharmacokinetics of esketamine in healthy participants. In addition, pretreatment with 
intranasal oxymetazoline HCl (1 hour prior to intranasal esketamine) did not affect the 
pharmacokinetics of esketamine in participants with allergic rhinitis. These results indicate 
that participants should wait for at least 1 hour after using an intranasal decongestant or 
corticosteroid before self-administering esketamine.
2.2.3.3.
Pharmacodynamics and Efficacy
Efficacy of IV esketamine at 0.20 mg/kg and 0.40 mg/kg doses given over 40 minutes for TRD 
was established in the ESKETIVTRD2001 study. The proportion of responders (reduction in 
MADRS total score by 50% from baseline [Day 1] on Day 2, 3, or 4 [prior to dosing]) was 66.7% 
and 63.6% in the esketamine 0.20 mg/kg group and esketamine 0.40 mg/kg group, respectively, 
compared with no responders in the placebo group. The onset of a therapeutic effect was noted at 
2 hours after the infusion for both 0.20 mg/kg and 0.40 mg/kg of esketamine, which was sustained 
with repeated dosing through to the end of the study.
Intranasal esketamine 56 and 84 mg achieved similar concentration as the 0.2 mg/kg IV dose and 
therefore could have similar efficacy. This was investigated in the double-blind phase of the 
TRD2003 study in non-Japanese participants with TRD. Intranasal esketamine had a rapid onset 
of effect within 24 hours, and repeated treatment sessions sustained the response throughout the 
study duration. A clear dose response was observed for the 28 mg, 56 mg, and 84 mg doses. While 
the change in MADRS total score for the 28 mg dose was statistically significant, the magnitude 
of effect was small. The AD effect for the 84 mg dose was sustained with twice-weekly dosing 
and the 56-mg dose effect was less well sustained. The AD effect for the 28 mg dose was the least 
well sustained with twice weekly dosing. Investigation of efficacy and safety of 14 mg dose group 
was completed in Japan.
Based on the efficacy and safety data from the TRD2003 study, the efficacy and safety of intranasal 
esketamine was further investigated in Phase 3 short-term studies in adults 18 to 64 years of age 
with TRD (TRD3001 [fixed doses of 56 mg or 84 mg] and TRD3002 [flexible doses of 56 mg or 


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84 mg]) and in elderly adults ≥65 years of age with TRD (TRD3005 [flexible doses of 28 mg, 
56 mg, or 84 mg]). Esketamine, administered in combination with a newly initiated SSRI/SNRI, 
demonstrated robust and statistically significant relief of symptoms of depression in 
Study TRD3002 in participants with TRD who had not responded to 2 or more ADs for their 
current depression episode. Results in this Phase 3 study were consistent with those for the 
placebo-controlled Phase 2 adjunctive study (TRD2003) in showing a rapid onset of efficacy. 
Based on flexible dose Study TRD3002, clinical improvement with esketamine was observed as 
early as 24 hours and generally increased in subsequent weeks, with the full AD effect observed 
by the end of Week 4. Although not achieving statistical significance, results of similarly designed 
Phase 3 studies in adult (TRD3001) and elderly (TRD3005) participants with TRD numerically 
favored the esketamine administered in combination with a newly initiated SSRI/SNRI group. In 
addition, in Studies TRD3001 and TRD3002, results numerically favored esketamine administered 
in combination with a newly initiated SSRI/SNRI for the efficacy measure of onset of response by 
Day 2.
In the long-term relapse-prevention study (TRD3003; using a randomized withdrawal design in 
the context of newly initiated SSRI/SNRI treatment), the efficacy of intranasal esketamine at 
flexible doses (56 mg or 84 mg) was assessed in adult participants with TRD. Results demonstrated 
that a statistically significantly longer time to relapse was observed with continued esketamine 
treatment relative to discontinuation of esketamine in participants who had achieved stable 
remission (or stable response) of their depression symptoms during 16 weeks of treatment with 
esketamine in combination with a newly initiated SSRI/SNRI. Relapse events occurred during the 
maintenance phase for 26.7% of participants in the esketamine in combination with a newly 
initiated SSRI/SNRI group and 45.3% of participants in the newly initiated SSRI/SNRI in 
combination with placebo group; this result indicated that relapse was, on average, 51% less likely 
for stable remitters who continued treatment with esketamine than for those who switched to 
placebo.
Data from the long-term safety and efficacy Study TRD3004 (flexible doses of 28 mg, 56 mg, or 
84 mg of intranasal esketamine) were consistent with long-term symptom improvements during 
up to 1 year of treatment with esketamine in combination with a newly initiated SSRI/SNRI in 
participants with TRD, although interpretation of the efficacy results from this study is limited 
since this was an unblinded and uncontrolled study. The improvements in measures of depression 
were consistent across multiple assessments of depressive symptoms over the 4-week induction 
phase and appeared to be sustained in participants who continued treatment up to the 1-year 
exposure. The improvements observed with esketamine administered in combination with a newly 
initiated SSRI/SNRI were in the range of the previous Phase 2 and Phase 3 short-term studies, 
although caution is needed in interpreting the results of Study TRD3004, given the absence of a 
control arm and given that participants were unblinded.
In addition, results from Study ESKETINSUI2001 supported the hypothesis that 84 mg of 
intranasal esketamine is an efficacious treatment for the rapid reduction of the symptoms of MDD, 
including suicidal ideation, in participants assessed to be at imminent risk for suicide. The 
participants included in this study were severely depressed and suicidal as evidenced by their high 


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baseline MADRS and Clinical Global Judgment of Suicide Risk (a module of the clinician-rated 
Suicide Ideation and Behavior Assessment Tool) scores. All participants received comprehensive 
treatment with initial hospitalization and optimized standard of care AD medication. Despite some 
non-specific improvement in the placebo group, the beneficial effect of esketamine on the 
symptoms of MDD, as measured by the MADRS total score and the MADRS suicidality item, 
could be distinguished at early time points as well as at the double-blind endpoint (Day 25).
2.2.3.4.
Safety Studies
As of 1 April 2019, the estimated cumulative number of participants exposed to esketamine in 
clinical trials (including healthy and special population [eg, renal and hepatic impairment but not 
with TRD or MDD] participants) was 2,955 (627 participants from Phase 1 program, 
295 participants from Phase 2 program and approximately 2,033 participants from Phase 3 
program). Key safety observations from this program are identified below.

The safety profile of esketamine is well characterized and tolerable with manageable risks. 
Over the proposed therapeutic dose range for use in a TRD population (28 to 84 mg), most 
intervention-emergent adverse events (AEs) with esketamine occur shortly after dosing, when 
participants will be under the supervision of a health care professional, are transient, and 
resolve on the same day. Transient postdose symptoms were consistent with findings from the 
Phase 1 and 2a esketamine IV studies and were expected based on the pharmacologic profile. 
No new safety concerns associated with esketamine treatment were identified in Phase 2 and 
3 studies.

The most commonly observed adverse drug reactions in TRD patients treated with esketamine 
in combination with a newly initiated SSRI/SNRI in Phase 2 and Phase 3 studies (incidence 
≥10% and greater than in the newly initiated SSRI/SNRI in combination with placebo group) 
were dissociation, dizziness, nausea, sedation, headache, vertigo, dysgeusia, hypoesthesia, 
anxiety, blood pressure increased, and vomiting.

Several of the more common adverse effects of esketamine, including dissociative 
symptoms/perceptual changes, dizziness/vertigo, and anxiety, occurred on the day of dosing 
and resolved the same day. Dissociative symptoms/perceptual changes attenuated with 
continued treatment.

The long-term safety profile of esketamine after continued treatment of up to 1 year was 
characterized in an uncontrolled, open-label study (TRD3004) of 802 participants (691 adults 
and 111 elderly [≥65 years of age]) with TRD. There were no new AEs reported with 
long-term repeated, intermittent weekly or every-other week dosing of esketamine (28, 56, or 
84 mg) (following a 4-week induction phase of twice-weekly dosing) over a duration of up to 
1 year.

Among the 1,708 participants treated with esketamine across the completed Phase 2 and 3 
studies in TRD, there were 4 deaths, including 2 completed suicides. In the ongoing 
esketamine studies, 4 additional deaths have been reported through 1 April 2019. In the 
ongoing long-term open-label safety extension Phase 3 study (TRD3008), 3 deaths (completed 
suicide, myocardial infarction, and death due to multiple injuries from car accident) were 
reported in esketamine-treated participants and 1 death (completed suicide) was reported in 
the ongoing MDD with imminent risk for suicide study (54135419SUI3001) in the 
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
Discontinuation of esketamine treatment due to intervention-emergent AEs was uncommon 
across all clinical studies and tended to be highest early in the course of treatment. With 
long-term treatment of up to 1 year, <10% of treated participants in the open-label long-term 
safety study (TRD3004)
experienced intervention-emergent AEs
that necessitated 
discontinuation of esketamine.

Overall, across Phase 2 and 3 TRD studies, suicidality-related events were reported at a 
frequency of ~1% to 5%, and most of the reported cases were those of suicidal ideation. Severe 
suicidality-related intervention-emergent AEs were reported at a low incidence (<1% for 
individual PTs) in each of the Phase 2 and 3 studies. Clinical review of suicidality-related 
intervention-emergent AEs indicated that most of these events were likely associated with the 
underlying disease.

The majority of participants who were administered esketamine experienced dissociative 
symptoms as assessed by the Clinician-Administered Dissociative States Scale. The 
symptoms peaked at around 40 minutes from the time of esketamine nasal spray 
administration and typically resolved by 2 to 4 hours after dosing. Across completed Phase 2 
and 3 studies, consistent with the observations captured in the Clinician-Administered 
Dissociative States Scale, median duration of the intervention-emergent AEs of dissociation, 
feeling abnormal, and feeling drunk across dosing sessions did not exceed 2 hours. 
Dissociation was reported as severe in intensity at an incidence of less than 4% across studies, 
was not considered serious for any participants in completed Phase 2 and 3 studies, and rarely 
led to discontinuation of study intervention. Transient dissociative/perceptual changes were 
more pronounced in participants receiving higher doses of esketamine.

Transient, primarily asymptomatic, increases in systolic and diastolic blood pressure (SBP 
and DBP) were observed following administration of esketamine nasal spray, with maximum 
mean changes typically observed within 40 minutes of dosing (consistent with peak plasma 
elevations) and mean blood pressure values returning to, or close to, predose values within the 
1.5-hour postdose timepoint. The blood pressure elevations did not appreciably attenuate over 
time with continued administration. Few participants (<2% across studies/study phase) 
discontinued esketamine treatment due to increased blood pressure.

In clinical trials, increases in SBP and DBP over time were about 7 to 9 mm Hg in SBP 
and 4 to 6 mm Hg in DBP at 40 minutes post dose and 2 to 5 mm Hg in SBP and 1 to 
3 mm Hg in DBP at 1.5 hours post dose in participants receiving esketamine nasal spray
plus oral ADs. The frequency of markedly abnormal blood pressure elevations of SBP 
(≥40 mm Hg increase) ranged from 8% (<65 years) to 17% (≥65 years) and DBP 
(≥25 mm Hg increase) ranged from 13% (<65 years) to 14% (≥65 years) in participants 
receiving esketamine nasal spray plus oral AD. The incidence of increased SBP 
(≥180 mm Hg) was 3% and DBP (≥110 mm Hg) was 4%.

In the short-term Phase 3 studies, treatment with esketamine in combination with a newly 
initiated SSRI/SNRI did not influence any aspect of cognition studied in adult participants with 
TRD and was not associated with any systematic changes in cognition in the elderly 
participants. In the long-term open-label safety study, overall group mean performance on 
multiple cognitive domains including visual learning and memory, as well as spatial 
memory/executive function, either improved or remained stable postbaseline in adult 
participants. In the subset of elderly participants (≥65 years of age) from this study, a slowing 
of reaction time was observed starting at Week 20 and through the end of the study; however, 
this appeared to represent an isolated observation related to processing speed and not a broad 


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attentional impairment. Performance on all other cognitive tests remained stable in elderly 
participants in this study.

Notably absent in the clinical studies with esketamine were respiratory depression, QT interval 
prolongation, development of psychotic-like symptoms or mania, interstitial or ulcerative 
cystitis, treatment-emergent hepatotoxicity, and clinically significant body weight gain.

Nasal tolerability in participants self-administering esketamine nasal spray, including that 
following long-term treatment, was good. There were no nasal examination findings or Nasal 
Symptom Questionnaire evidence to support an impact on nasal anatomy or function including 
the sense of smell.

Ketamine, the racemic mixture of arketamine and esketamine, has been reported as a drug of 
abuse. The potential for abuse, misuse, and diversion of intranasal esketamine is minimized 
due to the product’s design and the administration taking place under the supervision of a 
healthcare professional. Evidence of abuse, misuse, and diversion was not observed in clinical 
studies of intranasal esketamine.
2.2.4.
Comparator
Quetiapine Extended-Release28
Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, 
norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and 
norquetiapine exhibit affinity for brain serotonin (5-hydroxytryptamine [5HT]2) and dopamine D1-
and D2-receptors. It is this combination of receptor antagonism with a higher selectivity for 
5HT2 relative to D2-receptors, which is believed to contribute to the clinical antipsychotic 
properties and low extrapyramidal side effect liability of quetiapine compared to typical 
antipsychotics. Quetiapine and norquetiapine have no appreciable affinity at benzodiazepine 
receptors but high affinity at histaminergic and adrenergic alpha-1 receptors and moderate affinity 
at adrenergic alpha-2 receptors. Quetiapine also has low or no affinity for muscarinic receptors, 
while norquetiapine has moderate to high affinity at several muscarinic receptors, which may 
explain anti-cholinergic (muscarinic effects). Inhibition of the norepinephrine transporter and 
partial agonist action at 5HT1A sites by norquetiapine may contribute to the therapeutic efficacy 
of quetiapine XR as an AD.
Quetiapine XR is indicated as an add-on treatment of major depressive episodes in patients with 
MDD who have had suboptimal response to AD monotherapy.
Quetiapine XR should be administered prior to bedtime. The daily dose at the start of therapy is 
50 mg on Day 1 and 2, and 150 mg on Day 3 and 4. Antidepressant effect was seen at 150 and 
300 mg/day in short-term trials as add-on therapy. There is an increased risk of AEs at higher 
doses. Clinicians should therefore ensure that the lowest effective dose is used for treatment. The 
need to increase the dose from 150 to 300 mg/day should be based on individual patient evaluation.
Elderly
As with other antipsychotics and ADs, quetiapine XR should be used with caution in the elderly, 
especially during the initial dosing period. The rate of dose titration of quetiapine XR may need to 


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be slower, and the daily therapeutic dose lower, than that used in younger patients. The mean 
plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to 
younger patients. Elderly patients should be started on 50 mg/day. The dose can be increased in 
increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability 
of the individual patient.
In elderly patients with major depressive episodes in MDD, dosing should begin with 50 mg/day 
on Days 1-3, increasing to 100 mg/day on Day 4 and 150 mg/day on Day 8. Based on individual 
patient evaluation, if dose increase to 300 mg/day is required this should not be prior to Day 22 of 
treatment.
Clinical Efficacy in Major Depressive Episodes in MDD
Two short-term (6-week) studies enrolled patients who had shown an inadequate response to at 
least 1 AD. Quetiapine XR 150 and 300 mg/day, given as add-on treatment to ongoing AD therapy 
demonstrated superiority over AD therapy alone in reducing depressive symptoms as measured by 
improvement in MADRS total score (least squares [LS] mean change vs placebo of 2-3.3 points).
Long-term efficacy and safety in patients with MDD have not been evaluated as add-on therapy, 
however long-term efficacy and safety has been evaluated in adult patients as monotherapy (see 
below).
The following studies were conducted with quetiapine XR as monotherapy treatment, however 
quetiapine XR is only indicated for use as add-on therapy:
In 3 out of 4 short-term (up to 8 weeks) monotherapy studies, in patients with MDD, quetiapine 
XR 50, 150, and 300 mg/day demonstrated superior efficacy to placebo in reducing depressive 
symptoms as measured by improvement in the MADRS total score (LS mean change vs placebo 
of 2-4 points).
In a monotherapy relapse prevention study, patients with depressive episodes stabilized on 
open-label quetiapine XR treatment for at least 12 weeks were randomized to either quetiapine XR
once daily or placebo for up to 52 weeks. The mean dose during the randomized phase was 
177 mg/day. The incidence of relapse was 14.2% for quetiapine XR-treated patients and 34.4% 
for placebo-treated patients.
In a short-term (9 week) study, non-demented elderly patients (aged 66 to 89 years) with MDD, 
quetiapine XR dosed flexibly in the range of 50 to 300 mg/day demonstrated superior efficacy to 
placebo in reducing depressive symptoms as measured by improvement in MADRS total score 
(LS mean change vs placebo -7.54). In this study, patients randomized to quetiapine XR received 
50 mg/day on Days 1-3, the dose could be increased to 100 mg/day on Day 4, 150 mg/day on 
Day 8, and up to 300 mg/day depending on clinical response and tolerability. The mean dose was 
160 mg/day. Other than the incidence of extrapyramidal symptoms, the tolerability of quetiapine 
XR once daily in elderly patients was comparable to that seen in adults (aged 18 to 65 years). The 
proportion of randomized patients over 75 years of age was 19%.


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Clinical Safety
Higher rates of extrapyramidal symptoms were seen in quetiapine treated patients compared to 
those treated with placebo in short-term, placebo-controlled clinical trials in MDD and bipolar 
depression. In short-term, placebo-controlled monotherapy clinical trials in MDD, the aggregated 
incidence of extrapyramidal symptoms was 5.4% for quetiapine XR and 3.2% for placebo. In a 
short-term placebo-controlled monotherapy trial in elderly patients with MDD, the aggregated 
incidence of extrapyramidal symptoms was 9.0% for quetiapine XR and 2.3% for placebo. In both 
bipolar depression and MDD, the incidence of the individual AEs (eg, akathisia, extrapyramidal 
disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor 
hyperactivity, and muscle rigidity) did not exceed 4% in any treatment group.
Suicide
Physicians should consider the potential risk of suicide-related events after abrupt cessation of 
quetiapine treatment, due to the known risk factors for the disease being treated.
Other psychiatric conditions for which quetiapine is prescribed can also be associated with an 
increased risk of suicide-related events. In addition, these conditions may be comorbid with major 
depressive episodes.
Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal 
ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts 
or suicide attempts and should receive careful monitoring during treatment. A meta-analysis of 
placebo-controlled clinical trials of AD drugs in adult patients with psychiatric disorders showed 
an increased risk of suicidal behavior with ADs compared to placebo in patients less than 25 years 
old.
Close supervision of patients, in particular those at high risk, should accompany drug therapy,
especially in early treatment and following dose changes. Suicidal risk monitoring will be 
performed in this study as described in Section 8.2.5.
In clinical studies of patients with MDD the incidence of suicide-related events observed in young 
adult patients (younger than 25 years of age) was 2.1% (3/144) for quetiapine and 1.3% (1/75) for 
placebo. A population-based retrospective study of quetiapine for the treatment of patients with 
MDD showed an increased risk of self-harm and suicide in patients aged 25 to 64 years without a 
history of self-harm during use of quetiapine with other ADs.
Adverse Drug Reactions
The most commonly reported adverse drug reactions with quetiapine (≥10%) are somnolence, 
dizziness, headache, dry mouth, withdrawal (discontinuation) symptoms, elevations in serum 
triglyceride levels, elevations in total cholesterol (predominantly low-density lipoprotein
cholesterol), decreases in high-density lipoprotein cholesterol, weight gain, decreased hemoglobin,
and extrapyramidal symptoms.


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Overdose
In general, reported signs and symptoms were those resulting from an exaggeration of the active 
substance’s known pharmacological
effects;
ie, drowsiness and sedation, tachycardia, 
hypotension, and anti-cholinergic effects.
Overdose could lead to QT-prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory 
depression, urinary retention, confusion, delirium and/or agitation, coma, and death. Patients with 
pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose.
For further information regarding the comparator refer to the Summary of Product Characteristics 
(SmPC)28 (or local equivalent, if applicable).
2.3.
Benefit-Risk Assessment
A structured approach was applied to the selection and analysis of all the endpoints in the Phase 3 
esketamine program in TRD that have an important effect on the benefit-risk balance. Proportions 
of beneficial events were compared to proportions of harmful events. While some of the 
dichotomous endpoints (remission and response rates) that underlay these comparisons are not 
associated with formal statistical testing, they do characterize clinically significant differences and 
provide an overall picture of the benefit-risk balance for esketamine. More detailed information 
about the known and expected benefits and risks of esketamine nasal spray may be found in the 
IB.15
The totality of evidence supports a positive benefit-risk balance for esketamine nasal spray as a 
new treatment for adults with TRD. The extensive clinical study program for esketamine in TRD 
demonstrates the rapid, robust, and sustained efficacy for improving depression symptoms in this 
difficult-to-treat population. Benefit-risk assessments6 estimate that between 6 and 18 more 
patients per 100 treated achieve remission of depression symptoms after 4 weeks of treatment with 
esketamine in combination with a newly initiated SSRI/SNRI compared to initiating treatment 
with an SSRI/SNRI alone. Further, once remission has been achieved on esketamine, continued 
maintenance treatment with esketamine nasal spray in combination with an SSRI/SNRI is 
estimated to result in 19 to 32 fewer relapses per 100 patients relative to those who discontinue 
esketamine. The safety experience with esketamine nasal spray indicated that most of the adverse 
reactions seen with the drug, including those of common events such as dissociative symptoms, 
dizziness/vertigo, increased blood pressure, and sedation, occur shortly after dosing while the 
patient is under the supervision of a health care provider, and resolve the same day. In addition, 
certain AEs such as dissociation, dizziness/vertigo, and nausea/vomiting tend to lessen in 
frequency with continued dosing.
While the potential for abuse exists with esketamine nasal spray, there were no intervention-
emergent AEs of drug abuse or overdose and no reports of confirmed diversion in clinical trials. 
Several risk mitigation initiatives to lessen the potential for abuse and misuse are in place in regions 
where esketamine nasal spray has been launched and will be in place at the time of product launch 
in other regions. Patient preference study findings indicate that patients with TRD, both with and 
without esketamine treatment experience, place a higher value on improved depression symptoms 


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over those of short-term unusual postdose sensations and drug administration logistics or 
hypothesized extreme safety risks associated with ketamine abuse.
The benefits of esketamine nasal spray are considered to outweigh the risks of the infrequent severe 
or treatment-limiting side effects in the treatment-resistant MDD population.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
The primary objective of this study is to evaluate 
the efficacy of flexibly dosed esketamine nasal 
spray compared with quetiapine extended-release 
(XR), both in combination with a continuing 
selective serotonin reuptake inhibitor 
(SSRI)/serotonin-norepinephrine reuptake inhibitor 
(SNRI), in achieving remission in participants who 
have treatment-resistant MDD with a current 
moderate to severe depressive episode. 
Remission at the Week 8 visit, defined as a 
Montgomery-Asberg Depression Rating Scale 
(MADRS) total score of ≤10.
Key Secondary
To assess the efficacy of esketamine nasal spray 
compared with quetiapine XR, both in combination 
with a continuing SSRI/SNRI, in the proportion of 
participants being relapse-free at Week 32 after 
remission at Week 8.
Remission at Week 8 visit (ie, MADRS total score 
of ≤10 at the end of Week 8) and no relapse within 
the consecutive 24 weeks until the end of the 
prospective observation period at Week 32 visit.
Note: A relapse is defined by any of the following:
d)
Worsening of depressive symptoms as 
indicated by MADRS total score 
≥22 confirmed by 1 additional assessment of 
MADRS total score ≥22 within the next 5 to 
15 days. The date of the second MADRS 
assessment will be used for the date of 
relapse.
e)
Any psychiatric hospitalization for

worsening of depression

suicide prevention or due to a suicide 
attempt
for any of these events, the start date of 
hospitalization will be used for the date of 
relapse.
f)
Suicide attempt, completed suicide, or any 
other clinically relevant event determined per 
the investigator’s clinical judgment to be 
indicative of a relapse of depressive illness, 
but for which the participant was not 


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Objectives
Endpoints
hospitalized. The onset of the event will be 
used for the date of relapse.
In case more than 1 of the relapse criteria are met, 
the earliest date will be defined as the date of 
relapse for that participant.
Other Secondary
To assess the effect of esketamine nasal spray 
compared with quetiapine XR, both in combination 
with a continuing SSRI/SNRI, in:
Change from baseline at all visits for the following 
scale scores:

Clinician-rated overall severity of depressive 
illness 

Clinician-rated MADRS:

Overall severity of depressive illness 
(total score)

Early onset of action

Early onset of action (change in total 
score from baseline at Day 8 visit) 

Depressive symptoms (individual items)

Clinician-rated depressive symptoms

Clinician-rated overall severity of depressive 
illness: 

Clinical Global Impression – Severity 
(CGI-S)

Clinical Global Impression – Change 
(CGI-C), is a measure of change, 
analyzed as a score not as change from 
baseline

Participant-reported depressive symptoms

Participant-reported functional impairment 
and associated disability

Participant-reported health-related quality of 
life and health status

Participant-reported work productivity 

Participant-reported depressive symptoms: 
Patient Health Questionnaire 9-item (PHQ-9) 

Participant-reported functional impairment 
and associated disability: Sheehan Disability 
Scale (SDS)

Participant-reported health-related quality of 
life and health status: 36-item Short-Form 
Health Survey (SF-36)

Participant-reported Quality of Life in 
Depression Scale (QLDS)

Participant-reported European Quality of Life 
(EuroQoL) Group, 5-Dimension, 5-Level 
(EQ-5D-5L) questionnaire

Participant-reported work productivity: Work 
Productivity and Activity Impairment 
(WPAI): Depression (D) questionnaire


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Objectives
Endpoints
To assess the safety and tolerability of esketamine 
nasal spray compared with quetiapine XR, both in 
combination with a continuing SSRI/SNRI.
Intervention-emergent adverse events (AEs), 
including intervention-emergent AEs of special 
interest
Suicidal ideation and behavior: Columbia-Suicide 
Severity Rating Scale (C-SSRS)
Exploratory
To assess the potential relationship of biomarkers 
with response/nonresponse to study intervention in 
participants with treatment-resistant MDD.
-
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESES
The primary and secondary hypotheses are provided in Section 9.1, Statistical Hypotheses.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomized, open-label, rater-blinded, active-controlled, international, multicenter study 
to evaluate the efficacy, safety, and tolerability of flexibly dosed esketamine nasal spray compared 
with quetiapine XR, both in combination with a continuing SSRI/SNRI, in participants 18 to 
74 years of age, inclusive, with treatment-resistant MDD. A psychiatrist should determine 
eligibility of participants for inclusion in the study.
To be eligible for enrollment in the study:

Participant must be on a current antidepressive treatment that includes an SSRI/SNRI at 
screening that resulted in nonresponse (less than 25% improvement of symptoms) after having 
been given at an adequate dosage (based on antidepressive dosages from SmPC [or local 
equivalent, if applicable]) for an adequate duration of at least 6 weeks and having been 
uptitrated to the maximum tolerated dose; however, at screening the participant must show 
signs of minimal clinical improvement to be eligible for the study. 

In addition, the current antidepressive treatment must have been immediately preceded by 
nonresponse to at least 1 but not more than 5 different consecutive treatments (all within the 
current moderate to severe depressive episode) with ADs taken at an adequate dosage for an 
adequate duration of at least 6 weeks.

“At least 1 but not more than 5” means that participants may be screened and enrolled 
while receiving treatment with their second to sixth consecutive treatment with oral ADs 
taken at adequate dosage for an adequate duration of at least 6 weeks to which they are 
having a nonresponse. 
o
If a participant was receiving an oral AD at an adequate dosage for an adequate 
duration of at least 6 weeks and then had an augmentation therapy added or had


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combination AD therapy initiated, it would then be considered the next consecutive 
treatment with AD if taken at an adequate dosage for an adequate duration of at least 
6 weeks. 

For treatments with AD(s) to be counted as consecutive, there may have been interspersed 
insufficient treatments (ie, insufficient duration and/or at insufficient dosage). These 
insufficient treatments are allowed but will not be considered when documenting 
participant nonresponse.

Participant must have been treated with at least 2 different antidepressive substance classes 
among the treatments taken at an adequate dosage for an adequate duration of at least 6 weeks
resulting in nonresponse in the current moderate to severe depressive episode (including the 
current treatment with an SSRI/SNRI).

Participant must be on a single oral SSRI/SNRI on Day 1 prior to randomization.

Participants who are taking combination ADs and/or augmentation (other than quetiapine 
XR which is exclusionary at doses >50 mg/day) for the current moderate to severe 
depressive episode at screening are eligible for the study. All AD treatments, including 
any augmenting substances, must be stopped prior to randomization on Day 1 according 
to applicable SmPCs (or local equivalents, if applicable), except the SSRI/SNRI to be 
continued.
The study has 4 phases: an up-to-14-day screening phase, an 8-week acute phase, a 24-week 
maintenance phase, and a 2-week safety follow-up phase. During the acute phase, participants in 
the esketamine arm will have twice-weekly visits from Week 1 to Week 4 and once weekly visits 
from Week 5 to Week 8; during the maintenance phase from Week 9 to Week 32, visits will be 
once weekly or every 2 weeks (even weeks) based on dosing. Participants in the comparator arm 
will have weekly visits from Week 1 to Week 4, and then every 2 weeks for the remainder of the 
acute phase (Week 6 and Week 8) and the maintenance phase (Week 10, Week 12, etc) through 
Week 32. All participants have a safety follow-up visit 2 weeks following the last dose of study 
intervention. The total duration of the study is approximately 36 weeks for all participants.
A total of 622 participants will be randomly assigned on Day 1 (baseline) in a 1:1 ratio to 1 of 
2 open-label study intervention arms (311 participants per arm):

Esketamine Arm: Participants will continue to take their current SSRI/SNRI in combination
with esketamine nasal spray. 

Study intervention (ie, esketamine nasal spray in combination with a continuing 
SSRI/SNRI) will be administered as described in Section 6.1.1.

Comparator Arm: Participants will continue to take their current SSRI/SNRI which will be
augmented with quetiapine XR as per its SmPC (or local equivalent, if applicable).

Study intervention (ie, quetiapine XR in combination with a continuing SSRI/SNRI) will 
be administered as described in Section 6.1.2.
The study intervention will be considered discontinued if either component of the randomized 
combination therapy (ie, esketamine nasal spray, quetiapine XR, or continuing SSRI/SNRI) is 
stopped.


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
If the SSRI/SNRI is discontinued at any time during the acute or maintenance phase, the 
esketamine nasal spray or quetiapine XR must also be discontinued. The participant will be 
switched to an alternative standard of care treatment at the discretion of the investigator and 
continue follow-up visits through Week 32.

If esketamine nasal spray or quetiapine XR is discontinued at any time during the acute or 
maintenance phase, the participant will be switched to an alternative standard of care 
treatment, which may or may not include the continuing SSRI/SNRI, at the discretion of the 
investigator and continue follow-up visits through Week 32. If determined by the investigator 
that the alternative standard of care will include esketamine nasal spray (when commercially 
available in country of participation) or quetiapine XR for a participant, it will not be provided 
to the participant, rather, the investigator must prescribe the medication to the participant.
A diagram of the study design is provided in Section 1.2, Schema.
All procedures and assessments will be performed according to the Schedule of Activities.
If necessary, the screening phase may be extended to allow additional time to obtain 
documentation for prior treatments with ADs (according to Appendix 3, Regulatory, Ethical, and 
Study Oversight Considerations: Source Documents) or to accommodate retesting. In all other 
cases, the screening phase may be extended only after approval by the Sponsor, as assessed on a 
case-by-case basis. Once all inclusion criteria are confirmed and none of the exclusion criteria are 
met, the baseline visit (which is also the date of randomization) can be scheduled with a participant 
immediately.
Baseline (Day 1) Visit and Acute (Weeks 1 to 8) and Maintenance (Weeks 9 to 32) Phases
All visit-specific patient-reported outcome (PRO) assessments (PHQ-9, QLDS, EQ-5D-5L, SF-36, 
SDS, and WPAI:D) should be conducted/completed before clinician-rated assessments, any tests
(other than the urine drug screen at baseline visit [Day 1]; see Section 8.2.4, Clinical Safety 
Laboratory Assessments), procedures, other consultations, or esketamine nasal spray 
administration (in applicable participants) to prevent influencing participant perceptions.
Efficacy will be assessed using clinician-rated scales (MADRS, CGI-S, and CGI-C) and PROs. 
As the MADRS is used to assess the primary and major secondary endpoints in the study, it must 
be performed by a qualified independent blinded rater as described in Section 8.1.1.2.
Blood samples will be collected for exploratory analysis of biomarkers. Blood samples will also 
be collected to allow pharmacogenomic (DNA and RNA) research (where local regulations 
permit). Biomarker and pharmacogenomic blood samples will only be collected at select study 
sites. Participation in the biomarker and pharmacogenomic research is optional for participants.
For participants in the esketamine arm:

All clinician-rated scales must be completed before the nasal treatment session at each visit. 
Esketamine nasal spray dosing and related safety-monitoring procedures MUST be performed 
LAST at all visits.


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
At the Week 4 visit, evidence of therapeutic benefit will be evaluated clinically by the 
investigator as described in Section 6.1.1.4.
Beginning at the Week 8 visit, all participants in both study intervention arms will undergo regular 
assessments of symptom changes from baseline (ie, treatment continuation assessment) to ensure 
that study intervention continuation is appropriate. This will be operationalized using the CGI-C 
clinician-rated scale (referring to study baseline [Day 1]) every 4 weeks, and treatment decisions 
will be made using cut-off values in Table 1.
Table 1:
Treatment Continuation Assessment of Study Intervention 
CGI-C ≥4 (“no change” or worse) 
at 2 consecutive visits
Recommendation to reconsider appropriateness of study intervention
and to switch to an alternative standard-of-care treatment.
CGI-C <4 (“Minimally improved” or 
better) at any visit
Study intervention may be continued at the discretion of the 
investigator.
CGI-C= Clinical Global Impression – Change
Safety assessments include the monitoring of AEs, physical/nasal examinations, measurement of 
body weight, vital sign measurements, clinical laboratory tests, ECGs, and pregnancy testing. 
Suicide risk will also be assessed throughout the study using the C-SSRS.
There is no requirement to change a participant’s standard of care treatment when they complete 
the maintenance phase at the Week 32 visit. Refer to Section 6.7, for information regarding 
standard of care treatment following completion of the study.
Participants Who Discontinue the Study Intervention Early
Participants who discontinue the study intervention early (ie, discontinue either component of the 
randomized combination therapy) will remain in the study and continue to return for follow-up 
visits every 2 weeks through the Week 32 visit and have assessments performed according to the 
Schedule of Activities. Refer to Section 6.7 for information regarding standard of care treatment 
following early discontinuation of the study intervention. Refer to Section 8.3.1 for details of AE
reporting for participants who discontinue study intervention early.
After early discontinuation of study intervention, the CGI-C will still be performed at follow-up 
visits according to the Schedule of Activities; however, treatment decisions will be at the discretion 
of the investigator and not based on the criteria for the treatment continuation assessment.
Early Study Withdrawal Visit
If a participant withdraws from the study, an early study withdrawal visit should be conducted 
within 1 week of the date of withdrawal unless they withdraw consent, are lost to follow-up, or 
have died.
Safety Follow-Up Visit
For participants in the esketamine arm who complete the study, the safety follow-up visit will be 
performed 2 weeks after the last nasal treatment session. In participants with a dosing frequency 


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of every 2 weeks, this visit will be at Week 32, and for participants with a dosing frequency of 
once weekly, this visit will be at Week 33.
For participants in the comparator arm who complete the study, a safety follow-up visit will be 
performed following the Week 32 visit. The safety follow-up visit will be performed 2 weeks after 
the last dose of study intervention (ie, quetiapine XR in combination with a continuing 
SSRI/SNRI) was taken during the study.
For participants who discontinue the study intervention early, all safety follow-up visit assessments 
as specified in the Schedule of Activities will be performed in addition to the assessments 
scheduled at their first 2-week follow-up visit, or if study intervention is discontinued after the 
Week 30 visit, the safety follow-up visit will be performed 2 weeks after their last dose.  
Participants who are taking study intervention at the time of early withdrawal from the study 
should return for the safety follow-up visit 2 weeks after their last dose unless they withdraw 
consent, are lost to follow-up, or have died.
4.2.
Scientific Rationale for Study Design
4.2.1.
Selection of Participant Population
The study population will include adult men and women, 18 to 74 years of age (inclusive); this 
age range is considered appropriate based on the disorder being studied and the available dosing 
information for the study interventions.
Each participant must meet Diagnostic and Statistical Manual of Mental Disorders, fifth edition 
(DSM-5) diagnostic criteria for single-episode MDD or recurrent MDD, without psychotic 
features, based on clinical assessment and confirmed by the Mini International Neuropsychiatric 
Interview (MINI), and have an Inventory of Depressive Symptomatology Clinician-Rated 
30 Items Scale (IDS-C30) total score of 34, which corresponds to moderate to severe depression.
Presentation, diagnosis, and treatment of late-onset MDD (first episode after 50 or 60 years of age) 
differs from earlier onset MDD due to confounding vascular risk factors, age-related cognitive 
deficits, and other comorbid medical conditions.12,22 Decreased efficacy of AD treatments in adults 
and elderly with late-onset depression has been associated with diverse pathophysiological 
underpinnings 
(especially 
cerebrovascular 
disease), 
potentially 
related 
to 
increased 
neuromorphological changes and magnetic resonance imaging signal hyperintensities16,17 and 
treatment resistance.22 In this study, older adults and the elderly who had onset of their first episode 
of MDD at 55 years of age are excluded.
According to the European Medicines Agency’s guideline on clinical investigation of medicinal 
products in the treatment of depression,9 “In a clinical pragmatic view a patient has been 
considered suffering from TRD when consecutive treatment with 2 products of different 
pharmacological classes, used for a sufficient length of time at an adequate dose, fail to induce a 
clinically meaningful effect (inadequate response).” In line with the guideline and expanding to 
include patients who have had more than 2 consecutive treatment failures, participants in this study 


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must have had nonresponse (ie, lack of clinically meaningful improvement, defined as 
≤25% improvement) to at least 1 but not more than 5 different, consecutive treatments with ADs 
taken at an adequate dosage for an adequate duration of at least 6 weeks in their current moderate 
to severe depressive episode and currently be receiving treatment with their second to sixth 
consecutive treatment to which they are having a nonresponse. Additionally, participants must 
show signs of minimal clinical improvement on their current treatment, which must include an 
SSRI/SNRI, to be eligible for the study. Participants must have been treated with at least 2 different 
antidepressive substance classes among the treatments taken at adequate dosage for an adequate 
duration of at least 6 weeks resulting in nonresponse in the current moderate to severe depressive 
episode (including the current treatment with an SSRI/SNRI).
Refer to Section 5.1 for the detailed inclusion criteria for participant entry into the study.
4.2.2.
Selection of Active Comparator
Quetiapine XR was selected as the active comparator because it is labeled for an add-on treatment 
of major depressive episodes in patients with MDD who have had suboptimal response to AD 
therapy. It is widely used in patients with previous treatment failures, and its use is supported by 
various international guidelines for patients with previous treatment failures. Additional 
information on the efficacy of augmenting an ongoing AD with quetiapine XR is provided in 
Section 2.2.4.
Low-dose treatment with quetiapine, which in clinical practice is used for treatment of isolated 
symptoms (eg, insomnia or agitation), is not considered an appropriate antidepressive 
augmentation strategy (ie, 150 to 300 mg/day) according to the prescribing information. Therefore, 
participants who were taking ≤50 mg/day of quetiapine (XR or immediate-release) at screening 
are allowed to enter the study provided the quetiapine is washed-out by at least 7 days prior to 
randomization.
4.2.3.
Selection of SSRI/SNRI as the Classes of Concomitant Oral 
Antidepressants 
The SSRI and SNRI classes of ADs were selected because they are the most commonly prescribed 
AD classes in this population, they are generally well-tolerated, and they can be combined with 
quetiapine XR. In the Phase 3 studies of esketamine nasal spray in combination with SSRIs/SNRIs, 
it was shown that the combination was safe and well tolerated. The use of this combination also 
corresponds with the approved label for esketamine nasal spray. The continuing SSRI/SNRI being 
taken by a participant must be labeled for treatment of depression/MDD in their country of 
participation; off-label use of an SSRI/SNRI is not permitted. The continuing SSRI/SNRI must 
not be contraindicated in its SmPC (or local equivalent, if applicable) for augmentation with 
quetiapine XR.
4.2.4.
Screening
The screening period of up to 2 weeks allows sufficient time for confirmation and documentation 
(according to Appendix 3, Regulatory, Ethical, and Study Oversight Considerations: Source 


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Documents) of nonresponse to prior treatment with ADs and nonresponse but signs of minimal 
clinical improvement to the current treatment with an SSRI/SNRI as described in Section 8.1.1.1.
4.2.5.
Follow-up
At the start of follow-up after early discontinuation of study intervention, further clinical/standard
of care for the treatment of depression will be arranged by the study investigator and/or the 
participant’s treating physician.
4.2.6.
Blinding, Control, Study Phase, Intervention Groups
This is an open-label study, study intervention blinding procedures are not applicable.
An active control will be used to determine the sensitivity of the clinical endpoints in this study.
There is no placebo arm in this study. Randomization will be used to minimize bias in the 
assignment of participants to intervention groups, to increase the likelihood that known and 
unknown participant attributes (eg, demographic and baseline characteristics) are evenly balanced 
across intervention groups, and to enhance the validity of statistical comparisons across 
intervention groups. The randomization will be balanced by using randomly permuted blocks and 
will be stratified by age (18 to 64 years [inclusive]; 65 to 74 years [inclusive]) and total number of 
treatment failures (2; 3 or more [inclusive of current antidepressive treatment at screening used to 
determine eligibility]).
To minimize bias on the MADRS score (total score is used for primary and key secondary 
endpoints), the MADRS will be assessed by a qualified independent on-site rater who is blinded
to the participant’s treatment and who is not involved in any other study assessments or treatment 
decisions for a given study participant.
4.2.7.
Clinician and Participant-reported Efficacy Assessments
Medication guidelines for the treatment of MDD recommend changes in treatment tactics or 
strategies at critical decision points based on changes in baseline symptom severity. Self-reported 
or clinician ratings that provide simple measures of symptom severity may facilitate the 
implementation of such clinical procedures in representative practice and efficacy trials. The 
clinician and participant-reported scales in this study have been selected as they are validated, 
reliable, and acceptable to regulatory health authorities and health-technology assessment bodies
to assess the efficacy of treatments in TRD.
Refer to Section 8 for details on the clinician and PRO scales used in this study.
4.2.8.
Safety Evaluations
Evaluation of intervention-emergent AEs, concomitant therapies, clinical laboratory tests, 
pregnancy tests, vital signs (including blood pressure measurements), 12-lead ECGs, nasal 
examinations, and body weight will be performed throughout the study as per the Schedule of 
Activities to monitor participant safety.


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4.2.9.
Biomarker and Pharmacogenomic (DNA/RNA) Collection
Blood samples may be collected for the analysis of one or more candidate genes and/or the analysis 
of genetic and epigenetic markers as well as RNA expression markers. In addition, blood samples 
may be collected for the exploratory analysis of biomarkers (protein and metabolites) related to 
immune system activity, hypothalamic–pituitary–adrenal (HPA) axis activation, neurotrophic and 
metabolic factors.
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in intervention distribution and response and can also serve as a marker for disease 
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to an intervention. The goal of the pharmacogenomic component is to collect DNA to 
allow the identification of genetic and/or epigenetic factors that may influence the 
pharmacokinetics, pharmacodynamics, efficacy, safety, or tolerability of study intervention and to 
identify genetic factors associated with MDD. Specifically, genes and epigenetic changes in genes 
known to be in pathways relevant to depression (HPA axis, inflammation, growth factors, 
monoamine transporters, ion channels, circadian rhythm) will be evaluated. Expression analyses 
may include testing of known messenger RNA/microRNA transcripts or transcriptome-wide
analysis in relationship to AD treatment response and MDD.
Increasingly, it is recognized that psychiatric disorders may be associated with altered 
immune/metabolic activation patterns. Blood samples will be used to explore biomarkers related 
to immune system activity, HPA axis activation, and neurotropic factors (including but not limited 
to growth factors, inflammation, or endocrine markers). Biomarker samples will be used to 
evaluate the mechanism of action of esketamine or help to explain interindividual variability in 
clinical outcomes or may help to identify population subgroups that respond differently to an 
intervention. 
The DNA, RNA, protein, and metabolic biomarker samples may be used to help address emerging 
issues and to enable the development of safer, more effective, and ultimately individualized 
therapies.
4.2.10.
Study-Specific Ethical Design Considerations
The safety profile of esketamine nasal spray indicates that it is considered safe to use in the current 
study population based on the pre-clinical and clinical data noted earlier (Section 2.2, 
Background).
The comparator group will receive quetiapine XR, which is approved for augmentation therapy in 
MDD. A brief summary of the safety profile for quetiapine XR is provided in Section 2.2.4, 
Comparator; additional information can be found in its SmPC28 (or local equivalent, if applicable).
Participants must be taking an SSRI/SNRI that is approved for use in depression in their country 
of participation. Potential participants who are taking an SSRI/SNRI off-label are not eligible for 
this study.


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Potential participants will be fully informed of the risks and requirements of the study and, during 
the study, participants will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only participants who are fully able to understand the risks, benefits, 
and potential AEs of the study, and provide their consent voluntarily will be enrolled.
Participants at select study sites will be offered participation in optional biomarker and 
pharmacogenomic research components including collection of blood samples for biomarker and/or 
DNA and RNA analysis. Participants may decide to opt out of this optional research. The decision 
to opt out of either optional research component will not impact the eligibility to participate in the 
main study. Participants that take part in the optional research component(s) of the study will sign 
an additional informed consent form (ICF).
The total blood volume to be collected is considered an acceptable amount of blood to be collected 
over this time period for the population in this study.
4.3.
Justification for Dose
Esketamine Arm
All participants in the esketamine arm will receive flexible doses (either 28 [elderly participants
and adults of Japanese ancestry only], 56, or 84 mg) of esketamine nasal spray, based on their 
tolerability and response to a first dose of 28 mg (elderly participants and adults of Japanese
ancestry only) or 56 mg (adult participants) on Day 1.
The dose selections used in this study are in line with previous Phase 2 and Phase 3 studies where 
esketamine was administered at doses of 28 mg, 56 mg, or 84 mg. Phase 1 and 2 studies in elderly 
and Japanese participants, which indicated higher mean plasma esketamine Cmax and AUCvalues
at studied doses, support the initial dose of 28 mg in these 2 populations. The Phase 3 short-term 
double-blind study (TRD3001) evaluated 2 fixed doses of esketamine (56 mg or 84 mg). Flexible 
dosing of esketamine was evaluated in the other Phase 3 short-term studies, TRD3002 (56 mg and 
84 mg) and TRD3005 (28 mg, 56 mg, or 84 mg), as well as in the relapse prevention study 
(TRD3003) and long-term open-label study (TRD3004). A flexible dosing schedule was used to 
facilitate improved tolerability by gradually increasing the dose higher and to align with clinical 
practice, as many clinicians prefer to gradually increase the dose of AD medication and then adjust 
as clinically required. The fixed-dose design in Study TRD3001 was used to separately evaluate 
the superiority of esketamine doses of 56 mg and 84 mg in combination with a newly initiated
SSRI/SNRI to the newly initiated SSRI/SNRI in combination with placebo comparator treatment. 
Based on the approved label for esketamine nasal spray, this study is being conducted with a 
flexible dosing scheme.
Dosing of nasal study treatments (esketamine or placebo) was twice weekly during the 
Phase 2 TRD2003 study and during the induction phases (ie, Week 1 to Week 4) of the Phase 3 
studies. The initial twice-weekly administration schedule was selected based on results of 
Study KETIVTRD2002 in which similar efficacy was seen in participants with TRD receiving 


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ketamine, administered as 40-minute IV infusions either 2 or 3 times per week over a 15-day 
period. In the longer-term Phase 3 studies (TRD3003 and TRD3004), the frequency of nasal dosing 
after the induction phase was individualized to once weekly or every other week to achieve the 
lowest dosing frequency for an individual participant that could sustain initial improvements in 
depressive symptomatology. Data from the up-to-9-week open-label phase of Study TRD2003 
showed that reducing the dosing frequency from twice-weekly to weekly or every other week did 
not impact the ability to maintain the AD activity of esketamine.
Comparator Arm
Quetiapine XR is labeled for add-on treatment of major depressive episodes in MDD and will be 
uptitrated according to its SmPC (or local equivalent, if applicable) at the discretion of the 
investigator to achieve a therapeutic dose (at least 150 mg/day).
Continuing SSRI/SNRI
All participants must be taking an SSRI/SNRI at screening to be eligible for the study. Participants 
must be taking an SSRI/SNRI that is approved for use in depression in their country of 
participation; off-label use of any SSRI/SNRI is not permitted. The continuing SSRI/SNRI dosage 
may be optimized throughout the study, at the investigator’s discretion and based on the SmPC (or 
local equivalent, if applicable).
4.4.
End of Study Definition
End of Study Definition
The end of study is considered as the last visit for the last participant in the study. The final data 
from the study site will be sent to the sponsor (or designee) after completion of the final participant 
assessment at that study site, in the time frame specified in the Clinical Trial Agreement.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed 
assessments through Week 32.
5.
STUDY POPULATION
The study will be conducted internationally. Screening for eligible participants will be performed 
within 14 days before administration of the study intervention. Refer to Section 5.4, Screen 
Failures for conditions under which the repeat of any screening procedures are allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about these criteria, the investigator must consult with the appropriate sponsor 
representative and resolve any issues before enrolling a participant in the study. Waivers are not 
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2, 
Sample Size Determination.


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5.1.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1.
male or female, 18 years (or older if the minimum legal age of consent in the country in 
which the study is taking place is >18 years) to 74 years of age, inclusive, at the time of 
signing the ICF.
2.
at screening, each participant must meet DSM-5 diagnostic criteria for single-episode 
MDD or recurrent MDD, without psychotic features, based on clinical assessment and 
confirmed by the MINI (see Section 8.1.1.1).
3.
at screening and baseline, each participant must have an IDS-C30 total score of 34 (see 
Section 8.1.1.1).
4.
criterion changed per Amendment 1.
4.1
must be on a current antidepressive treatment that includes an SSRI/SNRI at screening 
that resulted in nonresponse (less than 25% improvement of symptoms) after having been 
given at an adequate dosage (based on antidepressive dosages from SmPC [or local 
equivalent, if applicable]) for an adequate duration of at least 6 weeks and having been 
uptitrated to the maximum tolerated dose; however, at screening the participant must 
show signs of minimal clinical improvement to be eligible for the study. (See also 
exclusion criterion 4.)
Clinical improvement of a participant on their current AD treatment will be 
retrospectively evaluated in a qualified psychiatric interview performed by an 
experienced clinician; additional guidance for this interview is provided in 
Section 8.1.1.1. 
At baseline (Day 1) prior to randomization, the investigator will evaluate any changes in 
the participant’s signs/symptoms of depression since the screening assessment and 
confirm that the inclusion criteria for the current AD treatment are still met (ie, 
nonresponse and minimal clinical improvement).
5.
criterion changed per Amendment 1.
5.1
the current antidepressive treatment was immediately preceded by nonresponse to at least 
1 but not more than 5 different consecutive treatments (all within the current moderate to 
severe antidepressive episode) with ADs taken at an adequate dosage for an adequate 
duration of at least 6 weeks and must be documented (as described in Appendix 3, 
Regulatory, Ethical, and Study Oversight Considerations: Source Documents) during 
screening.
6.
criterion changed per Amendment 1.
6.1
must have been treated with at least 2 different antidepressive substance classes among 
the treatments taken at an adequate dosage for an adequate duration of at least 6 weeks


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resulting in nonresponse in the current moderate to severe depressive episode (including 
the current treatment with an SSRI/SNRI).
7.
must be on a single oral SSRI/SNRI on Day 1 prior to randomization.
Participants who are taking combination ADs and/or augmentationa at screening are 
eligible for the study. All AD treatments, including any augmenting substances, must be 
stopped prior to randomization on Day 1 according to applicable SmPCs (or local 
equivalents, if applicable), except the SSRI/SNRI to be continued; investigator guidance 
for discontinuing other AD treatment(s) is provided in Section 6.5, Concomitant Therapy.
a
Other than quetiapine XR which is exclusionary at doses >50 mg/day for the 
current moderate to severe depressive episode; see exclusion criterion 2.
8.
must be medically stable based on physical examination, medical history, vital signs 
(including blood pressure) at screening. 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 participant’s source documents.
9.
must be comfortable with self-administration of nasal medication and be able to follow 
the nasal administration instructions provided.
10.
must sign an ICF indicating that he or she understands the purpose of, and procedures 
required for, the study and is willing to participate in the study.
11.
must sign a separate ICF at baseline (Day 1) visit if he or she agrees to provide optional 
biomarker and/or genomic (DNA and RNA) samples for research (where local regulations
permit). Refusal to give consent for the optional biomarker and/or genomic DNA and 
RNA research samples does not exclude a participant from participation in the main study.
12.
a woman of childbearing potential must have a negative highly sensitive serum pregnancy 
test (-human chorionic gonadotropin [-hCG]) at screening and a negative urine 
pregnancy test prior to the first dose of study intervention on Day 1.
13.
a woman must be (as defined in Appendix 6, Contraceptive and Barrier Guidance and 
Collection of Pregnancy Information)

Not of childbearing potential

Of childbearing potential and practicing a highly effective, preferably user-
independent method of contraception (failure rate of <1% per year when used 
consistently and correctly) and agrees to remain on a highly effective method while 
receiving study intervention and until at least 6 weeks after last dose – the end of 
relevant systemic exposure. 
Examples of highly effective methods of contraception are located in Appendix 6, 
Contraceptive and Barrier Guidance and Collection of Pregnancy Information.


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14.
a man who is sexually active with a woman of childbearing potential during the study (ie, 
from Day 1 prior to first dosing) and for a minimum of 1 spermatogenesis cycle (defined 
as approximately 90 days) after receiving the last dose of study intervention (ie, 
esketamine nasal spray or quetiapine XR, both in combination with continuing 
SSRI/SNRI), must fulfill the following criteria:

must be practicing a highly effective method of contraception with his female partner.

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 participant, must begin a highly effective method of birth control, as described 
above. Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical 
studies.
15.
willing and able to adhere to the lifestyle restrictions specified in this protocol 
(Section 5.3).
5.2.
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study:
1.
received treatment with esketamine or ketamine in the current moderate to severe 
depressive episode.
2.
received treatment with quetiapine extended- or immediate-release in the current 
moderate to severe depressive episode of a dose higher than 50 mg/day.
Note: If participants are receiving quetiapine (extended- or immediate-release) of ≤50 mg 
in the current episode, it needs to be stopped (wash-out period) at least 7 days prior to 
randomization.
3.
had depressive symptoms in the current moderate to severe depressive episode that 
previously did not respond to an adequate course of treatment with electroconvulsive 
therapy (ECT), defined as at least 7 treatments with unilateral/bilateral ECT.
4.
has no signs of clinical improvement at all or with a significant improvement on their 
current AD treatment that includes an SSRI/SNRI as determined at screening by an 
experienced clinician during the qualified psychiatric interview (Section 8.1.1.1, 
Screening Evaluations).
Note: If a participant does not show signs of minimal clinical improvement at screening 
on their current treatment with AD that includes an SSRI/SNRI, they may be rescreened 
(1 time) on the next consecutive line of treatment with AD (if it includes an SSRI/SNRI) 


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after they have taken it at an adequate dosage for an adequate duration of at least 6 weeks 
(see Section 5.4, Screen Failures).
5.
received vagal nerve stimulation or has received deep brain stimulation in the current 
episode of depression.
6.
criterion changed per Amendment 1.
6.1
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.
7.
age at onset of first episode of MDD was 55 years. 
8.
has homicidal ideation or intent, per the investigator’s clinical judgment; or has suicidal 
ideation with some intent to act within 1 month prior to screening, 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, or a history of 
suicidal behavior within the past year prior to screening. Participants reporting suicidal 
ideation with intent to act or suicidal behavior prior to the start of the acute phase should 
also be excluded.
9.
history of moderate or severe substance use disorder or severe alcohol use disorder 
according to DSM-5 criteria, except nicotine or caffeine, within 6 months before the start 
of the screening or current clinical signs.
10.
history (lifetime) of ketamine, PCP, lysergic acid diethylamide (LSD), or 
3,4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder.
11.
has a neurodegenerative disorder (eg, Alzheimer’s disease, vascular dementia, 
Parkinson’s disease with clinical evidence of cognitive impairment) or evidence of mild 
cognitive impairment.
12.
is currently suffering from seizures, has a history of epilepsy, Neuroleptic Malignant 
Syndrome, or Tardive Dyskinesia.
13.
criterion changed per Amendment 1.
13.1
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).


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
history of intracerebral hemorrhage.

coronary artery disease with myocardial infarction, unstable angina, or
revascularization procedure (eg, coronary angioplasty or bypass graft surgery) within 
12 months before baseline (Day 1). Participants 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.

uncontrolled brady- or tachyarrhythmias that lead to hemodynamic instability.

hemodynamically significant valvular heart disease such as mitral regurgitation, 
aortic stenosis, or aortic regurgitation. 

confirmed or suspected cardiomyopathy or myocarditis.

New York Heart Association Class III-IV heart failure of any etiology.
14.
has clinically significant or unstable respiratory conditions, including, but not limited to:

significant pulmonary insufficiency, including chronic obstructive pulmonary 
disease.

sleep apnea with morbid obesity (body mass index ≥35).
15.
uncontrolled hypertension despite diet, exercise, or antihypertensive therapy on Day 1 or 
any history of hypertensive crisis or ongoing evidence of uncontrolled hypertension 
defined as a supine SBP >140 mmHg or DBP >90 mmHg.
Note: On Day 1 (prior to initiation of study intervention) a supine SBP >140 mmHg or 
DBP >90 mmHg is exclusionary.
Potential participants may have their current antihypertensive medication(s) adjusted 
during the screening phase and be re-evaluated to assess their blood pressure control prior 
to randomization.
16.
history of additional risk factors for torsade des pointes (eg, heart failure, hypokalemia, 
or family history of long QT syndrome).
17.
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 3 × the upper limit of normal in routine laboratory test
or medical record or at screening.
18.
has a fasting triglyceride concentration ≥500 mg/dL at screening.
19.
has 
positive 
urine 
test 
result(s) 
for 
drugs 
of 
abuse 
(including 
barbiturates, cannabinoids, methadone, opiates, cocaine, PCP, and amphetamine/
methamphetamine) on Day 1 prior to randomization, 
OR


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if prescribed psychostimulants (eg, amphetamine, methylphenidate) for MDD, the 
medication must be discontinued at screening and participants must agree not to take 
during the study. Participants are excluded if they have a positive urine test result for a 
prescribed psychostimulant for MDD on Day 1 prior to randomization. However, 
participants prescribed psychostimulants for indications other than MDD (eg, attention 
deficit hyperactivity disorder) are permitted to continue taking this medication during the 
study. Use of psychostimulants for recreational use is exclusionary.
Note: intermittent use of cannabinoids prior to the start of the screening phase is not 
exclusionary as long as the participant does not meet the criteria for substance use disorder 
or have a positive urine test result for cannabinoids on Day 1 prior to randomization.
See Section 8.2.4, Clinical Safety Laboratory Assessments for additional information on 
the timing of the urine drug screen at baseline (Day 1) visit.
20.
has uncontrolled diabetes mellitus, as evidenced by HbA1c >9% in the medical records, 
routine laboratory test, or history in the 3 months prior to baseline; or diabetic 
ketoacidosis, hyperglycemic coma, or severe hypoglycemia with loss of consciousness 
evaluated from medical history.
21.
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 evaluated from medical history.
22.
has any anatomical or medical condition that, per the investigator’s clinical judgment 
based on assessment, may impede delivery or absorption of esketamine nasal spray.
23.
has a history of malignancy within 5 years before baseline (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).
24.
has 
known 
allergies, 
hypersensitivity, 
intolerance, 
or 
contraindications 
to 
esketamine/ketamine, quetiapine XR, and/or any excipients.15,28
25.
has taken any prohibited therapies that would not permit dosing on Day 1 as defined in 
protocol (Section 6.5, Concomitant Therapy and Appendix 4, Prohibited Concomitant 
Medications).
26.
is taking a total daily dose of benzodiazepines greater than the equivalent of 4 mg/day of 
lorazepam on Day 1.
27.
has been included in any esketamine or ketamine clinical study, or has received an 
investigational drug (including investigational vaccines) or used an invasive 
investigational medical device within 60 days before the start of the screening phase, or 


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has participated in 2 or more MDD or other psychiatric condition clinical interventional 
studies (with different investigational medication) in the previous 1 year before baseline, 
or is currently enrolled in an investigational interventional study.
28.
any condition for which, in the opinion of the investigator, participation would not be in 
the best interest of the participant (eg, compromise the well-being) or that could prevent, 
limit, or confound the protocol-specified assessments.
29.
is a woman who is pregnant, breastfeeding, or planning to become pregnant or a man that 
plans to father a child while enrolled in this study or within 90 days after the last dose of 
study intervention.
30.
criterion added per Amendment 1.
has thyroid disease/disorder that has not been sufficiently treated:

pre-existing thyroid disease/disorder treated with thyroid hormones not on a stable 
dosage for 3 months prior to the start of the screening phase.

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 participant is not eligible.
31.
criterion added per Amendment 1.
has a white blood cell count (WBC) ≤2.0 × 103/µL at screening or history of drug induced 
neutropenia.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a participant’s clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study intervention is given 
such that he or she no longer meets all eligibility criteria, then the participant should be excluded 
from participation in the study. Section 5.4, Screen Failures, describes options for rescreening and 
retesting. The required source documentation to support meeting the enrollment criteria are noted 
in Appendix 3, Regulatory, Ethical, and Study Oversight Considerations: Source Documents.
5.3.
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions 
during the course of the study to be eligible for participation; following randomization, items 
9 through 12 will only apply to participants in the esketamine arm:
1.
refer to Section 6.5, Concomitant Therapy for details regarding prohibited and restricted 
therapy during the study.
2.
agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).


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3.
agree to remain at the study site at each visit until study procedures have been 
completed.
4.
agree to fast (water is permitted) for 8 hours before visits when clinical laboratory
(screening, Day 1, Week 8, Week 20, Week 32, 2-week safety follow-up visit) or 
optional biomarker (Day 1, Week 8) blood samples will be collected.
5.
agree to refrain from exercise/strenuous physical activity and the use of non-steroidal 
anti-inflammatory drugs (NSAIDs) for 24 hours before visits (Day 1, Week 8) when 
optional biomarker blood samples are collected, for applicable participants
6.
acknowledge that use of alcohol with study interventions in this study may cause 
sedation; therefore, alcohol consumption should be limited during the study.
7.
agree to restrict food and water intake from the time they arrive at the site for the 
baseline (Day 1) visit (once eligibility is confirmed and participants are randomly 
assigned to a study intervention arm, only those participants randomly assigned to the 
esketamine arm will be required to continue to restrict food and water intake [until after 
dosing]).
8.
agree to abstain from alcohol consumption for 24 hours before their baseline (Day 1) 
visit.
9.
agree to abstain from alcohol consumption for 24 hours before and after esketamine 
nasal treatment sessions.
10.
food will be restricted for at least 2 hours before each administration of esketamine 
nasal spray. Drinking of any fluids will be restricted for at least 30 minutes before the 
first nasal spray at each session.
11.
agree to remain at the study site after administration of esketamine nasal spray until the 
investigator determines clinically (ie, based on vital signs) that the participant is ready 
for discharge; the expected duration is up to 2 hours.
12.
agree to not to engage in potentially hazardous activities requiring complete mental 
alertness and motor coordination, such as driving a vehicle or operating machinery, 
after receiving esketamine nasal spray until the next day following a restful sleep. 
5.4.
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study-site contact for completeness.


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The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant 
identification and age at initial informed consent. In cases where the participant is not randomized 
into the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened, except where the reason for screen failure was that they did not meet the signs of 
minimal clinical improvement criteria (Section 8.1.1.1) on their current treatment with AD that 
includes an SSRI/SNRI. If a participant does not show signs of minimal clinical improvement at 
screening on their current treatment with AD, they may be rescreened (1 time) on the next 
consecutive line of treatment with AD (if it includes an SSRI/SNRI) after they have taken it at an 
adequate dosage for an adequate duration of at least 6 weeks. Participants who are rescreened will 
be assigned a new participant number, undergo the informed consent process, and then restart a 
new screening phase.
If clinical safety laboratory tests (serum chemistry, hematology, and urinalysis) or ECG results are 
abnormal at screening then retesting is allowed and screening may continue if a normal result is 
achieved. If the urine drug screen is positive on Day 1, the participant may have their Day 1 
(baseline) visit rescheduled 1 time, if negative on retest then the participant will be allowed to 
continue.
6.
STUDY INTERVENTION
6.1.
Study Interventions Administered
6.1.1.
Esketamine Nasal Spray in Combination With a Continuing
SSRI/SNRI
Study intervention (ie, esketamine nasal spray and continuing SSRI/SNRI) administration must be 
captured in the source documents and the electronic case report form (eCRF). Refer to 
Section 6.1.3, for information on the continuing SSRI/SNRI component of the study intervention.  
During the acute and maintenance phases, if esketamine nasal spray is discontinued at any visit, 
the participant will be switched to an alternative standard of care treatment, which may or may not
include the continuing SSRI/SNRI, at the discretion of the investigator. If the continuing 
SSRI/SNRI is discontinued at any visit, esketamine nasal spray must also be discontinued and the 
participant will be switched to an alternative standard of care treatment at the discretion of 
the investigator. If determined by the investigator that the alternative standard of care will 
include esketamine nasal spray (when commercially available in country of participation) or 
quetiapine XR for a participant, it will not be provided to the participant, rather, the investigator 
must prescribe the medication to the participant.
Participants who discontinue the study intervention early (ie, discontinue either component of the 
randomized combination therapy) will remain in the study and continue to return for all follow-up 
visits (every 2 weeks) according to the Schedule of Activities.


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Refer to Section 6.7 for information regarding standard of care treatment following completion of 
the study or early discontinuation of the study intervention.
6.1.1.1.
Esketamine Nasal Spray
Esketamine is provided as a nasal spray solution (eq. 140 mg/mL nasal spray) and is an aqueous 
solution of esketamine hydrochloride in water for injection, at a concentration of 161.4 mg/mL 
and an esketamine base equivalent concentration of 140 mg/mL, provided in a disposable single-
use nasal spray device. The device dispenses 2 sprays delivering a total volume of 0.2 mL of drug 
product containing a total of 32.3 mg of esketamine hydrochloride (equivalent to 28 mg of 
esketamine).
Esketamine nasal spray will be manufactured and provided under the responsibility of the sponsor. 
Refer to the IB for a list of excipients.
Each nasal spray device will be individually packaged in a blister tray and subsequently put into a 
carton box. Each carton box constitutes 1 non-child-resistant participant kit, labeled with a unique 
medication kit number. Study intervention labels will contain information to meet the applicable 
regulatory requirements.
Instructions for use documents for esketamine nasal spray administration will be provided for 
participants and healthcare providers.
Prior to the first nasal dose on Day 1, participants in the esketamine arm will practice spraying 
(into the air, not nasally) a demonstration nasal spray device that is filled with a placebo solution.
Food will be restricted for at least 2 hours before each administration of esketamine nasal spray. 
Drinking of any fluids will be restricted for at least 30 minutes before the first nasal spray at each 
session. Participants should abstain from alcohol consumption for 24 hours before and after 
esketamine nasal treatment sessions.
Nasal treatment sessions should not take place on 2 consecutive days. Dosing will be in an 
outpatient setting, or inpatient setting if participants are currently hospitalized. If the participant 
has nasal congestion on the dosing day, a nasal decongestant can be used to reduce congestion or 
the dosing day can be delayed (per the permitted visit window; see the Schedule of Activities). 
Participants who require a nasal corticosteroid or nasal decongestant on a dosing day should be 
advised not to administer these medicinal products 1 hour prior to esketamine nasal spray dosing.
Post-dosing, participants’ vital signs will be measured at approximately 40 minutes after 
esketamine nasal spray dose and subsequently as clinically warranted until blood pressure values 
decline. Participants must be monitored by a healthcare professional until the participant is 
considered clinically stable and ready to leave the study site. If blood pressure remains elevated 
for a prolonged period of time, assistance should promptly be sought from practitioners 
experienced in blood pressure management. Participants who experience symptoms of a 
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On all nasal dosing days, participants must remain at the study site until study procedures have 
been completed and they are ready for discharge. Participants must not engage in potentially 
hazardous activities requiring complete mental alertness and motor coordination, such as driving 
a vehicle or operating machinery, after receiving esketamine nasal spray until the next day 
following a restful sleep.
For a definition of esketamine nasal spray overdose, refer to Section 8.4, Treatment of Overdose.
6.1.1.2.
Esketamine Nasal Spray Dosing Recommendations
On Day 1, participants randomly assigned to the esketamine arm will have their first nasal 
treatment session as described in Section 6.1.1.3. Adult participants aged 18 to 64 years will start 
with a dose of 56 mg. Elderly participants aged 65 to 74 years and adults of Japanese ancestry will 
start with a dose of 28 mg. As of Day 4, the dose may be increased from 56 mg to 84 mg in adult 
participants, from 28 mg to 56 mg in elderly participants and adults of Japanese ancestry, or 
participants may remain at the starting dose, as determined by the investigator based on efficacy 
and tolerability. Elderly participants and adults of Japanese ancestry may be uptitrated in 28 mg 
increments at subsequent visits. Dosing may be increased at any visit, may remain the same, or 
may be reduced as determined by the investigator based on efficacy and tolerability (see 
Section 6.6.1, Figure 1 and Figure 2, respectively for adults Figure 3 and Figure 4, respectively for 
elderly participants and adults of Japanese ancestry). The highest dose that may be used in all 
participants is 84 mg.
The dosing recommendations for esketamine nasal spray for adults <65 years of age are shown in
Table 2 and for elderly participants 65 to 74 years of age, inclusive, and adults of Japanese ancestry 
in Table 3.
Table 2:
Recommended Dosing for Esketamine Nasal Spray in Adults <65 Years of Age
Weeks 1-4:
Starting Day 1 dose: 56 mg
Subsequent doses:
56 mg or 84 mg twice a week
Weeks 5-8:
56 mg or 84 mg once weekly
From Week 9:
56 mg or 84 mg every 2 weeks or 
once weekly
Evidence of therapeutic benefit should 
be evaluated at the end of Week 4 to 
determine need for continued 
treatment.
The need for continued treatment should be reexamined periodically. 
Beginning at the Week 8 visit and every 4 weeks thereafter, the 
treatment continuation assessment of study intervention (see Table 1) 
will be performed.


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Table 3:
Recommended Dosing for Esketamine Nasal Spray in Elderly Participants 65 to 74 Years of 
Age, Inclusive, and Adults of Japanese Ancestry
Weeks 1-4:
Starting Day 1 dose: 28 mg
Subsequent doses: 
28 mg, 56 mg, or 84 mg twice a 
week, all dose changes should be 
in 28 mg increments.
Weeks 5-8:
28 mg, 56 mg, or 84 mg once 
weekly, all dose changes should 
be in 28 mg increments.
From Week 9:
28 mg, 56 mg, or 84 mg every 
2 weeks or once weekly, all dose 
changes should be in 28 mg 
increments.
Evidence of therapeutic benefit should 
be evaluated at the end of Week 4 to 
determine need for continued 
treatment.
The need for continued treatment should be reexamined periodically. 
Beginning at the Week 8 visit and every 4 weeks thereafter, the 
treatment continuation assessment of study intervention (see Table 1) 
will be performed.
6.1.1.3.
Nasal Treatment Sessions
All participants in the esketamine arm will self-administer the esketamine nasal spray at nasal 
treatment sessions at the study site starting on Day 1. 
Esketamine nasal spray dosing and related safety-monitoring procedures MUST be performed 
LAST at all visits. Esketamine nasal spray must NOT be administered before all other visit 
assessments are completed.
Based on the dosing frequency in the maintenance phase, the last nasal treatment session will occur 
at Week 30 (every 2 weeks frequency) or Week 31 (once weekly frequency).
The esketamine nasal spray will be administered during nasal treatment sessions as described in
Table 4.
Table 4:
Nasal Treatment (Esketamine) Sessions
Nasal Study 
Intervention
Time of Administration 
0a
5 minutes
10 minutes
Nasal Device b
First
Second
Third
Esketamine 28 mg
1 spray of nasal spray
to each nostril
No device required
No device required
Esketamine 56 mg 
1 spray of nasal spray
to each nostril
1 spray of nasal spray 
to each nostril
No device required
Esketamine 84 mg
1 spray of nasal spray
to each nostril
1 spray of nasal spray
to each nostril
1 spray of nasal spray
to each nostril
a
Time 0 is defined as the time of administration of the first esketamine nasal spray to 1 nostril from the first 
nasal device.
b
One device will be used at each time point. Each nasal device contains 2 sprays. The esketamine nasal devices 
contain a total of 28 mg per individual device (ie, 2 sprays).
Recommendations for dose adjustments of esketamine nasal spray based on efficacy and 
tolerability during the acute and maintenance phases are provided in Section 6.6.1 in Figure 1 and 
Figure 2, respectively for adults and Figure 3 and Figure 4, respectively for elderly participants 
and adults of Japanese ancestry.


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6.1.1.4.
Acute (Weeks 1 to 8) and Maintenance (Weeks 9 to 32) Phases
Acute Phase: Week 1 to Week 8
The frequency of nasal treatment sessions will be twice weekly in Week 1 to Week 4 and will be 
reduced to once weekly in Week 5 to Week 8.
At the Week 4 visit, evidence of therapeutic benefit of the study intervention (ie, esketamine nasal 
spray in combination with continuing SSRI/SNRI) will be evaluated clinically by the investigator.
In the evaluation of therapeutic benefit, the full scope of clinical improvement should be evaluated 
including any improvement in depressive symptoms, general functioning, social functioning, and 
self-care. If there is no evidence of therapeutic benefit, the investigator and the participant should 
discuss the treatment strategy and mutually agree on whether to continue or discontinue 
esketamine nasal spray. At this visit, if esketamine nasal spray is discontinued, the participant will 
be switched to an alternative standard of care treatment, which may or may not include the 
continuing SSRI/SNRI, at the discretion of the investigator.
Beginning at the Week 8 visit, the treatment continuation assessment of study intervention (see
Section 4.1, Table 1) should be the basis for the decision to continue study intervention.
At the Week 8 visit the investigator will determine if a participant’s frequency of nasal treatment 
sessions during the maintenance phase should remain once weekly or be changed to every 2 weeks
based on the severity of depressive symptoms and their discretion.
Maintenance Phase: Week 9 to Week 32
The frequency of nasal treatment sessions for participants in the esketamine arm can be further 
individualized during this phase on even week visits (Week 10, Week 12, etc) from once weekly 
to every 2 weeks based on the severity of depressive symptoms and at the discretion of the 
investigator. If participants show early signs of worsening of depressive symptoms after reduced 
frequency of the nasal treatment sessions, the frequency can be changed back to once weekly at 
any visit. Nasal treatment session frequency should be increased prior to increasing the esketamine 
nasal spray dose during this phase. Uneven week visits will only be performed for participants 
who are on a once weekly dosing schedule. Recommendations for dose adjustments of esketamine 
nasal spray based on efficacy and tolerability during the acute and maintenance 
phases are provided in Section 6.6.1 in Figure 1 and Figure 2, respectively for adults and Figure 3
and Figure 4, respectively for elderly participants and adults of Japanese ancestry.
During this phase, the treatment continuation assessment of study intervention (Week 12, 
Week 16, etc) (see Section 4.1, Table 1) should be the basis for the decision to continue study 
intervention.
6.1.2.
Quetiapine Extended-Release in Combination With a Continuing 
SSRI/SNRI 
Study intervention (ie, quetiapine XR in combination with a continuing SSRI/SNRI) 
administration must be captured in the source documents and the eCRF. Study-site personnel will 
instruct participants on how to store quetiapine XR for at home use as indicated for this protocol.


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Refer to Section 6.1.3, for information on the continuing SSRI/SNRI component of the study 
intervention.  
Participants in this arm will have weekly visits from Week 1 to Week 4, and then every 2 weeks 
for the remainder of the acute phase (Week 6 and Week 8) and the maintenance phase (Week 10, 
Week 12, etc) through Week 32.If quetiapine XR is discontinued, the participant will be switched 
to an alternative standard of care treatment, which may or may not include the continuing 
SSRI/SNRI, at the discretion of the investigator. If the continuing SSRI/SNRI is discontinued at 
any visit, quetiapine XR must also be discontinued and the participant will be switched to an 
alternative standard of care treatment at the discretion of the investigator. If determined by the 
investigator that the alternative standard of care will include quetiapine XR or esketamine nasal 
spray (when commercially available in country of participation) for a participant, it will not be 
provided to the participant, rather, the investigator must prescribe the medication to the participant.
Participants who discontinue the study intervention early (ie, discontinue either component of the 
randomized combination therapy) will remain in the study and continue to return for all follow-up 
visits according to the Schedule of Activities.
Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhea, vomiting, dizziness 
and irritability have been described after the sudden discontinuation of quetiapine. Treatment 
discontinuation by gradual dose reduction over 1 to 2 weeks is recommended.
Refer to Section 6.7 for information regarding standard of care treatment following completion of 
the study or early discontinuation of the study intervention.
6.1.2.1.
Quetiapine Extended-Release
Quetiapine XR tablets will be obtained from commercial stock and will be re-packed (whenever 
required) into a child-resistant packaging to constitute a participant kit. These will be labeled 
according to applicable regulatory requirements, will be identified with a unique medication kit 
number, and provided under the responsibility of the sponsor. Storage should occur in accordance 
with the label. Please refer to the SmPCs (or local equivalents, if applicable) for the physical 
description and a list of excipients.
It is recommended that quetiapine XR be administered prior to bedtime, or as directed by the 
investigator based on individual participant circumstances.
Week 1 to Week 32
Participants will continue to take their current SSRI/SNRI which will be augmented with 
quetiapine XR as per the SmPC (or local equivalent, if applicable) starting on Day 1 and will 
continue through Week 32.
The recommended uptitration schedule for quetiapine XR for adults (aged 18 to 64 years) and 
elderly (aged 65 to 74 years) participants is provided in Table 5. Dosing may be adapted as 
determined by the investigator based on efficacy and tolerability.


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Quetiapine XR will be dispensed at the Day 1 visit and then as necessary at subsequent visits based 
on a participant’s dose. If necessary, participants may need to return for an unscheduled visit to 
allow for dispensing of a new supply of quetiapine XR to accommodate changes in dosing.
According to the SmPC (or local equivalent, as applicable) for quetiapine XR, the minimum 
therapeutic dose for add-on treatment of major depressive episodes in MDD is 150 mg/day. 
Participants should be uptitrated to at least 150 mg/day according to the recommended uptitration 
schedule and based on individual tolerability no later than the Week 2 visit (ie, end of Week 2). If 
participants cannot tolerate at least 150 mg/day of quetiapine XR by the end of Week 2 (or at any 
subsequent time during the study), they must have quetiapine XR discontinued.
The need to increase the dose from 150 up to 300 mg/day should be based on individual patient 
evaluation.
Table 5:
Recommended Uptitration Schedule for Quetiapine Extended-Release
Age Group
Day
Dosage
Adults (18-64 years) 
1-2
50 mg/day
3-4
150 mg/day
5 or after
300 mg/day (based on individual participant evaluation)
Elderly (65-74 years) 
1-3
50 mg/day
4-7
100 mg/day
8
150 mg/day
22 (no earlier than)
300 mg/day (based on individual participant evaluation)
Beginning at the Week 8 visit, the treatment continuation assessments of study intervention (see 
Section 4.1, Table 1) should be the basis for the decision to continue study intervention.
6.1.3.
Continuing SSRI/SNRI 
Participants will continue to take their current SSRI/SNRI as prescribed. For participants who are 
taking combination ADs and/or augmentation at screening, refer to Section 6.5 for guidance on 
discontinuing other AD treatment(s). The current SSRI/SNRI tablets or capsules being taken by 
participants will not be provided by the sponsor.
The continuing SSRI/SNRI being taken by a participant must be labeled for treatment of 
depression/MDD in their country of participation and the dosage being taken should be according 
to the respective SmPC (or local equivalent, if applicable). Off-label use of an SSRI/SNRI is not 
permitted.
The investigator may optimize the dose of the continuing SSRI/SNRI, up to the maximum tolerated 
dose as per the respective SmPC (or local equivalent, if applicable). Once optimized, a stable dose 
should be maintained; however, dose modifications may be made, if necessary, at the 
investigator’s discretion.
6.1.4.
Medical Devices

The sponsor-manufactured medical devices (or devices manufactured for the sponsor by a 
third party) provided for use in this study are disposable single-use nasal spray devices.


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
Instructions for medical device use documents for esketamine nasal spray administration will 
be provided for participants and healthcare providers.

All device deficiencies (including malfunction, use error, and inadequate labeling) shall be 
documented and reported by the investigator throughout the clinical investigation, see 
Section Error! Reference source not found.,
Medical Device Deficiencies, and 
appropriately managed by the sponsor.
6.2.
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study intervention component preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study intervention components (ie, esketamine 
nasal spray and quetiapine XR) received at the site are inventoried and accounted for throughout 
the study.
The esketamine nasal spray administered to the participant must be documented on the intervention 
accountability form. All esketamine nasal spray will be stored and disposed of according to the 
sponsor’s instructions.
The dispensing of quetiapine XR, and the return of quetiapine XR from the participant (if 
applicable), must be documented on the intervention accountability form. Participants must be 
instructed to return all original containers, whether empty or containing quetiapine XR. Study-site 
personnel must not combine contents of the quetiapine XR containers.
Study intervention components 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 and used esketamine nasal spray, and 
quetiapine XR returned by the participant, 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 
intervention components, or used returned study intervention components for destruction, will be 
documented on the intervention return form. When the study site is an authorized destruction unit 
and study intervention component supplies are destroyed on-site, this must also be documented on 
the intervention return form.
Study intervention components 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 intervention 
components will be supplied only to participants participating in the study. Returned study 
intervention components must not be dispensed again, even to the same participant. Whenever a 
participant brings his or her quetiapine XR to the study site for pill count, this is not seen as a 
return of supplies. Study intervention may not be relabeled or reassigned for use by other 
participants. The investigator agrees neither to dispense the study intervention components from, 
nor store them at, any site other than the study sites agreed upon with the sponsor. Further guidance 


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and information for the final disposal of unused study intervention components are provided in the 
pharmacy manual/study-site investigational product and procedures manual.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of 2 study intervention groups in a 1:1 ratio based on a computer-generated randomization 
schedule prepared before the study by or under the supervision of the sponsor. The randomization 
will be balanced by using randomly permuted blocks and will be stratified by age (18 to 64 years
[inclusive]; 65 to 74 years [inclusive]) and total number of treatment failures (2; 3 or more
[inclusive of current antidepressive treatment at screening used to determine eligibility]).
The interactive web response system (IWRS) will assign a unique intervention code, which will 
dictate the intervention assignment and matching study intervention kit (esketamine nasal spray or
quetiapine XR) for the participant. The requestor must use his or her own user identification and 
personal identification number when contacting the IWRS and will then give the relevant 
participant details to uniquely identify the participant.
Blinding
As this is an open-label study, study intervention blinding procedures are not applicable.
To minimize bias, the MADRS (total score is used for primary and key secondary endpoints) will 
be assessed by a qualified independent rater-blinded to the participant’s treatment and who is not 
involved in any other study assessments or treatment decisions for a given study participant (see 
Section 8.1.1.2).
6.4.
Study Intervention Compliance
All doses of esketamine nasal spray will be self-administered by the participants at the 
investigative site under the direct supervision of the investigator or designee and will be recorded.
Participants will receive instructions on compliance with quetiapine XR dosing. During the study, 
the investigator or designated study-site personnel will be responsible for providing additional 
instruction to re-educate (ie, medication compliance counseling) any participant to ensure 
compliance with taking quetiapine XR.
The investigator or designated study-site personnel will maintain a log of all esketamine nasal 
spray devices self-administered by participants and of the oral study intervention component (ie, 
quetiapine XR) dispensed and returned. Study intervention component supplies for each 
participant will be inventoried and accounted for throughout the study.
Quetiapine XR compliance will be assessed by performing pill counts (ie, compliance check) and 
drug accountability at the time points specified in the Schedule of Activities.


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The SSRIs/SNRIs are not provided by the sponsor. Study-site personnel will provide medication 
compliance counseling regarding the continuing SSRI/SNRI to all participants at the time points 
specified in the Schedule of Activities.
6.5.
Concomitant Therapy
Prestudy non-AD therapies administered up to 30 days before screening must be recorded.
All consecutive treatment(s) with AD taken at an adequate dosage (based on antidepressive 
dosages from label) for adequate duration of at least 6 weeks, including adjunctive treatment for 
MDD, during the current moderate to severe depressive episode (ie, including those taken more 
than 30 days prior to screening) will be documented at screening (see Appendix 3, Regulatory, 
Ethical, and Study Oversight Considerations: Source Documents).
Participants who were taking ≤50 mg/day of quetiapine (XR or immediate-release) at screening 
(eg, for insomnia or agitation) are allowed to enter the study provided it is washed-out by at least 
7 days prior to randomization.
Participants who are taking combination ADs and/or augmentation (other than quetiapine XR, 
which is exclusionary at doses >50 mg/day for the current moderate to severe depressive episode) 
at screening must stop all AD treatment, including any augmenting substances, prior to 
randomization on Day 1, except the SSRI/SNRI to be continued.

For participants taking combination therapy with an SSRI/SNRI and an antipsychotic 
medication or any other augmenting substances, the antipsychotic medication and other 
augmenting substances need to be down-titrated and stopped prior to randomization. The 
investigator should follow the SmPCs (or local equivalents, if applicable) for all treatments 
that need to be discontinued. Although not standard practice, should a participant be taking 
more than 1 SSRI/SNRI at screening, the investigator should choose the one most likely to 
have a beneficial effect on depressive symptoms when combined with intranasal esketamine 
or augmented with quetiapine XR, based on individual participant characteristics. The choice 
of the SSRI/SNRI to continue should take into account potential side-effects when given in 
combination with quetiapine XR, should the patient be randomized to that arm. 
A list of prohibited concomitant medications is provided in Appendix 4 as general guidance for 
the investigator (but is not all-inclusive). Investigators should refer to the applicable SmPCs (or 
local equivalent, if applicable) for prohibited concomitant medications for the continuing 
SSRI/SNRI. Any prescribed medications will not be discontinued without the agreement of the 
participant’s treating physician.
Drugs of abuse (including barbiturates, methadone, opiates, cocaine, cannabinoids, PCP, and 
amphetamine/methamphetamine) are not permitted during the study. If a participant has a positive 
urine test result(s) for drugs of abuse on Day 1 prior to randomization, the participant may have 
their Day 1 visit rescheduled 1 time. If negative on retest then the participant will be eligible if 
remaining inclusion and exclusion criteria are confirmed. See Section 8.2.4, Clinical Safety 
Laboratory Assessments, for additional information on the timing of the urine drug screen at 
baseline (Day 1) visit.


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If a participant is prescribed psychostimulants (eg, amphetamine, methylphenidate) for MDD, the 
medication must be discontinued at screening and participants must agree not to take during the 
study. The investigator should allow adequate time between the screening and randomization visit 
for wash-out of these medications. Participants will be excluded if they have a positive urine test 
result for a prescribed psychostimulant for MDD prior to randomization on Day 1 (as above, 
1 retest will be allowed). However, participants prescribed psychostimulants for indications other 
than MDD (eg, attention deficit hyperactivity disorder) are permitted to continue taking this 
medication during the study. Use of psychostimulants for recreational use is not allowed during 
the study.
Electroconvulsive therapy is not allowed during the study while the participant is receiving study 
intervention. If study intervention is discontinued early, ECT is allowed as a standard of care 
treatment and it must be recorded in the eCRF.
Participants should continue to take their permitted concomitant medications (eg, antihypertensive 
medications) at their regular schedule; however, restrictions related to timing of certain 
medications on days of nasal treatment sessions in the esketamine arm as outlined in Appendix 4, 
Prohibited Concomitant Medications, should be considered.
Concomitant therapies (including psychotherapy) must be recorded throughout the study 
beginning with signing of the informed consent and continuing up to the last visit. Concomitant 
therapies should also be recorded beyond the last study visit only in conjunction with new or 
worsening AEs until resolution of the event.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as psychotherapy, acupuncture, special diets, and 
exercise regimens) different from the study intervention must be recorded in the eCRF.
Modification of an effective pre-existing therapy should not be made for the explicit purpose of 
entering a participant into the study, unless permitted by protocol (eg, adjustment of blood pressure 
medications).
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
6.5.1.
Psychotherapy
The investigator needs to ensure that participants have all necessary information for 
psychotherapeutic options available. To minimize bias, psychotherapy has to be discussed with 
the participant prior to randomization.
During this discussion, participants who are currently undergoing psychotherapy should be 
encouraged by the investigator to continue it during the study. In addition to psychotherapy, 
supportive therapies like psycho-education and/or counseling should be continued.
For participants not currently undergoing psychotherapeutic intervention, investigators should 
discuss available options in line with routine clinical practice; this discussion must be documented 


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by the investigator. If considered as beneficial and in line with national (eg, German Society for 
Psychiatry, Psychotherapy and Neurology S3 Guidelines, 2015; National Institute for Health and 
Care Excellence [NICE] Guidelines, 2010) and international guidelines (eg, World Federation of 
Societies of Biological Psychiatry Guidelines, 2013), the investigator should recommend to 
participants that they should seek psychotherapy. The selection of the psychotherapeutic 
intervention is at the discretion of the investigator and should be individually selected according 
to local availability (internal or external) and should reflect the needs and preference of a 
participant. Participants must choose if they will start psychotherapy and what type of 
psychotherapy prior to randomization. Due to waiting time in settings with limited availability, 
participants are allowed to start their first psychotherapeutic session after randomization according 
to their choice prior to randomization.
All standardized psychotherapy, psycho-education, support, or counseling that participants were 
undergoing prior to the study or individually prescribed and started based on the choice before 
randomization should be categorized into the appropriate category: 1. Cognitive–behavioral
therapy (CBT); 2. Nondirective supportive therapy (SUP); 3. Behavioral activation therapy (BA);
4. Psychodynamic therapy (DYN); 5. Systemic therapy; 6. Problem-solving therapy (PST);
7. Interpersonal psychotherapy (IPT); 8. Social skills training (SST); 9. Other (any standardized 
intervention that cannot be captured under 1 to 8). The category of psychotherapeutic intervention,
start date, stop date, frequency, reason for starting, reason for stopping, reason for change to 
another psychotherapeutic intervention, and participant’s adherence to the psychotherapeutic 
intervention must be documented accordingly in the source documents and on the concomitant 
therapy eCRF.
Participants will not be provided with psychotherapy by the study sponsor but will be allowed to 
receive it from external providers based on local standard-of-care and infrastructural availability.
If available, participants may receive psychotherapy at the site. The study sponsor will not 
reimburse for psychotherapy.
6.6.
Dose Modification
Any dose/dosage adjustment should be overseen by medically-qualified study-site personnel 
(principal or subinvestigator unless an immediate safety risk appears to be present) and should be 
documented in the participant’s source document as well as in the eCRF.
6.6.1.
Esketamine Nasal Spray
The decision to proceed to the next dose level of esketamine nasal spray (either an increase or a 
decrease) will be made by the investigator based on safety, tolerability, and efficacy assessed for 
each individual participant at their current dose level.
When the investigator wants to reduce nasal treatment in a stable episode, the dosing frequency 
should be reduced before considering reducing the dosage.
Recommendations for dose modification of esketamine nasal spray based on efficacy and 
tolerability during the acute and maintenance phases are provided in Figure 1 and Figure 2, 


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respectively for adults and Figure 3 and Figure 4, respectively for elderly participants and adults 
of Japanese ancestry.
Figure 1:
Adults: Recommendations for Dose Modification of Esketamine Nasal Spray to Optimize 
Efficacy During the Acute and Maintenance Phases
Notes: During the maintenance phase, the frequency of treatment with esketamine nasal spray may be individualized on even week visits from 
once weekly to every 2 weeks based on severity of depressive symptoms and at the discretion of the investigator. If participants show 
early signs of worsening of depressive symptoms after reduced treatment frequency, the treatment frequency can be changed back to 
once weekly at any visit.
Figure 2:
Adults: Recommendations for Dose Modification of Esketamine Nasal Spray to Handle 
Decreased Tolerability During the Acute and Maintenance Phases


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Figure 3:
Elderly and Adults of Japanese Descent: Recommendations for Dose Modification of 
Esketamine Nasal Spray to Optimize Efficacy During the Acute and Maintenance Phases
Notes: During the maintenance phase, the frequency of treatment with esketamine nasal spray may be individualized on even week visits from 
once weekly to every 2 weeks based on severity of depressive symptoms and at the discretion of the investigator. If participants show 
early signs of worsening of depressive symptoms after reduced treatment frequency, the treatment frequency can be changed back to 
once weekly at any visit.
Figure 4:
Elderly and Adults of Japanese Descent: Recommendations for Dose Modification of 
Esketamine Nasal Spray to Handle Decreased Tolerability During the Acute and Maintenance 
Phases


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6.6.2.
Quetiapine Extended-Release
The decision to proceed to the next dose level of quetiapine XR (either an increase or a decrease) 
will be made by the investigator based on safety, tolerability, and efficacy assessed for each 
individual participant at their current dose level and according to the SmPC (or local equivalent, 
if applicable). Additional information regarding dose adjustments is provided in Section 6.1.2.1.
6.6.3.
Continuing SSRI/SNRI
For the continuing SSRI/SNRI, the decision to proceed to the next dose level (either an increase 
or a decrease) will be made by the investigator based on safety, tolerability, and efficacy assessed 
for each individual participant at their current dose level and according to the respective SmPC (or 
local equivalent, if applicable).
Additional information regarding dose adjustments is provided in Section 6.1.3, Continuing 
SSRI/SNRI.
6.7.
Intervention After the End of the Study
After participants have completed study intervention (Week 32), they should return to their 
primary physician to determine standard of care. In exceptional situations, where participants 
would not have access to commercially available esketamine nasal spray, those participants who, 
at the discretion of the investigator, could benefit from continuing treatment with esketamine nasal 
spray following their Week 32 visit, will be advised on how continuation of treatment can be 
assured. Country-specific details on accessibility will be evaluated by the sponsor on a case-by-
case basis considering, among others, regulatory and operational requirements.
Participants who discontinue esketamine nasal spray or quetiapine XR early (ie, before Week 32), 
continue in the study and will be switched to an alternative standard of care treatment, which may 
or may not include the continuing SSRI/SNRI, at the discretion of the investigator. If determined 
by the investigator that the alternative standard of care will include esketamine nasal spray (when 
commercially available in country of participation) or quetiapine XR for a participant, it will not 
be provided to the participant, rather, the investigator must prescribe the medication to the 
participant.
Standard of care treatment after completion of the study is at the discretion of the investigator or 
primary physician; there is no requirement to change a participant’s standard of care treatment 
when they complete the study at Week 32.
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
A participant’s study intervention must be discontinued if:

The participant withdraws consent to receive study intervention.


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
The investigator believes that for safety reasons or tolerability reasons (eg, AE), not expected 
to be resolved by dose and/or frequency adjustment, it is in the best interest of the participant 
to discontinue study intervention.

The investigator believes there is no evidence of clinical improvement and further 
continuation of study intervention would not be in the best interest of the participant.

A participant in the comparator arm cannot tolerate at least 150 mg/day of quetiapine XR by 
the end of Week 2, or at any subsequent time during the study.

The participant becomes pregnant. Refer to Appendix 6, Contraceptive and Barrier Guidance 
and Collection of Pregnancy Information.
Participants who discontinue study intervention early (ie, discontinue either component of the 
randomized combination therapy) for any reason (except withdrawal of consent, lost to follow-up, 
or death) before the end of the study will remain in the study and continue to return for all follow-up 
visits according to the Schedule of Activities through Week 32 (safety follow-up visit is performed 
as part of first 2-week follow-up visit).
Study intervention assigned to the participant who discontinued study intervention may not be 
assigned to another participant. Additional participants will not be entered.
7.2.
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death
When a participant withdraws before study completion for any reason, the reason for withdrawal 
is to be documented in the eCRF and in the source document. If the reason for withdrawal from 
the study is withdrawal of consent, then no additional assessments are allowed.
Participants who withdraw early from the study must return for the safety follow-up visit 2 weeks 
after their last dose of study intervention (ie, day when either component of the randomized 
combination therapy is stopped), unless they withdraw consent, are lost to follow-up, or have died.
7.2.1.
Withdrawal From the Use of Research Samples
A participant who withdraws from the study will have the following options regarding the optional 
research samples (ie, biomarker and/or DNA/RNA samples):

The collected sample(s) will be retained and used in accordance with the participant’s original 
separate informed consent for optional research samples.

The participant may withdraw consent for optional research sample(s), in which case the 
sample(s) will be destroyed and no further testing will take place. To initiate the sample 
destruction process, the investigator must notify the sponsor study site contact of withdrawal 
of consent for the optional research sample(s) and to request sample destruction. The sponsor 


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study site contact will, in turn, contact the appropriate sponsor representative to execute 
sample(s) destruction. If requested, the investigator will receive written confirmation from the 
sponsor that the sample(s) have been destroyed.
Withdrawal From the Optional Research Samples While Remaining in the Main Study
The participant may withdraw consent for optional research sample(s) while remaining in the 
study. In such a case, the optional research sample(s) will be destroyed. The sample destruction 
process will proceed as described above.
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of sample(s) for research (refer to Long-Term 
Retention of Samples for Additional Future Research in Appendix 3, Regulatory, Ethical, and 
Study Oversight Considerations). In such a case, sample(s) will be destroyed after they are no 
longer needed for the clinical study. Details of the sample retention for research are presented in 
the separate ICF for optional research samples.
7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed 
lost to follow-up until all reasonable efforts made by the study-site personnel to contact the 
participant are deemed futile. The following actions must be taken if a participant fails to return to 
the study site for a required study visit:

The study-site personnel must attempt to contact the participant to reschedule the missed visit 
as soon as possible, to counsel the participant on the importance of maintaining the assigned 
visit schedule, to ascertain whether the participant wishes to or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make every 
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, 
e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address, 
or local equivalent methods. These contact attempts should be documented in the participant’s 
medical records.

Should the participant continue to be unreachable, they will be considered to have withdrawn 
from the study.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities (Section 1.3) summarizes the frequency and timing of efficacy, 
biomarker, pharmacogenomic, and safety measurements applicable to this study.
The MINI used to confirm the diagnosis of single-episode MDD or recurrent MDD, without 
psychotic features, and the IDS-C30 used to determine symptom severity at screening are 
described in Section 8.1.1.1, Screening Evaluations.


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Visit-specific
PRO assessments should be conducted/completed
before clinician-rated 
assessments, any tests (other than the urine drug screen at baseline visit [Day 1]), procedures, other 
consultations, or administration of esketamine nasal spray (in applicable participants) to prevent 
influencing participant perceptions.
Actual dates of PRO and clinician-rated assessments will be recorded in the source documentation 
and eCRF.
A serum pregnancy test (central laboratory) will be performed during screening. Urine pregnancy 
tests (at site/local) will be performed on Day 1 and throughout the study in accordance with the 
Schedule of Activities (Section 1.3). 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 participation in the study. Counseling on pregnancy prevention 
will be provided at all visits, when applicable.
For each participant, the total blood drawn in this study will be approximately 30 mL. When 
optional biomarker and/or DNA/RNA samples are collected, approximately 48.5 mL (biomarker: 
two 10 mL samples per visit [40 mL total]; DNA: one 6 mL sample; RNA: one 2.5 mL sample) 
will be collected from each participant.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form.
Refer to the Schedule of Activities 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.
Study-Specific Materials
The investigator will be provided with the following supplies:

Practice nasal devices

Investigator’s Brochure for esketamine

SmPC (or local equivalent, if applicable) and local prescribing information for quetiapine XR
provided in English

Investigational Product Binder, including the investigational product procedures manual

Instructions for product quality complaint (PQC) reporting requirements

Clinician-administered and participant-completed outcomes assessments


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
Rater qualifications/requirements for select clinician-administered assessments

Electronic devices and associated materials, as applicable

IWRS Manual

Instructions for use documents for esketamine nasal spray for participants and healthcare 
providers

Procedural documents for Site-Independent Qualification Assessment

Independent Ethics Committee (IEC)/Institutional Review Board (IRB) approved participant 
materials

Central laboratory manual and materials
8.1.
Efficacy Assessments
8.1.1.
Clinician-Rated
At all scheduled visits indicated in the Schedule of Activities, all clinician-rated scales must be 
completed prior to administration of esketamine nasal spray (in applicable participants).
8.1.1.1.
Screening Evaluations
Mini International Neuropsychiatric Interview (MINI)
Participants will undergo the MINI30 (a brief, structured diagnostic interview) to confirm the 
diagnosis of MDD and to determine if there are other psychiatric conditions present. It has an 
administration time of approximately 60 to 80 minutes.
Inventory of Depressive Symptomatology Clinician-Rated 30 Items Scale (IDS-C30)
Participants will undergo the 30-item IDS-C30 at screening and baseline to assess the severity of 
depressive symptoms. The 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 major depressive episode.27 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.32 It has an 
administration time of approximately 30 minutes.
Guidance for Screening Interview to Determine Clinical Improvement
As part of screening, a retrospective evaluation of how much the participant has clinically 
improved on their current treatment with AD, which must include an SSRI/SNRI, will be 
performed. Even though a participant’s current treatment with AD must have resulted in 
nonresponse (less than 25% improvement of symptoms), the participant must show signs of 
minimal clinical improvement to be eligible for the study.
The qualified psychiatric interview is the core element of psychiatric examination. At screening, 
all sources available should be used to gather the necessary information to evaluate symptom 
improvement under a current antidepressive treatment.


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Clinical improvement will be assessed retrospectively starting on the date of initiation of the 
current antidepressive treatment through the date of the screening interview, which must not be 
performed until the potential participant has been on their current antidepressive treatment at an 
adequate dosage for an adequate duration of at least 6 weeks. During this retrospective assessment 
of clinical improvement, the following should be considered:
1.
All available patient files, referral letters, communication from treating physicians and the 
information the potential participant gives to evaluate the severity of the depressive syndrome 
at the timepoint of the initiation of the current treatment.
2.
During the psychiatric interview the following sources of information have to be taken in 
consideration to evaluate the validity of verbal information given by the potential participant: 
appearance, voice, facial expression, gesture, psychomotor activities, personal hygiene, 
general behavior.
3.
If medical records and or referral letters, etc. are available, the interviewer should verify and 
check the congruence with the potential participant’s statements.
4.
The potential participant should be given the opportunity to describe in detail and in their own 
words how they feel and let them give examples of what has changed since treatment 
initiation.
In the clinical psychiatric interview, the following dimensions of depression must be evaluated, 
and the interviewer needs to determine if there has been any improvement (after an adequate 
dosage for an adequate duration of at least 6 weeks) compared to the time point of the initiation 
of the current antidepressive treatment:

Depressive symptoms: reported sadness, inner tension, reduced sleep/hypersomnia, 
reduced/increased appetite, concentration difficulties, lassitude, exhaustibility, inability to 
feel, pessimistic thought, feeling of guilt, suicidal thoughts, somatic symptoms (body pain, 
headache, changes in digestions, etc)

Social functioning: Social interaction in the family, social interaction outside of family, 
pleasure in social interaction

General functioning: Ability to work/go to school, ability to take care of home 
responsibilities

Self-care: Body hygiene, clean and tidy clothes, general healthy behavior
In the evaluation of signs of clinical improvement, the full scope of potential clinical improvement 
should be evaluated. To be considered as showing signs of minimal clinical improvement, the 
participant must have “minimal improvement” in at least 1 domain and not “significant 
improvement” in any domain. If there is “no improvement at all” in all domains, the participant is 
not eligible for the study.


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Based on the evaluation by an experienced clinician, does the potential participant show any 
clinical improvement since the current treatment was initiated?
No improvement at all, or 
deterioration 
Minimal improvement
Significant improvement 
Depressive symptoms
Social functioning
General functioning
Self-care
If a participant does not show signs of minimal clinical improvement at screening on their current 
treatment with AD, which must include an SSRI/SNRI, they may be rescreened (1 time) on the 
next consecutive line of treatment with AD (if it includes an SSRI/SNRI) after they have taken it 
at an adequate dosage for an adequate duration of at least 6 weeks. Participants who are rescreened 
will be assigned a new participant number, undergo the informed consent process, and then restart 
a new screening phase.
8.1.1.2.
Montgomery-Asberg Depression Rating Scale (MADRS)
The MADRS is a clinician-rated scale designed to measure depression severity and detect changes 
due to AD treatment.21 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 at the time points specified in the Schedule of Activities.
Rating of the MADRS will be blinded (ie, to study intervention assignment) and will be conducted 
face-to-face with the participants by an independent rater. The independent rater should have 
sufficient qualifications as documented by experience or training prior to being assigned as rater. 
To minimize bias, the independent rater should not be involved in any study assessments, other 
than performing the MADRS rating, or treatment decisions for a given study participant. To avoid 
interrater variability, all efforts should be made to have the same independent rater rating the same 
study participants as much as possible. The MADRS takes about 30 minutes to complete.
The primary and secondary endpoints, as described in Section 3, use the rater-blinded MADRS 
(total score) to determine remission at Week 8 and as part of the criteria for relapse after Week 8.
8.1.1.3.
Clinical Global Impression – Severity (CGI-S) and Change (CGI-C)
The CGI-S and CGI-C are observer-rated scales that measure illness severity (CGI-S) and global 
improvement or change (CGI-C).13 The CGI has proved to be a robust measure of efficacy in many 
clinical drug trials, and is easy and quick to administer. The CGI-S is rated on a 7-point scale, with 
the severity of illness scale using a range of responses from 1 (normal) through to 7 (among the 
most severely ill participants). CGI-C scores range from 1 (very much improved) through to 
7 (very much worse) as compared to baseline. The CGI-S and CGI-C each take about 15 minutes 
to complete.


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Beginning at the Week 8 visit, the CGI-C scores (referring to study baseline [Day 1]) will be used 
in the treatment continuation assessment (Section 4.1, Table 1) that is performed every 4 weeks in 
participants who are taking study intervention. For participants who discontinue study intervention 
early, the CGI-C will still be performed at follow-up visits according to the Schedule of Activities; 
however, treatment decisions will be at the discretion of the investigator and not based on the 
criteria for the treatment continuation assessment.
8.1.2.
Patient-Reported Outcomes
Patient-reported outcomes will be completed by the participants at the timepoints indicated in the 
Schedule of Activities. As previously noted, all PRO assessments must be conducted/completed 
before clinician-rated assessments, any tests (other than the urine drug screen at baseline visit 
[Day 1]), procedures, other consultations, or administration of esketamine nasal spray (in 
applicable participants).
The PRO assessments should be performed in the order as listed in the subsections below and in 
the Schedules of Activities in Section 1.3.
8.1.2.1.
Patient Health Questionnaire, 9-Item (PHQ-9)
The PHQ-9 is a validated 9-item, PRO measure to assess depressive symptoms.31 The scale scores 
each of the 9-symptom domains of the DSM-5 MDD criteria and it has been used both as a 
screening tool and a measure of response to treatment for depression. Each item is rated on a 
4-point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). 
The participant’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 PHQ-9 takes about 5 minutes to 
complete.
8.1.2.2.
Quality of Life in Depression Scale (QLDS)
The QLDS is a disease-specific validated PRO measure which assesses the impact 
that depression has on a participant’s quality of life.14,20,33 It is a 34-item self-rated questionnaire 
which consists of dichotomous response questions, with the response being either True/Not 
True. It is scored binomially (0-1) and high scores on the QLDS indicate a lower quality of life. 
The scale has good reliability and internal consistency and has wide applicability. It has been 
shown to be user-friendly, both for respondents and investigators. The QLDS takes about 
10 minutes to complete.
8.1.2.3.
European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level 
(EQ-5D-5L)
The EQ-5D-5L is a validated standardized instrument for use as a measure of health outcome, 
primarily designed for self-completion by respondents.10,11 It consists of the EQ-5D-5L descriptive 
system and a 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).


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The participant 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 5 minutes.
8.1.2.4.
36-Item Short-Form Health Survey (SF-36v2)
The SF-36 is a validated 36-item questionnaire which measures quality of life across 8 domains, 
which are both physically and emotionally based.19,34 The 8 domains that the SF-36 measures are 
as follows: physical functioning; role limitations due to physical health; role limitations due to 
emotional problems; energy/fatigue; emotional wellbeing; social functioning; pain; general health. 
A single item is also included that identifies perceived change in health, making the SF-36 a useful 
indicator for change in quality of life over time and treatment. In addition to the 8 scales,
2 summary scales are calculated: the physical component summary scale (PCS) and the mental 
component summary scale (MCS). For each of the 8 domains and the 2 summary scales that the 
SF-36 measures, a norm-based score is produced. Higher scores indicate better functioning or 
quality of life. Version 2 of this questionnaire, with a 4-week recall (standard version) will be used 
for this study. The SF-36 takes about 15 minutes to complete.
8.1.2.5.
Sheehan Disability Scale (SDS)
The SDS will be used to assess the secondary objective of functional impairment and associated 
disability. The SDS is a validated PRO measure consisting of a 5-item questionnaire that has been 
widely used and accepted for assessment of functional impairment and associated disability.18,29
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 scores for the first 3 items are summed to 
create a total score of 0 to 30, where higher score indicates greater impairment. The SDS takes 
about 5 minutes to complete.
8.1.2.6.
Work Productivity and Activity Impairment (WPAI): Depression (D)
The WPAI:D questionnaire is a validated short instrument that assesses impairment in work and 
other regular activities over the past 7 days.26 The WPAI questionnaire assesses 4 separate 
measures: absenteeism (ie, the proportion of work time missed due to MDD), presenteeism (ie, the 
degree of impairment while working due to MDD), work productivity loss (ie, overall work 
impairment due to MDD/absenteeism plus presenteeism), and activity impairment (ie, the degree 
of impairment of regular, nonwork activity due to MDD). WPAI scores are expressed as percent 
impairment, with higher values indicating greater impairment. The WPAI:D takes about 5 minutes
to complete.
8.2.
Safety Assessments 
In the esketamine arm, on all nasal treatment session days, participants must remain at the site until 
study procedures have been completed and the participant is ready for discharge. Participants must
not engage in potentially hazardous activities requiring complete mental alertness and motor 


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coordination, such as driving a vehicle or operating machinery, after receiving esketamine nasal 
spray until the next day following a restful sleep.
A list of prohibited concomitant medications is provided in Appendix 4 as general guidance for 
the investigator (but is not all-inclusive).
Adverse events will be reported and followed by the investigator as specified in Section 8.3, 
Adverse Events and Serious Adverse Events and Appendix 5, Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-Up, and Reporting.
Any clinically relevant changes occurring during the study (from the time the informed consent is 
signed) must be recorded on the Adverse Event section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early study withdrawal
will be followed by the investigator until resolution or until a clinically stable condition is reached.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Schedule of Activities.
8.2.1.
Physical Examinations
Physical Examination
A physical examination will be performed at screening.
Body Weight and Height
Body weight will be measured as per the Schedule of Activities. Height will be measured at 
Screening.
Nasal Examinations
Nasal examinations (including the upper respiratory tract/throat) will be conducted by a qualified 
healthcare practitioner authorized by local regulation to conduct a physical examination. The 
objective of the examination at screening is to rule out any participants with anatomical or medical 
conditions that may impede drug delivery or absorption.
Subsequent examinations will only be performed in participants randomly assigned to the 
esketamine arm and 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.
8.2.2.
Vital Signs
Pulse/heart rate, respiratory rate, and blood pressure will be assessed.
Blood pressure and pulse/heart rate measurements will be assessed supine with a completely 
automated device or using manual techniques.


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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).
8.2.3.
Electrocardiograms
During the collection of local ECGs, participants should be in a quiet setting without distractions 
(eg, television, cell phones). Participants should rest in a supine position for at least 5 minutes 
before ECG collection and should refrain from talking or moving arms or legs.
Participants ECGs will be collected at screening, baseline (Day 1), and at additional time points 
identified in the Schedule of Activities. If ECG results are abnormal at screening, then retesting is 
allowed and screening may continue if a normal result is achieved. The ECG does not need to be 
repeated at baseline if the screening ECG was performed within 1 week before the Day 1 visit.
Electrocardiograms may be performed at the investigator’s site or at an external facility. The ECGs 
should be interpreted by a qualified reader, with sufficient clinical experience in ECG 
interpretation, at screening and with all subsequent ECGs compared to the screening ECG and 
post-screening ECGs to determine clinically relevant changes. If performed at an external facility, 
a report for each ECG, along with clinically relevant changes from the screening or post-screening 
ECGs will be provided to the investigator
prior to a participant’s scheduled visit. 
Electrocardiograms may be performed up to 1 week before a visit to allow time for the report to 
be sent to the investigator. The investigator is required to review the ECG report (internal or 
external) at the participant’s visit to assess for any potential safety concerns related to study 
intervention, as per respective SmPCs (or local equivalent, if applicable). Based on the review of 
the ECG report, the investigator should determine if it is appropriate to continue study intervention. 
The investigator must document this review and record any clinically relevant changes occurring 
during the study in the AE section of the eCRF. The ECG reports (internal or external) must be 
filed with the source documents.
If participants ECGs result in abnormalities, retesting may be conducted at the discretion of the 
investigator at screening or at any time during the study for individual participants based on 
potential safety concerns (eg, QT interval prolongation) that may be associated with study 
intervention (as per SmPCs [or local equivalents, where applicable]). For participants with 
clinically significant ECG abnormalities, the investigator should refer the participant to a 
cardiologist for follow-up.
If blood sampling or vital sign measurement is scheduled for the same time point as ECG 
recording, the procedures should be performed in the following order: ECG(s), vital signs, blood 
draw.
8.2.4.
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will 
be collected at screening, baseline (Day 1), and at additional time points identified in the Schedule 
of Activities and as noted in Appendix 2, Clinical Laboratory Tests. Participants should fast for at 
least 8 hours prior to visits when blood samples will be collected. The investigator must review 


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the laboratory results, document this review, and record any clinically relevant changes occurring 
during the study in the AE section of the eCRF. The laboratory reports must be filed with the 
source documents.
If clinical safety laboratory tests (serum chemistry, hematology, and urinalysis) results are 
abnormal at screening then retesting is allowed and screening may continue if a normal result is 
achieved. Hematology, chemistry, and urinalysis tests do not need to be repeated at baseline if 
screening tests were performed within 1 week before the Day 1 visit.
To alleviate unnecessary completion of clinician-rated scales and PRO questionnaires and other 
baseline assessments by ineligible participants, the urine drug screen should be performed first at 
the baseline visit (Day 1). If the urine drug screen is positive, the participant may have their Day 1 
visit rescheduled 1 time, if negative on retest then the participant will be allowed to continue with 
all assessments to have inclusion and exclusion criteria confirmed.
8.2.5.
Suicidal Risk Monitoring
There has been some concern that ADs may be associated with an increased risk of suicidal 
ideation or behavior when given to some participants with MDD. Although esketamine nasal spray
or other similar treatments in its class have not been shown to be associated with an increased risk 
of suicidal thinking or behavior when given to this participant population, the sponsor considers it 
important to monitor for such events before and during this clinical study.
Quetiapine XR is an atypical antipsychotic agent and suicidal risk is discussed in Section 2.2.4.
Participants being treated with study intervention, which includes an SSRI/SNRI as a component 
in each arm, should be monitored appropriately and observed closely for suicidal ideation and 
behavior or any other unusual changes in behavior. Consideration should be given to discontinuing
study intervention in participants who experience signs of suicidal ideation or behavior.
If the participant agrees, the investigator can request that families and caregivers of participants 
being treated with study intervention monitor participants for the emergence of unusual changes 
in behavior, as well as the emergence of suicidal ideation and behavior, and to report such 
symptoms immediately to the study investigator.
Baseline assessment of suicidal ideation and behavior and intervention-emergent suicidal ideation 
and behavior will be assessed during the study using the C-SSRS. If early signs of suicidal ideation 
are identified then the C-SSRS should be applied more frequently than the time points listed in the 
Schedule of Activities, at the discretion of the investigator.
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.25 It is a clinical interview 
which supports suicide risk assessment through a series of simple, plain-language questions. It 
identifies risk not only if someone has previously attempted suicide, but also if he or she has 
considered suicide, prepared for an attempt (for example, buying a gun, collecting pills, or writing 


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a suicide note), or aborted plans for suicide because of a last-minute change of heart or a friend’s 
intervention. Users of the C-SSRS tool ask people:

Whether and when they have thought about suicide (ideation)

What actions they have taken — and when — to prepare for suicide

Whether and when they attempted suicide or began a suicide attempt that was either 
interrupted by another person or stopped of their own volition.
8.3.
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information, including adverse 
events, serious adverse events, and PQCs, from clinical studies are crucial for the protection of 
participants, 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.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally acceptable representative) for the duration of the study.
For study intervention that meets the definition of a combination product, malfunctions or 
deficiencies of a device constituent will be reported as (a) PQC(s).
For further details on AEs and serious adverse events (SAEs) (Definitions and Classifications; 
Attribution Definitions; Severity Criteria; Special Reporting Situations; Procedures) as well as 
product quality complaints, refer to Appendix 5, Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting.
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
All AEs 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 participant’s 2-week safety follow-
up visit. Serious AEs, including those spontaneously reported to the investigator within 30 days 
after the last dose of study intervention, 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.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form, which must be completed and signed by a physician from the study site, and transmitted to 


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the sponsor within 24 hours. The initial and follow-up reports of a SAE should be made by 
facsimile (fax).
Adverse Event Reporting Following Early Discontinuation of Study Intervention 
For participants who discontinue study intervention early, the safety follow-up visit will be 
performed 2 weeks after their last dose of study intervention. These participants will remain in the 
study and continue to return for follow-up visits every 2 weeks through Week 32.
For participants who discontinue study intervention early but agree to continue the bi-weekly
follow-up assessments until Week 32 of the study: 
1.
If their alternative standard of care treatment includes commercial esketamine or another 
Janssen medicinal product for depression, AEs will continue to be collected after completion 
of the safety follow-up visit until Week 32 of the study.
2.
If their alternative standard of care treatment does not include commercial esketamine or 
another Janssen medication for depression, AEs will not be systemically collected after 
completion of the safety follow-up visit. For AEs that are not systematically collected 
(including AEs for Janssen medicinal products not indicated for depression) and where the 
participating physician considers there is at least a reasonable possibility of a causal 
relationship to a medicinal product (ie, spontaneous adverse drug reactions), the participating 
physician is requested to notify the manufacturer (ie, Janssen or other manufacturer) of the 
medicinal product or the appropriate regulatory/competent authority through the national 
spontaneous reporting system as soon as possible.
As described above, all SAEs spontaneously reported within 30 days after the last dose of 
study intervention must be reported using the Serious Adverse Event Form.)
Where available, reports of spontaneous adverse drug reactions will be summarized in the 
clinical study report.
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading 
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in Appendix 
5, Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting.
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute where 
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or 
sponsor where required) must report SUSARs to the appropriate IEC/IRB that approved the 
protocol unless otherwise required and documented by the IEC/IRB.


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An anticipated event is an adverse event that commonly occurs in the study population independent 
of exposure to the drug under investigation. For the purposes of this study the following SAEs will 
be considered anticipated events: 
For esketamine and major depressive disorder (MDD) (including TRD; based on DSM-5):

Suicidal thinking, ideation, and behavior

Sleep changes, difficulty sleeping, reduced sleep, abnormal sleep, tiredness, fatigue, and 
reduced energy

Difficulty in sexual desire, performance or satisfaction

Reduced appetite and weight changes (loss or increase)

Activation or hypomania/mania

Irritability, anger, and impulsive behavior

Agitation, tension, panic attacks, and phobia
These anticipated events will be periodically analyzed in aggregate by the sponsor during study 
conduct. The sponsor will prepare a safety report in narrative format if the aggregate analysis 
indicates that the anticipated event occurs more frequently in the treatment group than in the 
control group and the sponsor concludes there is a reasonable possibility that the drug under 
investigation caused the anticipated event.
The plan for monitoring and analyzing the anticipated events is specified in a separate Anticipated 
Events Safety Monitoring Plan. The assessment of causality will be made by the sponsor’s 
unblinded safety assessment committee.
The sponsor assumes responsibility for appropriate reporting of the listed anticipated events 
according to the requirements of the countries in which the studies are conducted.
8.3.5.
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants 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 SAEs and must be reported using the Serious Adverse Event Form.
Any participant who becomes pregnant during the study must discontinue further study 
intervention and continue follow-up visits through Week 32 (see Section 7.1); alternative standard 
of care treatment will be at the discretion of the investigator.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.


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8.3.6.
Disease-Related Events and Disease-Related Outcomes not 
Qualifying as Adverse Events or Serious Adverse Events
All events that meet the definition of a SAE will be reported as SAEs, regardless of whether they 
are protocol-specific assessments.
The cause of death of a participant in a study, whether or not the event is expected or associated 
with the study intervention, is considered a SAE.
8.3.7.
Adverse Events of Special Interest
Clinically relevant intervention-emergent AEs of special interest will be summarized separately,
grouped in the following MedDRA based categories:

Sedation: sedation; somnolence; altered state of consciousness; depressed level of 
consciousness; hypersomnia; stupor

Dissociation: depersonalisation/derealisation disorder; derealisation; dissociative disorder;
flashback; hallucination; hallucination, auditory; hallucination, visual; hallucination, illusion;
somatic hallucination; hyperacusis; tinnitus; diplopia; vision blurred; ocular discomfort; 
photophobia; visual impairment; dysesthesia; oral dysesthesia; paraesthesia; paraesthesia oral;
pharyngeal paraesthesia; time perception altered; daydreaming; delusional perception; feeling 
hot; feeling cold; feeling of body temperature change

Suicidality: completed suicide; depression suicidal; intentional overdose; intentional 
self-injury; multiple drug overdose intentional; poisoning deliberate; self-injurious behavior;
self-injurious ideation; suicidal behavior; suicidal ideation; suicide attempt; toxicity to various 
agents

Suggestive of abuse potential: aggression; confusional state; decreased activity; dependence;
disorientation; dissociation; dissociative disorder; dizziness; drug abuse; drug abuser; drug 
dependence; drug use disorder; drug detoxification; drug diversion; drug rehabilitation; drug 
tolerance; drug tolerance increased; drug withdrawal convulsions; drug withdrawal headache;
drug withdrawal syndrome; euphoric mood; feeling abnormal; feeling drunk; feeling of 
relaxation; hallucination; hallucination, auditory; hallucination, gustatory; hallucination, 
olfactory;
hallucination, 
synesthetic;
hallucination, 
tactile;
hallucination, 
visual;
hallucinations, mixed;
inappropriate affect;
mental impairment;
product tampering;
psychomotor hyperactivity; psychotic disorder; rebound effect; somatic hallucination;
somnolence; substance abuser; substance dependence; substance use; substance use disorder;
substance-induced mood disorder; substance-induced psychotic disorder; thinking abnormal;
withdrawal arrhythmia; withdrawal syndrome

Cystitis: allergic cystitis; chemical cystitis; cystitis; cystitis erosive; cystitis hemorrhagic;
cystitis interstitial; cystitis noninfective; cystitis ulcer active; cystitis-like symptom;
pollakiuria; dysuria; micturition urgency; nocturia

Hepatic impairment: cholestasis and jaundice of hepatic origin; hepatic failure; fibrosis and 
cirrhosis; other liver damage-related conditions
8.4.
Treatment of Overdose
For this study, any dose of esketamine nasal spray greater than 84 mg within a 24-hour time period
will be considered an overdose.


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In the event of an overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately.

Closely monitor the participant for AEs/SAEs and laboratory abnormalities until esketamine 
can no longer be detected systemically.

If respiratory depression occurs, supportive ventilation should be employed.

Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
For quetiapine XR and SSRIs/SNRIs, the investigator should refer to the respective SmPCs (or 
local equivalent, if applicable) for advice on overdose.
8.5.
Pharmacokinetics
Pharmacokinetic evaluations are not performed in this study.
8.6.
Pharmacodynamics
Pharmacodynamic evaluations are not performed in this study.
8.7.
Biomarker and Pharmacogenomic (DNA and RNA) Evaluations
Biomarker and pharmacogenomic blood samples will only be collected at select study sites. 
Participation in the biomarker and pharmacogenomic research is optional for participants and 
blood samples will only be collected from participants who provide consent.
Biomarker Evaluations
Blood samples will be collected as indicated in the Schedule of Activities for exploratory analysis 
of biomarkers (protein and metabolites) related to immune system activity, HPA axis activation, 
neurotrophic and metabolic factors. Exploratory analyses may be performed for additional 
biomarkers as well. Results may be presented in a separate biomarkers report. 
If possible, blood samples should be collected under fasting conditions (minimum 8 hours prior to 
biomarker sample collection, water is permitted). Participants should refrain from 
exercise/strenuous physical activity and the use of NSAIDs for 24 hours prior to blood collection. 
Not following these recommendations will not constitute a protocol violation.
Biomarkers may be added or deleted based on scientific information or technical innovations under 
the condition that the total volume of blood collected will not be increased.
All biomarker data obtained during this study may be included in ongoing cross-study analyses to 
investigate the relationship between depression severity and phenotypes and biomarkers.


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Information on menstrual cycle (date of first day of last period, average length of cycle) will be 
recorded on days when blood samples for biomarker analysis are collected.
Pharmacogenomic Evaluations
Whole blood samples for DNA and RNA analyses will be collected at the time points indicated in 
the Schedule of Activities. 
DNA samples will be analyzed for the assessment of genetic and epigenetic variation in genes in 
pathways relevant to MDD. Additional analyses may be conducted if it is hypothesized that this 
may help resolve issues with the clinical data. RNA expression analyses may include testing of 
known messenger RNA/microRNA transcripts or transcriptome-wide analysis in relationship to 
AD treatment response and MDD.
DNA and RNA samples will be used for research related to esketamine or MDD. They may also 
be used to develop tests/assays related to esketamine or MDD. Pharmacogenomic research may 
consist of the analysis of 1 or more candidate genes or of the analysis of genetic and epigenetic 
markers throughout the genome (as appropriate) in relation to esketamine or MDD clinical 
endpoints.
8.8.
Medical Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
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.
9.1.
Statistical Hypotheses
The primary hypothesis of this study is that among participants who have treatment-resistant MDD 
with a current moderate to severe depressive episode, the proportion of participants achieving 
remission at the Week 8 visit is greater in participants treated with flexibly dosed esketamine nasal 
spray than in participants treated with quetiapine XR, both administered in combination with a 
continuing SSRI/SNRI.
The major secondary hypothesis of this study is that among participants who have 
treatment-resistant MDD with a current moderate to severe depressive episode, the proportion of 
participants who achieved remission at the Week 8 visit and remain relapse-free through the 
Week 32 visit is greater in participants treated with esketamine nasal spray than in participants 
treated with quetiapine XR, both administered in combination with a continuing SSRI/SNRI.
Both the primary and major secondary endpoint will be analyzed using a non-responder imputation 
(NRI) approach, meaning that participants discontinuing study intervention will be considered as 


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having a negative outcome (non-remission for the primary endpoint, non-relapse-free-remission 
for the key secondary endpoint).
9.2.
Sample Size Determination
For the primary endpoint, the assumptions are that the rate of remission for completers at the 
Week 8 visit is 50% in the esketamine arm and 35% in the comparator arm, and that the rate for 
participants who discontinue study intervention between baseline and the Week 8 visit is 17.5% in 
both treatment arms (to be imputed as non-remitters). Combining these assumptions leads to an 
estimated remission rate at the Week 8 visit in NRI analysis of 41.25% in the esketamine arm and 
28.88% in the comparator arm. With a power of 90%, a 2-sided significance level of 0.05 and 
using chi-square test, a sample size of 311 participants per arm (622 participants in total) is needed 
to detect the difference between the study intervention arms.
For the key secondary endpoint, among participants who achieve remission at the Week 8 visit, a 
relapse rate of 30% is assumed for both study intervention arms and rates for participants who 
discontinue study intervention between the Week 8 and Week 32 visits (to be imputed as 
non-relapse-free after remission) is assumed to be 10% for the esketamine arm and 20% for the 
comparator arm.2,7,24 Combining these assumptions leads to an estimated rate of relapse-free after 
remission at the Week 32 visit in NRI analysis of 25.99% in the esketamine arm and 16.17% in 
the comparator arm. With a power of 80%, a 2-sided significance level of 0.05 and using a 
chi-square test, a sample size of 270 randomized participants per arm (540 participants in total) is 
needed to detect a difference between the study intervention arms.
When combining the 2 calculations above, a sample size of 311 participants per study intervention 
arm (622 participants in total) is needed to detect the difference between the study intervention 
arms with both a power of at least 90% on the primary endpoint and a power of 80% on the key 
secondary endpoint.
Randomization will be stratified by age (18 to 64 years [inclusive]; 65 to 74 years [inclusive]) and 
total number of treatment failures (2; 3 or more [inclusive of current antidepressive treatment at 
screening used to determine eligibility]).
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF
Full analysis set
All participants who are randomized in the study
Safety
All randomized participants who take at least 1 dose of study intervention
9.4.
Statistical Analyses
The statistical analysis plan will be developed prior to enrollment of the first participant in the 
study and it will include a more technical and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints.


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9.4.1.
General Considerations
Demographic and baseline characteristics and psychiatric history at baseline will be summarized 
by study intervention arm for the full and safety analysis sets. Continuous variables will be 
summarized using descriptive statistics (N, mean, standard deviation, median, minimum, and 
maximum). Categorical variables will be summarized using a frequency distribution with the 
number and percentage of participants in each category.
9.4.2.
Efficacy Endpoints
The efficacy analyses of data will be based on the full analysis set defined in Section 9.3.
The rate of remission at the Week 8 visit (primary endpoint) and the rate of remission at the 
Week 8 visit without relapse up to the Week 32 visit (key secondary endpoint) will be tested 
between study intervention arms using a Cochran-Mantel-Haenszel (CMH) chi-square test 
adjusting for age (18 to 64 years [inclusive]; 65 to 74 years [inclusive]) and total number of 
treatment failures (2; 3 or more). Participants will be considered as having a positive outcome on 
relapse-free after remission if they are in remission at the Week 8 visit and do not experience any 
relapse between the Week 8 and Week 32 visits. All other cases (participants not achieving 
remission at the Week 8 visit, or participants achieving remission at the Week 8 visit but 
experiencing a relapse between the Week 8 and Week 32 visits) will be considered as having a 
negative outcome. Both the primary and key secondary endpoints will be analyzed using a NRI 
approach as defined in Section 9.1. In sensitivity analyses, for participants who stopped study 
intervention, but are still followed in the study, no imputation will be performed, and their observed 
status will be used for the analyses.
For continuous/ordinal parameters (eg, MADRS, CGI-S, PHQ-9, EQ-5D-5L, SF-36, SDS, 
WPAI:D) descriptive statistics of the score or values and change from baseline will be provided 
for each study visit during the study for the full analysis set. For CGI-C descriptive statistics of the 
score will be provided for each study visit during the study for the full analysis set. Summaries of 
both observed and last observation carried forward (LOCF) data will be presented. The change 
from baseline at each visit will be analyzed using a mixed model for repeated measurements based 
on observed cases. The model will include baseline score as a covariate, and study intervention, 
stratification factors (age [18 to 64 years (inclusive); 65 to 74 years (inclusive)] and total number 
of treatment failures [2; 3 or more]), visit, and visit-by-study-intervention interaction as fixed 
effects. The change from baseline at each visit will also be analyzed using an analysis of covariance 
model including LOCF data with factors for treatment, stratification factors (age [18 to 64 years
(inclusive); 65 to 74 years (inclusive)] and total number of treatment failures [2; 3 or more]) and 
baseline score as a covariate. For all model approaches, LS estimates of the treatment differences 
and 95% confidence intervals will be presented.
Additionally, for scales that have a minimum clinically important difference (MCID), the 
proportion of participants having improved by at least the MCID will be described at each visit 
and compared between study interventions using CMH chi-square test adjusting for age (18 to 
64 years [inclusive]; 65 to 74 years [inclusive]) and total number of treatment failures (2; 3 or 
more). The same analysis will be conducted for the proportion of participants who deteriorate by 


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at least the MCID. The MCIDs used in the analysis will be documented in the Statistical Analysis 
Plan.
Time to event parameters (eg, time to improvement by at least MCID) will be analyzed by the 
Kaplan-Meier method and study interventions will be compared using a 2-sided log-rank test for 
the full analysis set. Time to event will be summarized with median, 25th and 75th percentile (if 
estimable). Confidence intervals of 25th, 50th, and 75th percentile of time to event will also be 
provided. Hazard ratios and their confidence intervals will be estimated using Cox proportional 
hazard models stratified by age (18 to 64 years [inclusive]; 65 to 74 years [inclusive]) and number 
of previous treatment failures (2; 3 or more).
9.4.3.
Other Secondary/Exploratory Endpoints
Subgroup analyses will be performed for age (18 to 64 years [inclusive]; 65 to 74 years[inclusive]) 
and total number of treatment failures (2; 3 or more), as well as sex and severity of depression. 
Analysis by geographical region may also be provided.
Details regarding the other secondary and exploratory analyses will be provided in the Statistical 
Analysis Plan.
9.4.4.
Safety Analyses
All safety analyses will be made on the Safety Population defined in Section 9.3.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using 
MedDRA. Intervention-emergent AEs are AEs occurring or worsening in severity after the start 
of study intervention. All reported intervention-emergent AEs will be included in the analysis. For 
each AE, the percentage of participants who experience at least 1 occurrence of the given event 
will be summarized by intervention group. In addition, comparisons between intervention groups 
will be provided if appropriate.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue intervention due to an AE, or who experience a severe or a 
SAE. Adverse events reported occurring after study intervention discontinuation will be tabulated.
Intervention-emergent AEs of special interest will be summarized separately, grouped in the 
MedDRA based categories specified in Section 8.3.7.
Vital Signs
Descriptive statistics of pulse/heart rate, respiratory rate, and supine blood pressure (SBP and 
DBP) values and changes from baseline will be summarized at each scheduled time point. The 
percentage of participants with values beyond clinically important limits will be summarized.


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Nasal Examination
Abnormalities observed during the targeted nasal examinations at screening and post-baseline will 
be summarized and listed by treatment group.
C-SSRS
Suicide-related thoughts and behaviors based on the C-SSRS will be summarized by study 
intervention in incidence and shift tables. Separate endpoints for suicidal ideation and suicidal 
behavior will be defined and summarized descriptively by study intervention. Missing scores will 
not be imputed.
9.4.5.
Other Analyses
Biomarker and Pharmacogenomic (DNA and RNA) Analyses 
Details of the analysis plan and summary of results from both biomarker and pharmacogenomic 
analyses will be reported separately.
9.5.
Interim Analysis
Not applicable.  


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS


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10.1.
Appendix 1: Abbreviations
5HT
5-hydroxytryptamine
AD
Antidepressant
ADE
adverse device effect
AE
adverse event
AUC
area under the plasma concentration-time curve
AUC
area under the plasma concentration-time curve from time 0 to infinity
CGI-C
Clinical Global Impression – Change
CGI-S
Clinical Global Impression – Severity
CLCR
creatinine clearance
Cmax
maximum plasma concentration
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus Infectious Disease 2019
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450, with any appended letters (2B6, 3A4, etc) indicating subtypes
DBP
diastolic blood pressure
DNA
deoxyribonucleic acid
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
EuroQoL
European Quality of Life
FDA
Food and Drug Administration
FT4
free thyroxine
GCP
Good Clinical Practice
HPA
hypothalamic–pituitary–adrenal
IB
Investigator’s Brochure
ICF
informed consent form
ICMJE
International Committee of Medical Journal Editors 
ICH
International Council on Harmonisation 
IDS-C30
Inventory of Depressive Symptomatology – Clinician-rated, 30 item 
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISO
International Organization for Standardization
IV
Intravenous
IWRS
interactive web response system
LS
least squares
LOCF
last observation carried forward
MADRS
Montgomery-Asberg Depression Rating Scale
MCID
minimum clinically important difference
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MINI
Mini International Neuropsychiatric Interview
NMDA
N-methyl-D-aspartate
NRI
non-responder imputation
NSAID
non-steroidal anti-inflammatory drug
PCP
Phencyclidine
PHQ-9
Patient Health Questionnaire, 9-item
PQC
product quality complaint
PRO
patient-reported outcome
QLDS
Quality of Life in Depression Scale
QTP
Quetiapine
RNA
ribonucleic acid


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SADE
serious adverse device effect
SAE
serious adverse event
SBP
systolic blood pressure
SDS
Sheehan Disability Scale
SF-36
36-item Short-Form Health Survey
SmPC
Summary of Product Characteristics
SNRI
serotonin-norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
TRD
treatment-resistant depression
TSH
thyroid stimulating hormone
WPAI:D
Work Productivity and Activity Impairment: Depression
XR
extended-release
Definitions of Terms
Electronic source 
system
Contains data traditionally maintained in a hospital or clinic record to document medical 
care or data recorded in an eCRF as determined by the protocol. Data in this system may 
be considered source documentation.
Esketamine Arm
Participants will receive treatment with esketamine nasal spray (28 mg [initial dose for 
elderly participants 65 to 74 years of age and adults of Japanese ancestry; may be used 
throughout the study in these populations; may be uptitrated in 28 mg increments], 56 mg 
[initial dose for adult participants aged 18 to 64 years and may be used for all age groups 
throughout the study], or 84 mg [maximum dose esketamine nasal spray may be uptitrated 
to]) in combination with continuing SSRI/SNRI.
Comparator Arm
Participants will receive treatment with a continuing SSRI/SNRI augmented with 
quetiapine XR as per the SmPC (or local equivalent, if applicable). In adult participants 
aged 18 to 64 years, the initial dose is 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 
[lowest effective dose]; a further dose increase to 300 mg/day as of Day 5 will be based on 
individual participant evaluation. In elderly participants aged 65 to 74 years, the initial 
dose is 50 mg/day on Days 1-3, 100 mg/day on Days 4-7, and 150 mg/day on Day 8; a 
further dose increase to 300 mg/day will be based on individual participant evaluation no 
earlier than Day 22.
Baseline
Day 1 randomization visit




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10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current International Council on Harmonisation (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 participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
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 participants, 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) involve only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
listed in the Contact Information page(s), which will be provided as a separate document. Except 
in emergency situations, this contact should be made before implementing any departure from the 
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the 
situation and agree on an appropriate course of action. The data recorded in the eCRF and source 
documents will reflect any departure from the protocol, and the source documents will describe 
this departure and the circumstances requiring it.
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.


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Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
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, participant compensation programs. This approval must clearly identify the 
specific protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first 
participant:

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
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the participants)

IB (or equivalent information) and amendments/addenda


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
Sponsor-approved participant recruiting materials

Information on compensation for study-related injuries or payment to participants 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 participants

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 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
Approval for the collection of optional samples for research and for the corresponding ICF must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to participants

If applicable, new or revised participant recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the study 
intervention

New information that may adversely affect the safety of the participants or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the participants

Report of deaths of participants under the investigator’s care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable


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
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help 
ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 4.2.10, Study-Specific Ethical Design 
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.10.
FINANCIAL DISCLOSURE
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) and contracts for details on financial 
disclosure.
INFORMED CONSENT PROCESS
Each participant 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 participant 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 participants the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Participants will be informed that their participation is voluntary and that they may withdraw 


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consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the participant will receive for the treatment of his or her disease. Participants 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 
participant 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 participant, to the extent permitted by the applicable law(s) or regulations. 
By signing the ICF the participant is authorizing such access. It also denotes that the participant 
agrees to allow his or her study physician to recontact the participant for the purpose of obtaining 
consent for additional safety evaluations, and subsequent disease-related treatments, if needed.
The participant 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 participant’s personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the participant. Participants who are rescreened (see Section 5.4) are 
required to sign a new ICF.
Participants will be asked for consent to provide optional samples for research (where local 
regulations permit). After informed consent for the study is appropriately obtained, the participant 
will be asked to sign and personally date a separate ICF indicating agreement to participate in the 
optional research components. Refusal to participate in either optional research component will 
not result in ineligibility for the study. A copy of this signed ICF will be given to the participant.
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants 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 participants confidential.
The informed consent obtained from the participant 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 participant 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 


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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, RNA, pharmacodynamic, biomarker, pharmacokinetic, and immunogenicity 
research is not conducted under standards appropriate for the return of data to participants. 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 participants 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.
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH 
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand esketamine, to understand 
depression, to understand differential intervention responders, and to develop tests/assays related 
to esketamine or 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. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples).
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding  esketamine or the sponsor’s 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including exploratory research data, generated as a result of 
this study, are considered confidential and remain the sole property of the sponsor. The investigator 
agrees to maintain this information in confidence and use this information only to accomplish this 
study and will not use it for other purposes without the sponsor’s prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of esketamine, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of exploratory 
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.


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Study participant 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 (ICMJE) 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 sub-study 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 18 months after the study end date, 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 ICMJE Recommendations 
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which 
state that the named authors must have made a significant contribution to the conception or design 
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required 
by law. The disclosure of the final study results will be performed after the end of study in order 
to ensure the statistical analyses are relevant.
DATA QUALITY ASSURANCE
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, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, handling, storage, and shipment of samples.


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Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review eCRF for accuracy and completeness during on-site monitoring visits and 
after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources.
CASE REPORT FORM COMPLETION
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. All data relating to the study must be recorded in eCRF. All eCRF entries, corrections, and 
alterations must be made by the investigator or authorized study-site personnel. The investigator 
must verify that all data entries in the eCRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the participant’s source documents. Data must be entered into
eCRF in English. The eCRF must be completed as soon as possible after a participant visit and the 
forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the electronic data capture (eDC) tool. If corrections to 
an eCRF are needed after the initial entry into the eCRF, this can be done in either of the following 
ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
SOURCE DOCUMENTS
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of study 
completion and reason for early discontinuation of study intervention or early withdrawal from the 
study, if applicable.
The author of an entry in the source documents should be identifiable.


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Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).
The following data may be recorded directly into the eCRF and will be considered source data:

Blood pressure and pulse/heart rate

Body weight and height

Confirmation of physical examination

Investigator-completed scales and assessments, when applicable and with the exception of 
MADRS
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and 
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:

Referral letter from treating physician containing full documentation of each treatment with 
antidepressive(s) and the current treatment with antidepressive(s) for the current moderate to 
severe depressive episode:

Substance name

Period during which it was taken by participant at least at recommended therapeutic 
dosage according to SmPC (see Appendix 7 List of Previous Antidepressive Treatments)
(duration and/or start/stop dates of this period); ie, excluding periods where the substance 
was given at a dose lower than the recommended therapeutic dose according to SmPC

Highest dose received by participant

Assessment of nonresponse: based on treating physician and participant’s feedback, was 
the amount (%) of improvement in depression he/she reported when they feel it was 
working at its best above or below 25%

Documentation of any overlap that qualifies as combination or augmentation
or

Complete history of medical notes at the site (including information specified above)
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol-required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or 
clinic record to document medical care (eg, electronic source documents) as well as the clinical 
study-specific data fields as determined by the protocol. This data is electronically extracted for 
use by the sponsor. If eSource is utilized, references made to the eCRF in the protocol include the 
eSource system but information collected through eSource may not be limited to that found in the
eCRF.
MONITORING
The sponsor will use a combination of monitoring techniques (central, remote, or on-site 
monitoring) to monitor this study.


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The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the
eCRF
with the source documents 
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the
eCRF are known to the sponsor and study-site personnel and are accessible for verification by the 
sponsor study-site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying 
that the recorded data are consistent with the original source data. Findings from this review will 
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the 
relevant study-site personnel will be available, the source documents will be accessible, and a 
suitable environment will be provided for review of study-related documents. The monitor will 
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study-site personnel will be available to provide an update on the progress of the 
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
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. Participant 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.
RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each participant, 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 


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investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports.
STUDY AND SITE START AND CLOSURE
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further esketamine nasal spray development


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10.4.
Appendix 4: Prohibited Concomitant Medications
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 participant’s SSRI/SNRI for information 
regarding prohibited concomitant medications.
Except where specifically noted (and as applicable per randomly assigned study intervention arm), 
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 study intervention (ie, esketamine nasal spray or 
quetiapine XR, both in combination with continuing SSRI/SNRI) until after the last dose of study 
intervention. Before prescribing any concomitant medications, an experienced clinician needs to 
evaluate the medical need and estimated risk for additional side effects. Additionally, the risk of 
cumulative increase in side effects (eg, sedation, QT-prolongation, weight gain) should be avoided.
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
Attention deficit 
hyperactivity disorder 
(ADHD) medications (eg, 
atomoxetine, guanfacine)
N
Y
Can be continued but must not be 
taken within 12 hours prior to the nasal 
treatment session or for 2 hours after 
the nasal treatment session for 
participants in the esketamine
treatment arm.
Safety
Amantadine
N
N
PD interaction
Anorexiants
(eg, phentermine, 
phendimetrazine)
N
N
Safety
Anti-cholinergic medications 
(eg, Atropine, Benztropine,
Biperiden)
N
N
As quetiapine has a moderate to strong 
affinity for several muscarinic receptor 
subtypes, concomitantly used with 
other medicines with anti-cholinergic 
effects can contributes to occurrence of 
ADR reflecting anti-cholinergic effects 
(eg, decreased intestinal motility and 
risk for intestinal obstruction)
Safety
Anticholinesterase inhibitors
N
N
Participant 
population is 
excluded
Anticonvulsants
N
N
Participants with seizures are 
excluded. Use as adjunctive treatment 
for MDD is prohibited.
- Note: Anticonvulsants used for 
indications other than seizures may 
be allowed (eg, valproate for 
migraine; pregabalin).
Safety and PD 
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Drug Class
Episodic 
Use (As 
Needed)
Continuous 
Use
Comments
Reason for 
Prohibition
Antidepressants (ADs)
(other than continuing 
SSRI/SNRI as described in 
Section 6.1.3)
N
N
-If a participant is taking a 
monoamine oxidase inhibitor
(MAOI) at screening, there must be a 
minimum wash-out interval of 
2 weeks prior to the first dose of 
study intervention.
- Even if used for indications other 
than MDD (eg, trazodone for sleep), 
the use of any ADs other than 
specified as study intervention is not 
permitted during treatment with 
study intervention.
Safety and PD 
interaction
Antipsychotics
N
N
PD interaction
Benzodiazepines (at dosages 
equal to or less than the 
equivalent of 4 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 esketamine nasal 
treatment session for participants in 
the esketamine arm.
The need for sleep medication should 
be evaluated critically and additional 
sedation should be taken in 
consideration.  
Safety and PD 
interaction
Benztropine
Y
N
Prohibited if use is continuous.
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, nasal, topical, and ophthalmic 
steroids are not prohibited. Nasally
administered corticosteroids should 
not be used from 1 hour prior to each 
esketamine nasal spray administration.
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
Nasally administered decongestants 
(vasoconstrictors) should not be used 
from 1 hour prior to each esketamine 
nasal spray administration.
Pseudoephedrine-containing oral 
products should not be used within 
12 hours prior to a nasal treatment 
session.
Safety and PD 
interaction


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Drug Class
Episodic 
Use (As 
Needed)
Continuous 
Use
Comments
Reason for 
Prohibition
CYP3A4 inducers - potent
N
N
Participants may not take a known 
potent inducer of hepatic CYP3A 
activity within 2 weeks of the first 
administration of study intervention
until at least 24 hours after the last
dose of study intervention.
Examples (not all-inclusive):
amiodarone, efavirenz, nevirapine, 
barbiturates, carbamazepine, 
glucocorticoids, modafinil, 
oxcarbazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, and 
St. John’s wort.
PK
CYP3A4 inhibitors
N
N
Participants may not take a known 
potent inhibitor of hepatic CYP3A 
activity within 2 weeks of the first 
administration of study intervention 
until at least 24 hours after the last 
dose of study intervention.
Examples (not all-inclusive):
erythromycin, clarithromycin, 
nefazodone, HIV-protease inhibitors, 
azole-antifungal agents; grapefruit
juice.
Dextromethorphan
N
N
PD interaction
Diphenhydramine
Y
N
Prohibited within 12 hours prior to the 
start of each nasal treatment session in
the esketamine arm.
The need for sleep medication should 
be evaluated critically, and additional 
sedation should be taken into
consideration.  
Safety
Ketanserin
N
N
Safety
Lithium
N
N
PD interaction


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Drug Class
Episodic 
Use (As 
Needed)
Continuous 
Use
Comments
Reason for 
Prohibition
Medications that cause 
electrolyte imbalance or QT-
prolongation (corrected 
according to Fridericia’s 
formula (QTcF): ≥450 msec 
(males); ≥470 msec 
(females) eg, 
Antiarrhythmics (quinidine, 
procainamide, disopromide, 
dofetilide, ibutilide, sotalol), 
Antihistamines (terfenadine, 
astemizole), Neuroleptic, 
(haloperidol, droperidol, 
thioridazine, 
chlorpromazine), Antibiotics 
(levofloxacin, moxifloxacin, 
erythromycin, 
clarithromycin), 
Antimalarials (quinine, 
halofantrine), Antiprotozoal 
(pentamidine), Antifungal 
(azole group)
N
N
Reported interaction with quetiapine.
Safety
Memantine
N
N
PD interaction
Methyldopa
N
N
Safety and PD 
Interaction
Metyrosine
N
N
Safety and PD 
interaction
Non-steroidal anti-
inflammatory drugs 
(NSAIDs)
Y
Y
Participants should not take within 
24 hours before biomarker blood 
sample collection at Day 1 and Week 8 
visits.
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)
N
Y
Prescribed psychostimulants taken for 
indications other than MDD can be 
continued but must not be taken:

Within 12 hours prior to the 
esketamine nasal treatment session 
or for 2 hours after the nasal 
treatment session in the esketamine 
arm.

Within 12 hours prior to visits in 
the comparator arm (minimize 
differences in study intervention
arms related to PROs)
Cardiovascular 
safety
Reserpine
N
N
PD interaction
Scopolamine
N
N
PD interaction
St. John’s wort
N
N
PD interaction 
and PK


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Drug Class
Episodic 
Use (As 
Needed)
Continuous 
Use
Comments
Reason for 
Prohibition
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: CYP=cytochrome P450; HIV= human immunodeficiency virus; IM=intramuscular; 
IV=intravenous; MDD=major depressive disorder; N=Prohibited; PD=pharmacodynamic; PK=pharmacokinetic; 
PO=oral; PRO=patient-reported outcomes; SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin-
norepinephrine reuptake inhibitor; Y=permitted, with restrictions (please refer to the column labeled “Comments” 
for additional guidance).


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10.5.
Appendix 5: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the intervention. An AE 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 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 AEs starting with the signing of the ICF (refer to All Adverse Events
under Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information, for time of last AE recording).
For combination products with a device constituent, adverse events include those resulting from 
insufficient or inadequate instructions for use, deployment, implantation, installation, or operation, 
or any malfunction of the device. It includes any adverse event resulting from use error or from 
intentional misuse of the investigational device.
Serious Adverse Event
A SAE 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 participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*  Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the participant or may 


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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 AE occurs for which there is evidence suggesting a causal relationship 
between the study intervention 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).
For combination products with a device constituent, serious adverse events include adverse device 
effects that resulted in any of the consequences characteristic of a serious adverse event.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product 
reference safety information. For esketamine nasal spray, the expectedness of an AE will be 
determined by whether or not it is listed in the IB. For quetiapine XR and the SSRIs/SNRIs, the 
expectedness of an AE will be determined by whether or not it is listed in the SmPC (if applicable).
ATTRIBUTION DEFINITIONS
Assessment of Causality
The causal relationship to study intervention is determined by the investigator. The following 
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the 
AE.
The term “reasonable causal relationship” means there is evidence to support a causal relationship.
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 participant (eg, laboratory abnormalities).


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SPECIAL REPORTING SITUATIONS
Safety reporting situations for a sponsor study intervention in an interventional study that may 
require expedited reporting or safety evaluation include, but are not limited to:

Overdose of a sponsor study intervention

Suspected abuse/misuse of a sponsor study intervention

Accidental or occupational exposure to a sponsor study intervention

Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study 
intervention

Unexpected therapeutic or clinical benefit from use of a sponsor study intervention

Medication error, intercepted medication error, or potential medication error involving a 
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson & 
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted 
prescribing or dispensing errors)

Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a SAE should be recorded on the SAE page of the eCRF.
PROCEDURES
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, 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 
AE to study therapy. All measures required for AE management must be recorded in the source 
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant 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 participant 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 personnel only)

Site number

Participant number

Any other information that is required to do an emergency breaking of the blind


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Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the participant’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 intervention or to factors unrelated 
to study conduct

It becomes unlikely that any additional information can be obtained (participant 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 SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a participant’s participation in a study must be reported as a SAE, except hospitalizations 
for the following:

Hospitalizations not intended to treat an acute illness or AE (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 SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.

For convenience the investigator may choose to hospitalize the participant for the duration of 
the intervention period.
The cause of death of a participant in a study, whether or not the event is expected or associated 
with the study intervention, is considered a SAE.
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
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, reliability, or performance of a distributed product, including its labeling, drug delivery 
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product. 
In addition, it includes any technical complaints, defined as any complaint that indicates a potential 


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quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product or the drug delivery system.
This definition includes any PQC related to a device constituent in a combination product, 
including those used in the administration of the study intervention or the comparator. A device 
deficiency is an inadequacy of a device with respect to its identity, quality, durability, reliability, 
safety, or performance. Device deficiencies include malfunctions, use errors, and inadequate 
labeling.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until 
a shipment request is received from the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
Esketamine-Specific Reporting Requirements for PQCs
Additional PQC reporting requirements for esketamine nasal spray will be provided in a separate 
document.


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10.6.
Appendix 6: Contraceptive and Barrier Guidance and Collection of 
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria. 
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and 
Appendix 5 Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting.
Definitions
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential

premenarchal
A premenarchal state is one in which menarche has not yet occurred.

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 may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of 
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required 
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if 
she wishes to continue HRT during the study.

permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) 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.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations 
regarding the acceptable methods of contraception for those participating in clinical studies.
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 participants in 
clinical studies.


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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT (PREFERRED METHOD FOR COMPOUNDS WITH POSSIBLE OR UNKNOWN 
TOXICITY AND RECOMMENDED METHOD FOR COMPOUNDS WITH SUSPECTED OR 
DEMONSTRATED TOXICITY)
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used consistently 
and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, 
additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 
74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used consistently 
and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb

oral

intravaginal

transdermal

injectable

Progestogen-only hormone contraception associated with inhibition of ovulationb

oral

injectable

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 intervention. 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 participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not considered 
to be highly effective - failure rate of 1% per year)

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of 
action.

Male or female condom with or without spermicidec

Cap, diaphragm, or sponge with spermicide

A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier 
methods)c

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus-interruptus)

Spermicides alone

Lactational amenorrhea method (LAM)
a) 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 participants in clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may reduce the efficacy of 
the contraceptive method. In addition, consider if the hormonal contraception may interact with the study intervention.
c) Male condom and female condom should not be used together (due to risk of failure with friction).






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10.8.
Appendix 8: Guidance on Study Conduct During a COVID-19 Pandemic
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for 
study-related participant management in the event of disruption to the conduct of the study. This 
guidance does not supersede any local or government requirements or the clinical judgement of 
the investigator to protect the health and well-being of participants and site staff. If, at any time, a 
participant’s safety is considered to be at risk, study intervention will be discontinued and study 
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Participants will also be questioned regarding 
general health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted via this COVID-19 Appendix after consultation with the sponsor. Missed 
assessments/visits will be captured in the clinical trial management system for protocol deviations. 
If a participant has tested positive for COVID-19, the investigator should contact the sponsor to 
discuss plans for study intervention and follow-up. Discontinuations of study interventions and 
withdrawal from the study should be documented indicating “COVID-19-related” in the eCRF. 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
Modifications made to the study conduct as a result of the COVID-19 pandemic should be 
summarized in the clinical study report.


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GUIDANCE SPECIFIC TO THIS PROTOCOL:
These emergency provisions are meant to ensure the safety of participants on study while site 
capabilities are compromised by any COVID-19-related restrictions. The situation should be 
continuously assessed throughout the evolution of the COVID-19 pandemic. Once any restrictions 
are lifted and the acute phase of a COVID-19 pandemic resolves, sites should revert to the original 
protocol conduct as soon as feasible.
Some medical or study procedures may make it impossible to practice physical distancing (eg, 
blood pressure or blood sampling will require a closer interaction between participant and study 
site staff), however such interactions should be limited to the absolute minimum required. During 
close interactions, the participant and site staff should follow strict sanitizing/hygiene measures to 
minimize the risk for exposure to COVID-19.
Remote Monitoring

Remote monitoring will be conducted (when possible) in-between on-site Monitoring Visits, 
to reduce the frequency of on-site monitoring visits to the lowest frequency possible. 
Risk-Based-Monitoring will be extensively used to monitor remotely the quality of data and 
optimize the frequency of on-site monitoring visits.
Screening and Randomization

For sites already initiated and where screening and randomization is ongoing, all screening 
and randomization activities should be stopped immediately in the event a participant’s safety 
or study procedures cannot be sufficiently assured. 

Screening and randomization activities should not be restarted until the situation resolves to 
an acceptable level as mutually agreed by the site staff and sponsor.

The participants who are in screening period but not yet randomized would have the 
possibility to be rescreened when the screening and randomization will restart.
Study Intervention

All efforts should be made to assure treatment continuation at the optimal individualized study 
dosing schedule for those that are on study intervention at the time when any restrictions are 
imposed. 

Administration of esketamine at an alternative location in the vicinity of the study site (under 
supervision of study staff), if permitted by local regulations, may be allowed as soon as the 
participant has passed the 8-week- acute phase of the study and after consultation with the 
sponsor. Reduction of visit frequency from weekly to every other week, is allowed for 
esketamine treatment arm during the maintenance phase based on clinical judgement eg, the 
dosing schedule for participants receiving 56 mg once weekly is recommended to be modified 
to 84 mg every 2 weeks.

Dispensing of quetiapine to participant home may be allowed if permitted by local regulation.

Study intervention can be discontinued at any visit and the participant can be switched to an 
alternative standard of care treatment (both pharmacological and non-pharmacological) at the 
discretion of the treating investigator.


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
In the event changes to the dosing schedule are introduced or doses are missed due to 
restrictive COVID-19 measures, then the required details should be captured in the patient’s 
source notes as well as the eCRF. Missed study intervention dosing does not result in 
automatic withdrawal from the study.
Protocol Assessments

MADRS rating in this study should be conducted by an independent on-site MADRS rater. In 
circumstances where a study participant is not allowed (due to self-quarantine, lockdown, 
local restrictions, etc) to visit the study site, remote MADRS rating by videoconference 
application (eg, Skype, Zoom) will be acceptable in replacement of on-site MADRS rating. 
The process for MADRS rating should revert to the original on-site rating as soon as possible.

Other clinician scales could be conducted by telephone interview in the event a participant is 
not allowed to visit the study site for a scheduled study visit.

PROs in this study are paper based. PROs can be completed by the participant at home in 
those instances where the participant cannot visit the study site or wants to limit the time spent 
during a scheduled study visit. Completion should happen as close as possible to the date of 
the planned study visit and required PROs will be mailed to (and collected from) the 
participant’s home by study staff.

In the event laboratory samples cannot be collected by Covance (eg, due to temporary 
COVID-19-related restrictions), local laboratory tests may be performed at the discretion of 
Principal Investigator. Local laboratory results should be reviewed to confirm any 
abnormalities and if considered clinically significant to be added as AEs in the eCRF.
Participants with COVID-19 Infection

If a participant develops COVID-19 disease, then all the study physical interactions should be 
temporarily interrupted until the infection resolves. Study intervention may be temporarily 
interrupted at the discretion of the investigator and considering the severity of the viral 
infection as well as safety and well-being of the participant. COVID-19 infection should be 
reported to the sponsor following the Adverse Event/Serious Adverse Event reporting 
requirements.

When a participant recovers from COVID-19 infection, study intervention may be resumed 
when safe to do so, as determined by the investigator in consultation with the sponsor prior to 
resuming study drug.


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10.9.
Appendix 9: Protocol Amendment History
This is the first protocol amendment for the study. The PROTOCOL AMENDMENT SUMMARY 
OF CHANGES TABLE for the current amendment is located directly before the Table of 
Contents.


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11.
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disorder. J Affect Disord. 2013;151(1):209-219.
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a review of current concepts and methods. Can J Psychiatry. 2007;52(1):46-54.
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esketamine [dissertation for PhD]. University of Basel, 2011.
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Daly EJ, Trivedi MH, Janik A, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment 
for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial 
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Accessed September 24, 2019.
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EuroQol Group. About EQ-5D. https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/. Accessed July 21, 2019.
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EuroQol Research Foundation. EQ-5D-5L User Guide, 2019. Available from: 
https://euroqol.org/publications/user-guides. Accessed December 6, 2019.
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Investigator’s Brochure and Addenda: JNJ-54135419-AAC (esketamine hydrochloride). Janssen Research & 
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dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive 
disorder. Int Clin Psychopharmacol. 2012;27:215-223.
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Knöchel C, Alves G, Friedrichs B, et al. Treatment-resistant late-life depression: challenges and perspectives. 
Curr Neuropharmacol. 2015;13:577-591.
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the Sheehan Disability Scale. Int J Psychiatry Med. 1997;27:93-105.
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McKenna SP, Hunt SM. A new measure of quality of life in depression: testing the reliability and construct 
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Naismith SL, Norrie LM, Mowszowski L, et al. The neurobiology of depression in later-life: clinical, 
neuropsychological, neuroimaging and pathophysiological features. Prog Neurobiol. 2012;98:99-143.


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Clinical Protocol 54135419TRD3013 Amendment 1
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
131
Status: Approved, Date: 8 October 2020
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Pharmacokinetic Report KET-PK-007. A randomized, open label, single center, single-dose, cross-over study 
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in healthy adult volunteers. Javelin Pharmaceuticals, Inc. (31 October 2008).
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Popova V, Daly EJ, Trivedi M, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray 
Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized 
Double-Blind Active-Controlled Study [published correction appears in Am J Psychiatry. 2019 Aug 
1;176(8):669]. Am J Psychiatry. 2019;176(6):428-438.
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internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 
2011;168:1266-1277.
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impairment measure. PharmacoEconomics. 1993;4(5):353-365.
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Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of Depressive Symptomatology 
(IDS): psychometric properties. Psychol Med. 1996;26:477-486.
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Seroquel XR [SmPC]. London, United Kingdom: AstraZeneca UK Ltd; 2018.
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the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J 
Clin Psychiatry. 1998;59 Suppl 20:22-33;quiz 34-57.
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Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: the PHQ 
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Trivedi MH, Rush AJ, Ibrahim HM, et al. The Inventory of Depressive Symptomatology, Clinician Rating 
(IDS-C) and Self-Report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, Clinician Rating 
(QIDS-C) and Self-Report (QIDS-SR) in public sector patients with mood disorders: a psychometric 
evaluation. Psychol Med. 2004;34:73-82.
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Tuynman-Qua H, de Jonghe F, McKenna SP. Quality of Life in Depression Scale (QLDS). Development, 
reliability, validity, responsiveness and application. Eur Psychiatry. 1997;12:199-202.
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Ware JE Jr and Sherbourne CD. The MOS 36-Item Short-Form Health Survey (SF-36): I. conceptual 
framework and item selection. Med Care. 1992;30:473-483.



SAP_001.pdf: 
CONFIDENTIAL
1
Status: Approved, Date: 12 September 2022
Janssen Research & Development
Statistical Analysis Plan
A Randomized, Open-Label, Rater-Blinded, Active-Controlled, International, Multicenter
Study to Evaluate the Efficacy, Safety and Tolerability of Flexibly Dosed Esketamine Nasal 
Spray Compared with Quetiapine Extended-Release in Adult and Elderly Participants 
with Treatment-Resistant Major Depressive Disorder who are Continuing a Selective 
Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor
ESCAPE-TRD
Protocol 54135419TRD3013; Phase 3b
JNJ-54135419  (esketamine)
Status:
Approved
Date:
12 September 2022
Prepared by:
 / Janssen Research & Development, LLC), 
 (CRO 
Valos J&J partner)
Document No.:
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
PPD
PPD
NCT04338321


JNJ-54135419  (esketamine)
Statistical Analysis Plan 54135419TRD3013
CONFIDENTIAL
2
Status: Approved, Date: 12 September 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Objectives and Endpoints ................................................................................................................ 5
1.2.
Study Design.................................................................................................................................... 6
2.
STATISTICAL HYPOTHESES............................................................................................................ 9
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 9
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS....................................................................... 9
5.
STATISTICAL ANALYSES............................................................................................................... 10
5.1.
General Considerations ................................................................................................................. 10
5.1.1.
Visit Windows ............................................................................................................................. 10
5.2.
Participant Dispositions.................................................................................................................. 10
5.3.
Primary Endpoint Analysis ............................................................................................................. 11
5.3.1.
Definition of Endpoint.................................................................................................................. 11
5.3.2.
Estimand..................................................................................................................................... 11
5.3.3.
Analysis Methods........................................................................................................................ 12
5.4.
Secondary Endpoint(s) Analysis .................................................................................................... 12
5.4.1.
Key Secondary Endpoint ............................................................................................................ 12
5.4.1.1.
Definition of Endpoint .............................................................................................................. 12
5.4.1.2.
Estimand(s).............................................................................................................................. 13
5.4.1.3.
Analysis Methods .................................................................................................................... 14
5.5.
Supportive Secondary Endpoint(s) ................................................................................................ 14
5.5.1.
General Analysis Methods.......................................................................................................... 14
5.5.2.
Montgomery-Asberg Depression Rating Scale (MADRS).......................................................... 15
5.5.3.
Relapse....................................................................................................................................... 16
5.5.4.
Clinical Global Impression – Severity (CGI-S) ........................................................................... 16
5.5.5.
Clinical Global Impression – Change (CGI-C)............................................................................ 16
5.5.6.
Therapeutic benefit assessment (esketamine arm) ................................................................... 17
5.5.7.
Treatment Continuation Assessment ......................................................................................... 17
5.5.8.
Patient Health Questionnaire – 9 item (PHQ-9) ......................................................................... 17
5.5.9.
Quality of Life in Depression Scale (QLDS) ............................................................................... 18
5.5.10.
European Quality of Life Group, 5-Dimension, 5-Level (EQ-5D-5L) .......................................... 19
5.5.11.
36-Item Short-Form Health Survey (SF-36v2)............................................................................ 20
5.5.12.
Sheehan Disability Scale (SDS) ................................................................................................. 23
5.5.13.
Work Productivity and Activity Impairment (WPAI-D)................................................................. 23
5.6.
Tertiary/Exploratory Endpoint(s) Analysis...................................................................................... 24
5.7.
(Other) Safety Analyses................................................................................................................. 24
5.7.1.
Extent of Exposure ..................................................................................................................... 24
5.7.2.
Adverse Events........................................................................................................................... 25
5.7.3.
Additional Safety Assessments .................................................................................................. 26
5.7.3.1.
Clinical Laboratory Tests......................................................................................................... 26
5.7.3.2.
Vital Signs and Physical Examination Findings....................................................................... 27
5.7.3.3.
Electrocardiogram ................................................................................................................... 27
5.7.3.4.
Nasal Examination................................................................................................................... 28
5.7.3.5.
Pregnancy testing.................................................................................................................... 28
5.7.3.6.
Columbia–Suicide Severity Rating Scale................................................................................ 28
5.7.3.7.
Other Safety Parameters......................................................................................................... 29


JNJ-54135419  (esketamine)
Statistical Analysis Plan 54135419TRD3013
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Status: Approved, Date: 12 September 2022
5.8.
Other Analyses............................................................................................................................... 29
5.8.1.
Pharmacokinetics ....................................................................................................................... 29
5.8.2.
Immunogenicity........................................................................................................................... 29
5.8.3.
Pharmacodynamics .................................................................................................................... 29
5.8.4.
Pharmacokinetic/Pharmacodynamic Relationships ................................................................... 29
5.8.5.
Biomarkers.................................................................................................................................. 29
5.8.6.
Health Economics....................................................................................................................... 29
5.8.7.
Definition of Subgroups .............................................................................................................. 30
5.9.
Interim Analyses............................................................................................................................. 30
5.10.
Follow-up Phase ............................................................................................................................ 30
6.
SUPPORTING DOCUMENTATION .................................................................................................. 32
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 32
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 33
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 34
6.3.1.
Demographics............................................................................................................................. 34
6.3.2.
Nasal examination ...................................................................................................................... 34
6.3.3.
Psychiatric history....................................................................................................................... 35
6.3.4.
Mini International Neuropsychiatric Interview (MINI).................................................................. 35
6.3.5.
Inventory of Depressive Symptomatology (Clinician-Rated)...................................................... 37
6.3.6.
Psychotherapy............................................................................................................................ 37
6.3.7.
Urine screen for drugs of abuse ................................................................................................. 38
6.3.8.
Preplanned surgeries/procedures .............................................................................................. 38
6.4.
Appendix 4 Major Protocol Deviations........................................................................................... 40
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 40
6.6.
Appendix 6 Medical History ........................................................................................................... 41
6.7.
Appendix 7 Intervention Compliance ............................................................................................. 41
6.8.
Appendix 8 Adverse Events of Special Interest............................................................................. 42
6.9.
Appendix 9 Medications of Special Interest................................................................................... 43
6.10.
Appendix 10 Criteria of Markedly Abnormal Laboratory Values.................................................... 44
7.
REFERENCES................................................................................................................................... 45


JNJ-54135419  (esketamine)
Statistical Analysis Plan 54135419TRD3013
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Status: Approved, Date: 12 September 2022
VERSION HISTORY
Table: SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
17 December 2021
Not Applicable
Initial release
2
12 September 2022
Update use of Visit Windows
Small changes
Add handling of missing data for 
primary endpoint and key 
secondary endpoint
Clarification
Time to relapse: calculation
Clarification
Time to relapse: add Kaplan-
Meier analysis
Additional analysis
CMH test: in main analysis CRF 
data will be used for 
stratification factors, in 
sensitivity analysis IXRS data 
will be used
Clarification
MMRM analysis: add overall 
analysis
Additional analysis
Sensitivity analysis for 
remission/relapse over time
Added sensitivity analysis


JNJ-54135419  (esketamine)
Statistical Analysis Plan 54135419TRD3013
CONFIDENTIAL
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Status: Approved, Date: 12 September 2022
1.
INTRODUCTION
This statistical analysis plan describes the definitions of analysis sets, derived variables, and 
statistical methods for all planned statistical analyses to be documented in the CSR for protocol 
54135419TRD3013. Additional (abbreviated) SAPs will be developed for various supplementary 
and post-hoc analyses. 
1.1.
Objectives and Endpoints
Primary objective
The primary objective of this study is to evaluate the efficacy of flexibly dosed esketamine nasal 
spray compared with quetiapine extended-release (XR), both in combination with a continuing 
selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI), 
in achieving remission in participants who have treatment-resistant MDD with a current moderate 
to severe depressive episode. Remission at the Week 8 visit is defined as a Montgomery-Asberg 
Depression Rating Scale (MADRS) total score of ≤10.
Key secondary objective
The key secondary endpoint is to assess the efficacy of esketamine nasal spray compared with 
quetiapine XR, both in combination with a continuing SSRI/SNRI, in the proportion of participants 
being relapse-free at Week 32 after remission at Week 8. The key secondary parameter is defined 
as remission at Week 8 visit (ie, MADRS total score of ≤10 at the end of Week 8) and no relapse 
within the consecutive 24 weeks until the end of the prospective observation period at Week 32 
visit.
Note: A relapse is defined by any of the following:
a) Worsening of depressive symptoms as indicated by MADRS total score ≥22 confirmed by 1 
additional assessment of MADRS total score ≥22 within the next 5 to 15 days. The date of the 
second MADRS assessment will be used for the date of relapse.
b) Any psychiatric hospitalization for:
-
worsening of depression;
-
suicide prevention or due to a suicide attempt.
For any of these events, the start date of hospitalization will be used for the date of relapse.
c) Suicide attempt, completed suicide, or any other clinically relevant event determined per the 
investigator’s clinical judgment to be indicative of a relapse of depressive illness, but for which 
the participant was not hospitalized. The onset of the event will be used for the date of relapse.
In case more than 1 of the relapse criteria are met, the earliest date will be defined as the date of 
relapse for that participant.
Other secondary objectives
To assess the effect of esketamine nasal spray compared with quetiapine XR, both in combination 
with a continuing SSRI/SNRI, in:

Clinician-rated overall severity of depressive illness;


JNJ-54135419  (esketamine)
Statistical Analysis Plan 54135419TRD3013
CONFIDENTIAL
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Status: Approved, Date: 12 September 2022

Early onset of action;

Clinician-rated depressive symptoms;

Participant-reported depressive symptoms;

Participant-reported functional impairment and associated disability;

Participant-reported health-related quality of life and health status;

Participant-reported work productivity;

Safety and tolerability.
Exploratory objective
To assess the potential relationship of biomarkers with response/non-response to study 
intervention in participants with treatment resistant MDD.
1.2.
Study Design
Study design and patient selection
This is a randomized, open-label, rater-blinded, active-controlled, international, multicenter study
in participants 18 to 74 years of age, inclusive, with treatment-resistant MDD.
To be eligible for enrollment in the study:

Participant must be on a current antidepressive treatment that includes an SSRI/SNRI at 
screening that resulted in nonresponse (less than 25% improvement of symptoms) after having 
been given at an adequate dosage (been uptitrated to maximum tolerated dose; based on 
antidepressive dosages from Summary of Product Characteristics [SmPC; or local equivalent, 
if applicable]) for an adequate duration of at least 6 weeks; however, at screening the 
participant must show signs of minimal clinical improvement to be eligible for the study.

In addition to the current antidepressive treatment, participant must have documented 
nonresponse within the current moderate to severe depressive episode to at least 1 but not 
more than 5 different, previous consecutive treatments with ADs taken at an adequate dosage 
for an adequate duration of at least 6 weeks and that each prior AD treatment did not produce 
any significant improvement (less than 25% improvement of symptoms).

Participant must have been treated with at least 2 different antidepressive substance classes 
among the failed treatments in the current moderate to severe depressive episode (including 
the current treatment with an SSRI/SNRI).

Participant must be on a single oral SSRI/SNRI on Day 1 prior to randomization.
Study phases
The study has 4 phases: an up-to-14-day screening phase, an 8-week acute phase, a 24-week 
maintenance phase, and a 2-week safety follow-up phase. During the acute phase, participants in 
the esketamine arm will have twice-weekly visits from Week 1 to Week 4 and once-weekly visits 
from Week 5 to Week 8; during the maintenance phase from Week 9 to Week 32, visits will be 
once weekly or every 2 weeks (even weeks) based on dosing. Participants in the comparator arm 
will have weekly visits from Week 1 to Week 4, and then every 2 weeks for the remainder of the 
acute phase (Week 6 and Week 8) and the maintenance phase (Week 10, Week 12, etc) through 
Week 32. All participants have a safety follow-up visit 2 weeks following the last dose of study 


JNJ-54135419  (esketamine)
Statistical Analysis Plan 54135419TRD3013
CONFIDENTIAL
7
Status: Approved, Date: 12 September 2022
intervention. Participants who discontinue the study intervention early (ie, discontinue either 
component of the randomized combination therapy) will remain in the study and continue to return 
for all follow-up visits through Week 32, according to the Schedule of Activities.
For participants in the esketamine arm:
At the Week 4 visit, evidence of therapeutic benefit of the study intervention (ie, esketamine nasal 
spray in combination with a continuing SSRI/SNRI) will be evaluated clinically by the 
investigator. In the evaluation of therapeutic benefit, the full scope of clinical improvement should 
be evaluated including any improvement in depressive symptoms, general functioning, social
functioning, and self-care. If there is no evidence of therapeutic benefit, the investigator and the 
participant should discuss the treatment strategy and mutually agree on whether to continue or 
discontinue esketamine nasal spray.
Beginning at the Week 8 visit, all participants in both study intervention arms will undergo regular 
assessments of symptom changes from baseline (ie, treatment continuation assessment) to ensure 
that study intervention continuation is appropriate. This will be operationalized using the CGI-C 
clinician-rated scale (referring to study baseline [Day 1]) every 4 weeks, and treatment decisions 
will be made using cut-off values below.
Treatment Continuation Assessment of Study Intervention
CGI-C ≥4 (“no change” or worse) at 2 consecutive 
visits
Recommendation to reconsider appropriateness of 
study intervention and to switch to an alternative 
standard-of-care treatment.
CGI-C <4 (“Minimally improved” or better) at any 
visit
Study intervention may be continued at the discretion 
of the investigator.
CGI-C= Clinical Global Impression – Change
Note: After early discontinuation of study intervention, the CGI-C will still be performed at follow-up visits according to the Schedule of 
Activities; however, treatment decisions will be at the discretion of the investigator and not based on the criteria for the treatment continuation 
assessment.
Randomization
A total of 622 participants will be randomly assigned on Day 1 (baseline) in a 1:1 ratio to 1 of 2 
open-label study intervention arms (311 participants per arm). The randomization will be balanced 
by using randomly permuted blocks and will be stratified by age (18 to 64 years [inclusive]; 65 to 
74 years [inclusive]) and total number of treatment failures (2; 3 or more [inclusive of current
antidepressive treatment at screening used to determine eligibility]).
Esketamine arm
Participants will continue to take their current SSRI/SNRI in combination with esketamine nasal 
spray. 
On Day 1, participants will have their first nasal treatment session. Adult participants aged 18 to 
64 years will start with a dose of 56 mg. Elderly participants aged 65 to 74 years and adults of 
Japanese ancestry will start with a dose of 28 mg. As of Day 4, the dose may be increased from 56 
mg to 84 mg in adult participants, from 28 mg to 56 mg in elderly participants and adults of 


JNJ-54135419  (esketamine)
Statistical Analysis Plan 54135419TRD3013
CONFIDENTIAL
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Status: Approved, Date: 12 September 2022
Japanese ancestry, or participants may remain at the starting dose, as determined by the 
investigator based on efficacy and tolerability. Elderly participants and adults of Japanese ancestry 
may be uptitrated in 28 mg increments at subsequent visits. The highest dose that may be used in 
all participants is 84 mg. Nasal treatment sessions will occur twice weekly during Week 1 to Week 
4, once weekly during Week 5 to Week 8, and once weekly or every 2 weeks, as determined by 
the investigator based on efficacy and tolerability, during the maintenance phase (Week 9 to Week 
32). Dosing may be increased at any visit, may remain the same, or may be reduced as determined 
by the investigator based on efficacy and tolerability. Nasal treatment sessions should not take 
place on 2 consecutive days. Esketamine nasal spray dosing and related safety-monitoring 
procedures MUST be performed LAST at all visits. Esketamine nasal spray must NOT be 
administered before all other visit assessments are completed. Food will be restricted for at least 2 
hours before each administration of esketamine nasal spray. Drinking of any fluids will be 
restricted for at least 30 minutes before the first nasal spray at each session.
Comparator Arm
Participants will continue to take their current SSRI/SNRI which will be augmented with 
quetiapine XR as per the SmPC (or local equivalent, if applicable) starting on Day 1 and will 
continue through Week 32. In adult participants aged 18 to 64 years, the initial dose of quetiapine 
XR is 50 mg/day on Days 1-2, 150 mg/day on Days 3-4 [lowest effective dose]; a further dose 
increase to 300 mg/day as of Day 5 will be based on individual participant evaluation. In elderly 
participants aged 65 to 74 years, the initial dose is 50 mg/day on Days 1-3, 100 mg/day on Days 
4-7, and 150 mg/day on Day 8; a further dose increase to 300 mg/day will be based on individual 
participant evaluation no earlier than Day 22. If participants cannot tolerate at least 150 mg/day of 
quetiapine XR by the end of Week 2 (or at any subsequent time during the study), they must have 
quetiapine XR discontinued.
Continuing SSRI/SNRI
The continuing SSRI/SNRI being taken by a participant must be labeled for treatment of 
depression/MDD in their country of participation and the dosage being taken should be according 
to the respective SmPC (or local equivalent, if applicable). Off-label use of an SSRI/SNRI is not 
permitted. The investigator may optimize the dose of the continuing SSRI/SNRI, up to the 
maximum tolerated dose as per the respective SmPC (or local equivalent, if applicable). Once 
optimized, a stable dose should be maintained; however, dose modifications may be made, if 
necessary, at the investigator’s discretion.
Treatment discontinuation
The study intervention will be considered discontinued if either component of the randomized 
combination therapy (ie, esketamine nasal spray, quetiapine XR, or continuing SSRI/SNRI) is 
stopped. If esketamine nasal spray or quetiapine XR is discontinued at any time during the acute 
or maintenance phase, the participant will be switched to an alternative standard of care treatment, 
which may or may not include the continuing SSRI/SNRI, at the discretion of the investigator and 
continue follow-up visits through Week 32. If determined by the investigator that the alternative 
standard of care will include esketamine nasal spray (when commercially available in country of 
participation) or quetiapine XR for a participant, it will not be provided to the participant, rather, 


JNJ-54135419  (esketamine)
Statistical Analysis Plan 54135419TRD3013
CONFIDENTIAL
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Status: Approved, Date: 12 September 2022
the investigator must prescribe the medication to the participant. If the SSRI/SNRI is discontinued 
at any time during the acute or maintenance phase, the esketamine nasal spray or quetiapine XR 
must also be discontinued. The participant will be switched to an alternative standard of care 
treatment at the discretion of the investigator and continue follow-up visits through Week 32.
2.
STATISTICAL HYPOTHESES
The primary hypothesis of this study is that among participants who have treatment-resistant MDD 
with a current moderate to severe depressive episode, the proportion of participants achieving 
remission at the Week 8 visit is greater in participants treated with flexibly dosed esketamine nasal 
spray than in participants treated with quetiapine XR, both administered in combination with a 
continuing SSRI/SNRI.
The key secondary hypothesis of this study is that among participants who have treatment-resistant 
MDD with a current moderate to severe depressive episode, the proportion of participants who 
achieved remission at the Week 8 visit and remain relapse-free through the Week 32 visit is greater 
in participants treated with esketamine nasal spray than in participants treated with quetiapine XR, 
both administered in combination with a continuing SSRI/SNRI.
3.
SAMPLE SIZE DETERMINATION
For the primary endpoint, the assumptions are that the rate of remission for completers at the Week 
8 visit is 50% in the esketamine arm and 35% in the comparator arm, and that the rate for 
participants who discontinue study intervention between baseline and the Week 8 visit is 17.5% in 
both treatment arms (to be imputed as non-remitters). Combining these assumptions leads to an 
estimated remission rate at the Week 8 visit in non-responder imputation (NRI) analysis of 41.25% 
in the esketamine arm and 28.88% in the comparator arm. With a power of 90%, a 2-sided 
significance level of 0.05 and using chi-square test, a sample size of 311 participants per arm (622 
participants in total) is needed to detect the difference between the study intervention arms.
For the key secondary endpoint, among participants who achieve remission at the Week 8 visit, a 
relapse rate of 30% is assumed for both study intervention arms and rates for participants who 
discontinue study intervention between the Week 8 and Week 32 visits (to be imputed as non-
relapse-free after remission) is assumed to be 10% for the esketamine arm and 20% for the 
comparator arm. Combining these assumptions leads to an estimated rate of relapse-free after 
remission at the Week 32 visit in NRI analysis of 25.99% in the esketamine arm and 16.17% in 
the comparator arm. With a power of 80%, a 2-sided significance level of 0.05 and using a chi-
square test, a sample size of 270 randomized participants per arm (540 participants in total) is 
needed to detect a difference between the study intervention arms.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
The following analysis sets will be used in this SAP:
Analysis Sets
Description
Enrolled Analysis Set
All participants who sign the ICF
Full Analysis Set (FAS)
The full analysis set includes all randomized 
participants.


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Analysis Sets
Description
Safety Analysis Set
The safety analysis set includes all randomized 
participants who received at least 1 dose of any study 
intervention.
Follow-up Analysis Set
The follow-up analysis set includes all randomized 
participants who received at least 1 dose of any study 
intervention, and who discontinue study intervention.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
5.1.1.
Visit Windows
As participants do not always adhere to the protocol visit schedule, the following rules are applied 
to assign actual visits (or data collection dates) to analysis visits. The reference day is Study Day 
1 (Baseline). If a participant has 2 or more actual visits in 1 visit window, the visit closest to the 
target day will be used as the analysis visit for that visit window. The other additional visit(s) will 
not be used in the summaries or analyses, but they can be used for determination of clinically 
important endpoints. If 2 actual visits are equidistant from the target day within a visit window, 
the later visit is used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point except for the endpoint. In Excel sheet 
“Visit_windows_v3.xlsx” are the analysis visit windows and the target days for each visit
associated to the different parameters defined in the protocol.
The above procedure will be used for all visits except for the Week 8 visit and the Week 32 visit. 
For both Week 8 and Week 32 visit, the actual visit with the nominal visit label will be assigned 
to the corresponding analysis visit.
5.2.
Participant Dispositions
Screened participants and reason for screen failures will be summarized overall.
The number of participants in the following disposition categories will be summarized throughout 
the study by intervention group and overall:

Participants randomized

Participants who received study intervention

Participants who completed the study
The number of participants in the following disposition categories will be summarized for the first 
8 weeks of the study, for the second part (week 9-32) and overall, by intervention group:

Participants who discontinued study intervention

Reasons for discontinuation of study intervention

Participants who terminated study prematurely

Reasons for termination of study


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A listing of participants will be provided for the following category:

Participants who were randomized yet did not receive study intervention.
5.3.
Primary Endpoint Analysis
5.3.1.
Definition of Endpoint
The MADRS is a clinician-rated scale designed to measure depression severity and to detect 
changes due to antidepressant treatment. The MADRS consists of 10 items that cover all of the 
core depressive symptoms (apparent sadness, reported sadness, inner tension, sleep, appetite, 
concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts). Each item is 
scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the 
symptom). A total score (0 to 60) is calculated by adding the scores of all 10 items. For each item 
as well as the total score, a higher score represents a more severe condition. If 2 or more items are 
missing, no imputation will be performed, and the total score will be left missing. Otherwise, the 
total score will be calculated as the sum of the items present multiplied by the ratio of the maximum 
possible number of items (i.e., 10) to the number of items present.
The primary endpoint is remission at the Week 8 visit, defined as a MADRS total score of ≤10.
5.3.2.
Estimand
Primary Trial Objective: to evaluate the efficacy of flexibly dosed esketamine nasal spray 
compared with quetiapine XR, both in combination with a continuing SSRI/SNRI, in achieving 
remission at the Week 8 visit in participants who have treatment resistant MDD with a current 
moderate to severe depressive episode.
Estimand Scientific Question of Interest: What is the proportion of participants considered to 
have benefited from esketamine versus quetiapine XR for the pre-specified duration (8 weeks), 
administered in combination with a continuing SSRI/SNRI?
Study intervention:

Flexibly dosed esketamine nasal spray in combination with a continuing SSRI/SNRI

Quetiapine XR in combination with a continuing SSRI/SNRI.
Population: Participants

18 to 74 years of age (inclusive) with treatment resistant MDD

on a current antidepressive treatment that includes an SSRI/SNRI that resulted in nonresponse,
but the participant shows signs of minimal clinical improvement

must have documented nonresponse within the current moderate to severe depressive episode 
to at least 1 but not more than 5 different, previous consecutive treatments with ADs taken at 
an adequate dosage for an adequate duration of at least 6 weeks, and that each prior AD 
treatment did not produce any significant improvement

must have been treated with at least 2 different antidepressive substance classes among the 
failed treatments in the current depressive episode.
Variable: Remission (binary variable), where remission is defined as a participant achieving a 
MADRS total score of ≤10 at the Week 8 visit, who does not before week 8 visit:




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For any of these events, the start date of hospitalization will be used for the date of relapse.
c) Suicide attempt, completed suicide, or any other clinically relevant event determined per 
the investigator’s clinical judgment to be indicative of a relapse of depressive illness, but 
for which the participant was not hospitalized. The onset of the event will be used for the 
date of relapse. 
In case more than 1 of the relapse criteria are met, the earliest date will be defined as the date of 
relapse for that participant.
The key secondary endpoint is remission at Week 8 visit (ie, MADRS total score of ≤10 at the end 
of Week 8) and no relapse within the consecutive 24 weeks until the end of the prospective 
observation period at Week 32 visit.
5.4.1.2.
Estimand(s)
Key Secondary Trial Objective: to evaluate the efficacy of flexibly dosed esketamine nasal spray 
compared with quetiapine XR, both in combination with a continuing SSRI/SNRI, in achieving 
remission at the Week 8 visit and having no relapse within the consecutive 24 weeks until the end 
of the prospective observation period at Week 32 visit in participants who have treatment resistant 
MDD with a current moderate to severe depressive episode.
Estimand Scientific Question of Interest: What is the proportion of participants considered to 
have benefited from esketamine versus quetiapine XR for the pre-specified duration (32 weeks), 
administered in combination with a continuing SSRI/SNRI?
Study intervention:

Flexibly dosed esketamine nasal spray in combination with a continuing SSRI/SNRI

Quetiapine XR in combination with a continuing SSRI/SNRI.
Population: Participants

18 to 74 years of age (inclusive) with treatment resistant MDD

on a current antidepressive treatment that includes an SSRI/SNRI that resulted in nonresponse, 
but the participant shows signs of minimal clinical improvement

must have documented nonresponse within the current moderate to severe depressive episode 
to at least 1 but not more than 5 different, previous consecutive treatments with ADs taken at 
an adequate dosage for an adequate duration of at least 6 weeks, and that each prior AD 
treatment did not produce any significant improvement

must have been treated with at least 2 different antidepressive substance classes among the 
failed treatments in the current depressive episode.
Variable: Week-32-response (binary variable), where week-32-response is defined as a participant 
achieving remission at the Week 8 visit (defined as a MADRS total score of ≤10) and having no 
relapse within the consecutive 24 weeks until the end of the prospective observation period at 
Week 32 visit, who does not:

discontinues (any component of) study intervention, or

withdraws from the study.
Summary measure (population-level summary): Difference in proportions.




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(inclusive); 65 to 74 years (inclusive)] and total number of treatment failures [2; 3 or more]) and 
baseline score as a covariate. For all model approaches, LS estimates of the treatment differences
at each visit and 95% confidence intervals will be presented. Additionally, for the MMRM model, 
the LS mean change from baseline averaged over all visits will be presented with 95% confidence 
interval per treatment group. The corresponding treatment difference will be presented with 95% 
confidence interval and two-sided p-value.
Additionally, for scales that have a minimum clinically important difference (MCID), the 
proportion of participants having improved by at least the MCID will be described at each visit 
and compared between study interventions using CMH chi-square test adjusting for age (18 to 64 
years [inclusive]; 65 to 74 years [inclusive]) and total number of treatment failures (2; 3 or more). 
The same analysis will be conducted for the proportion of participants who deteriorate by at least 
the MCID.
Time to event parameters (eg, time to improvement by at least MCID) will be analyzed by the 
Kaplan-Meier method and study interventions will be compared using a 2-sided log-rank test for 
the full analysis set. Time to event will be summarized with median, 25th and 75th percentile (if 
estimable). Confidence intervals of 25th, 50th, and 75th percentile of time to event will also be 
provided. Hazard ratios and their confidence intervals will be estimated using Cox proportional 
hazard models stratified by age (18 to 64 years [inclusive]; 65 to 74 years [inclusive]) and number 
of previous treatment failures (2; 3 or more).
5.5.2.
Montgomery-Asberg Depression Rating Scale (MADRS)
Definitions
The MADRS is a clinician-rated scale designed to measure depression severity and to detect 
changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored 
from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), for 
a total possible score of 60. Higher scores represent a more severe condition. The MADRS 
evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, 
lassitude, interest level, pessimistic thoughts, and suicidal thoughts. The test exhibits high 
inter-rater reliability.
If 2 or more items are missing, no imputation will be performed, and the total score will be left 
missing. Otherwise, the total score will be calculated as sum of the non-missing items multiplied 
by the ratio of the maximum number of items (i.e., 10) to the number of non-missing items.
A subject is defined as a responder at a given time point if the percent improvement in MADRS 
total score from baseline is ≥ 50% or if the MADRS total score is ≤10.
A subject is defined as being in remission at a given time point if the MADRS total score is ≤10.
Rating of the MADRS will be conducted face-to-face with the participants by an independent rater. 
However, there may be situations where the rating is done remotely. The proportion of ratings by 
type of contact (site visit, home visit, remote video call) will be summarized by visit and study 
intervention.
Analysis Methods
See section 5.5.1 for the analysis of the MADRS total score.


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The proportion of subjects who responded and who are in remission will be summarized for each 
scheduled visit with N and % in each category by study intervention. Summaries of both observed 
and LOCF data will be presented. Stacked bar graphs will be made to show the proportion of 
subjects who are in remission and who responded but not in remission over time. In a sensitivity 
analysis, the proportions will be calculated with observed data in the numerator and the full 
analysis set in the denominator.
5.5.3.
Relapse
Definitions
The definition of relapse is described in section 5.4.1.1.
The remission time point is the first time point at which the participant is in remission. The time 
to first relapse will be calculated from the remission time point until the date of first relapse.
Analysis Methods
This analysis will only include participants for whom the remission time point is before or at Week 
8. The number of patients with a relapse and the reason(s) for relapse, being ‘MADRS total score 
>=22 for 2 assessments separated by 5 to 15 days’; ‘subject been hospitalized for worsening of 
depression, or for suicide prevention or due to a suicide attempt’; ‘Has there been a suicide attempt, 
completed suicide or any other clinically relevant event determined per the investigator’s clinical 
judgement to be indicative of a relapse of depressive illness, but for which the participant was not 
hospitalized’, will be summarized with N and % in each category by study intervention.
The time to first relapse will be summarized with descriptive statistics (N, mean, standard 
deviation [SD], median and range [minimum and maximum]). Time to first relapse (from 
remission time point) will be analyzed by the Kaplan-Meier method. Time to relapse will be 
summarized with median, 25th and 75th percentile (if estimable). Confidence intervals of 25th, 
50th, and 75th percentile of time to relapse will also be provided.
The relapse narratives will be listed.
5.5.4.
Clinical Global Impression – Severity (CGI-S)
Definitions
The CGI-S evaluates the severity of psychopathology on a scale of 1 to 7. Considering total clinical 
experience, a subject is assessed on severity of mental illness at the time of rating according to: 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.
Analysis Methods
See section 5.5.1 for the analysis of the CGI-S score.
In addition, a frequency distribution will be provided for each scheduled visit. Summaries of both 
observed and LOCF data will be presented.
5.5.5.
Clinical Global Impression – Change (CGI-C)
Definitions


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The CGI-C evaluates the total improvement whether or not due entirely to drug treatment on a 
scale of 1 to 7. Compared to the condition at baseline, a subject is assessed on how much he/she 
has changed, according to: 1 = very much improved; 2 = much improved; 3 = minimally improved; 
4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse.
Analysis Methods
A frequency distribution will be provided for each scheduled visit. Summaries of both observed 
and LOCF data will be presented.
5.5.6.
Therapeutic benefit assessment (esketamine arm)
Definitions
The therapeutic benefit assessment at visit week 4 for the esketamine receiving subjects consists 
of 3 Yes/No questions: “Did the evaluation of therapeutic benefit take place?”, “Was there 
evidence of therapeutic benefit?” and “Was the treatment with esketamine continued?”. If there 
was no evidence of therapeutic benefit and the treatment with esketamine continued, the reason is 
reported as: “Longer time to response / remission expected”, “Negative life event / unstable life 
circumstances”, “Other”.
Analysis Methods
A frequency distribution will be provided for each question. The specifications of reason “Other” 
will be listed.
5.5.7.
Treatment Continuation Assessment
Definitions
The treatment continuation assessment is scheduled for every 4 weeks starting as of visit week 8. 
The treatment decision is based on the CGI-C value of the visit, and is recorded as “Study 
intervention continued”, “Study intervention not continued and switch to alternative SoC”. The 
reason for continuation of study intervention in case of CGI-C >4 at 2 consecutive visits is recorded 
as: “Patient’s preference”, “Longer time to response/remission is expected”, “Negative life 
event/unstable life circumstances”, “Lack of alternative treatment option”, “Other”.
Analysis Methods
A frequency distribution will be provided for each question for each scheduled visit. The 
specifications of reason “Other” will be listed.
5.5.8.
Patient Health Questionnaire – 9 item (PHQ-9)
Definitions
The PHQ-9 is a validated 9-item, PRO measure to assess depressive symptoms. Each item is rated 
on a 4-point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every  
day). The participant’s item responses are summed to provide a total score (range of 0 to 27), with 
higher scores indicating greater severity of depressive symptoms. In addition, the question “If you 
checked off any problems, how difficult have these problems made it for you to do your work, 
take care of things at home, or get along with other people?” is scored as “Not difficult at all”, 
“Somewhat difficult”, “Very difficult”, “Extremely difficult”.
A subject is defined as a responder at a given time point if the percent improvement from baseline 
in PHQ-9 total score is ≥ 50%.


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A subject is defined as a remitter at a given time point if the PHQ-9 total score is ≤9 at that time 
point.
Analysis Methods
See section 5.5.1 for the analysis of the PHQ-9 total score.
Frequency distributions will be provided for the addition question on the PHQ-9, PHQ-9 response 
and PHQ-9 remission for each scheduled visit. Summaries of both observed and LOCF data will 
be presented.
5.5.9.
Quality of Life in Depression Scale (QLDS)
Definitions
The QLDS is a disease-specific validated PRO measure which assesses the impact that depression 
has on a participant’s quality of life. It is a 34-item self-rated questionnaire which consists of 
dichotomous response questions, with the response being either True/Not True. Each statement on 
the QLDS is given a score of "1" or "0". A score of "1" is indicative of adverse quality of life. All 
item scores are summed to give a total score that ranges from 0 (good quality of life) to 34 (very 
poor quality of life). As the measure contains positive as well as negative items, item scores are 
not always in the same order - that is, not all ‘true’ responses are allocated a score of “1”. Listed 
below are the statements with the alternative responses and their associated scores:
I just want time to pass
True
1
Not true
0
I feel hopeful about the future
True
0
Not true
1
I find it hard to hold a conversation
True
1
Not true
0
I like to know what is going on in the world
True
0
Not true
1
I feel as if my life is wasting away
True
1
Not true
0
I feel as if I am not in control of my life
True
1
Not true
0
I am reluctant to leave the house
True
1
Not true
0
On the whole, I enjoy the things I do
True
0
Not true
1
I have lost all pleasure in life
True
1
Not true
0
I feel as if I have nothing to offer anyone
True
1
Not true
0
I turn away from people I care about
True
1
Not true
0
I take good care of myself
True
0
Not true
1
I am able to think about the future
True
0
Not true
1
I just want to hide away
True
1
Not true
0
I look forward to things
True
0
Not true
1
I’ve forgotten what it’s like to enjoy myself
True
1
Not true
0


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I can’t be bothered with my friends
True
1
Not true
0
I can cope easily with everyday tasks
True
0
Not true
1
I cut myself off from other people
True
1
Not true
0
It is difficult for me to make even simple decisions
True
1
Not true
0
I feel as if I am a burden to people
True
1
Not true
0
Most of the time I just sit and stare into space
True
1
Not true
0
I can’t face anyone
True
1
Not true
0
I shut everything out
True
1
Not true
0
I’m neglecting my appearance
True
1
Not true
0
I can see the funny side of things
True
0
Not true
1
I don’t take in what people say to me
True
1
Not true
0
I feel as if I’m letting everyone down
True
1
Not true
0
I dread each coming day
True
1
Not true
0
I enjoy my food
True
0
Not true
1
I avoid people if I can
True
1
Not true
0
I am reluctant to answer the door or the telephone
True
1
Not true
0
My life has no meaning
True
1
Not true
0
I am able to cope with everyday problems
True
0
Not true
1
In case there are missing items, it is recommended that for respondents with between one and six 
missing responses (that is, cases with less than 20% missing data), the total score is calculated as 
follows:
T = x / (34 – m) * 34
where T is the final total score, x is the item summation score, m is the number of missing items.
Cases with more than six missing responses cannot be allocated a total score.
Analysis Methods
See section 5.5.1 for the analysis of the QLDS total score.
5.5.10.
European Quality of Life Group, 5-Dimension, 5-Level (EQ-5D-5L)
Definitions
The EQ-5D-5L is a validated 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 a visual analogue scale (EQ-VAS). 


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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 = no problem, level 2 = slight problems, level 3 = moderate 
problems, level 4 = severe problems, level 5 = extreme problems). The participant 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. Individual scores from the 5 
dimensions will be used to obtain a weighted health status index as follows: 
i)
Scores from each dimension will be combined to obtain a 5L health state: e.g., a score of 
1 for each dimension will give a 5L health state of 11111. Dimension scores will be 
combined in the following order: Mobility, Self-Care, Usual Activities, Pain/Discomfort, 
Anxiety/Depression;
ii) The EuroQol Group coordinated a study that administered both the 3-level and 5-level 
versions of the EQ-5D, in order to develop a “crosswalk” between the EQ-5D-3L value 
sets and the new EQ-5D-5L descriptive system, resulting in crosswalk value sets for the 
EQ-5D-5L.
Interim Scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to EQ-5D-3L Value Sets (Van 
Hout et al, 2012);
iii) The UK value set will be used to get the health utility values for all the countries 
participating in the study. See “EQ-5D-5L_Crosswalk_Value_Sets.xls”.
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.
Analysis Methods
See section 5.5.1 for the analysis of the EQ-Health-Utility and the EQ-VAS.
Frequency distributions will be provided for the 5 dimensions of the EQ-5D-5L descriptive system 
for each scheduled visit. Summaries of both observed and LOCF data will be presented.
5.5.11.
36-Item Short-Form Health Survey (SF-36v2)
Definitions
The SF-36 is a validated 36-item questionnaire which measures quality of life across 8 domains, 
which are both physically and emotionally based. Version 2 of this questionnaire, with a 4-week 
recall (standard version) will be used for this study. The 8 domains that the SF-36 measures are as 
follows: physical functioning; role limitations due to physical health; role limitations due to 
emotional problems; energy/fatigue; emotional wellbeing; social functioning; pain; general health. 
In addition to the 8 scales two summary scales are calculated, the physical component summary 
scale (PCS) and the mental component summary scale (MCS). A single item (item 2) is also 
included that identifies perceived change in health, “Compared to one year ago, how would you 
rate your health in general now?”. 
Individual items will be scored on a 3-point, 5-point or 6-point scale. To construct the 8 
dimensions, items will be recoded, the item values will be summed and transformed to a score of 
0 to 100, where 100 indicates the best possible answer and 0 the worst possible answer. Finally, a 


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norm-based score will be calculating. See the following table that defines the domains and the item 
recoding.
Dimension
Item
Abbreviated Item Content
Precoded
Final value
Physical
Functioning
(PF)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
Vigorous activities, such as running, lifting heavy
objects, or participating in strenuous sports
Moderate activities, such as moving a table,
pushing a vacuum cleaner, bowling, or playing
golf
Lifting or carrying groceries
Climbing several flights of stairs 
Climbing one flight of stairs
Bending, kneeling, or stooping
Walking more than a mile
Walking several hundred yards
Walking one hundred yards
Bathing or dressing oneself
1, 2, 3
1, 2, 3
Role-
Physical
(RP)
4a
4b
4c
4d
Cut down the amount of time one spent on work or
other activities
Accomplished less than you would like
Limited in kind of work or other activities
Had difficulty performing work or other activities 
(e.g., it took extra effort)
1, 2, 3, 4, 5
1, 2, 3, 4, 5
Bodily Pain
(BP)
7
8
Intensity of bodily pain
Extent pain interfered with normal work
1, 2, 3, 4, 5, 6
If item 7 is not 
answered:
1, 2, 3, 4, 5
If item 7 is answered
as 1 and item 8 as 1
If item 7 is answered
as 2-6 and item 8 as 1
If item 7 is answered
as 1-6 and item 8 as: 
2, 3, 4, 5
6.0, 5.4, 4.2, 3.1, 2.2, 
1.0
6.0, 4.75, 3.5, 2.25, 
1.0
6
5
4, 3, 2, 1
General
Health (GH)
1
11a
11b
11c
11d
Is your health: excellent, very good, good, fair,
poor
Seem to get sick a little easier than other people
As healthy as anybody I know
Expect my health to get worse
Health is excellent
1, 2, 3, 4, 5
1, 2, 3, 4, 5
1, 2, 3, 4, 5
1, 2, 3, 4, 5
1, 2, 3, 4, 5
5.0, 4.4, 3.4, 2.0, 1.0
1, 2, 3, 4, 5
5, 4, 3, 2, 1
1, 2, 3, 4, 5
5, 4, 3, 2, 1
Vitality (VT)
9a
9e
9g
9i
Feel full of life
Have a lot of energy
Feel worn out
Feel tired
1, 2, 3, 4, 5
1, 2, 3, 4, 5
1, 2, 3, 4, 5
1, 2, 3, 4, 5
5, 4, 3, 2, 1
5, 4, 3, 2, 1
1, 2, 3, 4, 5
1, 2, 3, 4, 5
Social
Functioning
(SF)
6
10
Extent health problems interfered with normal
social activities
Frequency health problems interfered with social
1, 2, 3, 4, 5
1, 2, 3, 4, 5
5, 4, 3, 2, 1
1, 2, 3, 4, 5
Role-
Emotional
(RE)
5a
5b
5c
Cut down the amount of time spent on work or
other activities
Accomplished less than you would like
Did work or other activities less carefully than
usual
1, 2, 3, 4, 5
1, 2, 3, 4, 5


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Dimension
Item
Abbreviated Item Content
Precoded
Final value
Mental
Health (MH)
9b
9c
9d
9f
9h
Been very nervous
Felt so down in the dumps that nothing
could cheer you up
Felt calm and peaceful
Felt downhearted and depressed
1, 2, 3, 4, 5
1, 2, 3, 4, 5
1, 2, 3, 4, 5
1, 2, 3, 4, 5
1, 2, 3, 4, 5
1, 2, 3, 4, 5
1, 2, 3, 4, 5
5, 4, 3, 2, 1
1, 2, 3, 4, 5
5, 4, 3, 2, 1
Reported
2
How health is now compared to 1 year ago
1, 2, 3, 4, 5
1, 2, 3, 4, 5
An excerpt from the User's Manual for the SF-36v2 Health Survey
Each raw scale score will be transformed to a 0 – 100 scale using the formula shown below and
using the information of the following table:
Scale
Lowest possible raw score
Possible raw score range
Physical Functioning (PF)
10
20
Role-Physical (RP)
4
16
Bodily Pain (BP)
2
10
General Health (GH)
5
20
Vitality (VT)
4
16
Social Functioning (SF)
2
8
Role-Emotional (RE)
3
12
Mental Health (MH)
5
20
If PF is the raw score for the Physical Functioning scale, then:
PFtrans = 100 * ( PF – “lowest possible raw score” ) / “possible raw score range”
For ease of interpretation the domain scores are converted to norm-based scores with mean=50 
and SD=10, using the formulas (given for Physical Functioning scale):
PFz-score = (PFtrans – meanPF) / SDPF
Norm-based PF = PFz * 10 + 50
The mean and SD to calculate the z-scores for the 8 scales are in the following table:
SF-36 scale
Mean
SD
PF
83.29094
23.75883
RP
82.50964
25.52028
BP
71.32527
23.66224
GH
70.84570
20.97821
VT
58.31411
20.01923
SF
84.30250
22.91921
RE
87.39733
21.43778
MH
74.98685
17.75604
(see: Ware JE, Kosinski M, Dewey JE. How to Score Version 2 of the SF-36® Health Survey. Lincoln, RI: 
QualityMetric Incorporated, 2000).


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The physical component summary scale (PCS) and the mental component summary scale (MCS). 
are calculated as follows:
PCS =
PFz * 0.42402 + RPz * 0.35119 + BPz * 0.31754 + GHz * 0.24954 +
VTz * 0.02877 + SFz * -0.00753 + REz * -0.19206 + MHz * -0.22069
MCS = PFz * -0.22999 + RPz * -0.12329 + BPz * -0.09731 + GHz * -0.01571 +
VTz * 0.23534 + SFz * 0.26876 + REz * 0.43407 + MHz * 0.48581
And then both scales will be converted to norm-based score in the same way as above.
Analysis Methods
See section 5.5.1 for the analysis of the norm-based scores of the 8 SF-36v2 dimensions and the 
two summary scores.
Frequency distributions will be provided for item 2 of the SF-36v2 for each scheduled visit.
Summaries of both observed and LOCF data will be presented.
5.5.12.
Sheehan Disability Scale (SDS)
Definitions
The SDS will be used to assess the secondary objective of functional impairment and associated
disability. The SDS is a validated PRO measure consisting of a 5-item questionnaire that has been 
widely used and accepted for assessment of functional impairment and associated disability. The 
first 3 items assess disruption of (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 recall period for this study is 
7 days. The first item (work/school) may be missing due to not working/studying unrelated to the 
disease.
The scores for the first 3 items are summed to create a total score of 0 to 30, where higher score 
indicates greater impairment. Scores ≤ 2 for each item and ≤ 6 for the total score are considered 
functional remission. If one of the first three items is missing, the total score will be calculated by 
imputing the missing item with the average of the other two items. Otherwise the total score will 
be set to missing as well as remission status.
Analysis Methods
See section 5.5.1 for the analysis of the SDS total score and the days lost items.
Frequency distributions will be provided for the SDS remission for each scheduled visit.
Summaries of both observed and LOCF data will be presented.
5.5.13.
Work Productivity and Activity Impairment (WPAI-D)
Definitions
The WPAI:D questionnaire is a validated short instrument that assesses impairment in work and 
other regular activities over the past 7 days. The WPAI yields four types of scores:
1. Absenteeism (work time missed)
2. Presenteeism (impairment at work / reduced on-the-job effectiveness)


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3. Work productivity loss (overall work impairment / absenteeism plus presenteeism)
4. Activity Impairment. 
The first three scores will be derived only for respondents who are working (should be missing for 
non-working), but the last score is applicable for all respondents. WPAI scores are expressed as 
percent impairment, with higher values indicating greater impairment. A score cannot be 
calculated if there is a missing response to the corresponding item.
The questions of the WPAI-D are:
Q1 = currently employed
Q2 = hours missed due to problems associated with depression
Q3 = hours missed other reasons
Q4 = hours actually worked
Q5 = degree depression affected productivity while working
Q6 = degree depression affected regular activities
The 4 scores are calculated as follows:
1. Absenteeism: Q2*100/(Q2+Q4)
2. Presenteeism: Q5*10
3. Work productivity loss: 100*[ Q2/(Q2+Q4) + (1 - Q2/(Q2+Q4)) * Q5/10 ]
4. Activity Impairment: Q6*10
Analysis Methods
See section 5.5.1 for the analysis of the 4 WPAI scores.
5.6.
Tertiary/Exploratory Endpoint(s) Analysis
Not applicable.
5.7.
(Other) Safety Analyses
All safety analyses will be based on the safety analysis set (based on actual intervention received), 
unless otherwise specified.
For all continuous safety variables, descriptive statistics by intervention group will include the N, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by intervention group using frequency counts and percentages.
5.7.1.
Extent of Exposure
The number and percentage of participants who receive each study agent within a study 
intervention will be summarized. 
Descriptive statistics for duration of study intervention (N, mean, SD, median, and range 
(minimum, maximum)) will be summarized.


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Study intervention duration is defined as (date of last dose of study intervention – date of first dose 
of study intervention) +1.
A frequency distribution of the total number of dosing sessions of intranasal study medication will 
be presented.
Starting dose for a participant is defined as the first dose taken after randomization. Modal dose 
for a participant is defined as the most frequently taken dose by a participant. Mean dose of a 
participant is calculated as the sum of doses during the phase divided by the total number of days 
exposed in the phase. The final dose is the last non-zero dose received during the phase. The 
calculation of mean, modal and final dose will exclude days off study drug.
Descriptive statistics (N, mean, SD, median, minimum and maximum) of starting dose, modal 
dose, mean dose and final dose will be presented for quetiapine XR and oral AD. For esketamine 
a frequency distribution will be presented.
The number (%) of participants with a dose adjustment/dose not administered will be summarized
for each study agent within a study intervention. Reasons for dose adjustments/doses not 
administered will also be summarized.
5.7.2.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). All AEs 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 participant’s 2-week safety follow-up visit. Serious AEs, 
including those spontaneously reported to the investigator within 30 days after the last dose of 
study intervention, must be reported.
Any AE occurring at or after the initial administration of study intervention through completion 
of the participant’s 2-week safety follow-up visit is considered to be treatment emergent. Serious 
AEs reported within 30 days after the last dose of study intervention are also regarded as treatment
emergent. If the event occurs on the day of the initial administration of study intervention, and 
either event time or time of administration are missing, then the event will be assumed to be 
treatment emergent. If the event date is recorded as partial or completely missing, then the event 
will be considered to be treatment emergent unless it is known to be prior to the first administration 
of study intervention based on partial onset date or resolution date. All reported treatment-
emergent adverse events will be included in the analysis. For each adverse event, the number and 
percentage of participants who experience at least 1 occurrence of the given event will be 
summarized by intervention group.
Summary tables, for the first 8 weeks and for the whole study, will be provided for treatment-
emergent adverse events:

AEs

Serious AEs (SAEs)

AEs leading to discontinuation of each study agent within a study intervention

AEs by severity


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
AEs by relationship to each study agent within a study intervention

AEs leading to dose interruption/dose modification of each study agent within a study 
intervention.
In addition to the summary tables, listings will be provided for participants who:

Had SAEs

Had AEs leading to discontinuation of study intervention.
Incidence of treatment-emergent adverse events of special interest will be summarized, grouped 
in the following MedDRA-based categories: sedation, dissociation, suicidality, suggestive of 
abuse potential, cystitis, and hepatic impairment. See Appendix 8 for a list of adverse events in 
each category.
The number and percentage of participants taking concomitant medication for dissociation events 
(preferred term of Dissociation) at any time during each treatment phase will be provided.
A listing of participants who died will be provided.
5.7.3.
Additional Safety Assessments
5.7.3.1.
Clinical Laboratory Tests
Clinical laboratory tests will be displayed for the participants included in the safety analysis set.
Descriptive statistics (N, mean, SD, median and range) for observed values and changes from 
baseline will be provided for clinical laboratory tests (hematology, chemistry, and urinalysis) at 
each scheduled time point by intervention group. 
Clinical laboratory tests that meet the criteria for markedly abnormal will be listed by participant
for each phase. The incidence of treatment-emergent markedly abnormal laboratory values that 
occurred at any time during the treatment phase will be presented. Clinical laboratory test values 
will be considered treatment-emergent markedly abnormal (TEMA) using the criteria defined by 
the sponsor listed in Attachment 10. The identification of TEMA laboratory values is based on the 
post-baseline value being out of range while the baseline value is either missing or within the range 
given in Attachment 10. If post-baseline laboratory results are above the upper limit and the 
baseline value is below the lower limit, then the post-baseline abnormality will also be considered 
TEMA. The same applies to the post-baseline value being below the lower limit with the baseline 
value being above the upper limit.
The incidence of participants with ALT or AST values > 3*upper normal limit (ULN) will be 
presented. Additionally, incidence of hepatic toxicity (Hy’s Law) defined as ALT or AST values 
> 3*ULN AND total bilirubin values > 2*ULN will be presented. Similar to the markedly 
abnormal analysis, only participants with baseline ALT or AST values ≤ 3*ULN (AND baseline 
total bilirubin values ≤ 2*ULN for hepatic toxicity) (or if the baseline value is missing) will be 
eligible for these analyses.


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5.7.3.2.
Vital Signs and Physical Examination Findings
Vital sign parameters weight, pulse, blood pressure (systolic and diastolic) and respiratory rate will 
be summarized at each assessment time point, including the change from baseline, will be 
summarized by intervention group. 
In addition, descriptive statistics of pre-dose and post-dose pulse rate, blood pressure (systolic and 
diastolic) values and respiratory rate, and changes from pre-dose will be provided for each 
intranasal dosing day.
Abnormality criteria (based on criteria defined in the table below) will be applied to baseline and 
postbaseline values. For baseline values, increase or decrease criteria are not applied.
Postbaseline values will be considered TE if they meet both value and change criteria in the table 
below.
For criteria that do not include an increase or decrease from baseline:

TE will be concluded if the postbaseline value is above the upper limit and the baseline value 
is below the upper limit (eg, Normal or Low). The same applies to the postbaseline value 
being below the lower limit with the baseline value being above the lower limit (eg, Normal 
or High).

If the baseline value is missing, a postbaseline abnormality will always be considered as TE.
Incidence of treatment-emergent abnormal vital signs during intervention, as defined in the table 
below, will be summarized for participants who had a baseline assessment and at least 1
postbaseline assessment for that vital sign.
Table: Treatment-Emergent Abnormality Categories for Vital Signs
Vital Parameter
Post-baseline value outside of normal limit if:
Abnormally low
Abnormally high
Pulse (bpm)
A decrease from Baseline of 15 to a 
value 50
An increase from Baseline of 15 to a 
value 100
Systolic BP (mmHg)
A decrease from Baseline of 20 to a 
value 90
An increase from Baseline of 20 to a 
value 180
Diastolic BP (mmHg)
A decrease from Baseline of 15 to a 
value 50
An increase from Baseline of 15 to a 
value 105
Respiratory rate (breaths per 
minute)
Any value < 10
Any value > 24
BP = blood pressure; Baseline is defined in Section Error! Reference source not found..
The proportion of subjects who experienced treatment-emergent acute hypertension (systolic BP 
≥ 180 or diastolic BP ≥ 110) at any time during each treatment phase will be summarized.
5.7.3.3.
Electrocardiogram
For the scheduled time points the following items will be summarized:

Was the ECG performed, Yes / No;

Overall interpretation, Normal / Abnormal / Not evaluable;

Clinically significant, Yes / No.


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In case the interpretation is abnormal, the specification will be listed.
In case the abnormality is assessed to be clinically significant, the associated Medical History 
Condition and/or Adverse Event will be listed.
5.7.3.4.
Nasal Examination
During the predose nasal examination the grade of the symptoms epistaxis, nasal crusts, nasal 
discharge and nasal erythema, scored as absent, mild, moderate or severe, will be summarized as 
frequency distributions. Comments to the symptom assessments will be listed.
5.7.3.5.
Pregnancy testing
The results of the pregnancy test (positive, negative, borderline, invalid) will be summarized at 
each scheduled time point as frequency distributions.
5.7.3.6.
Columbia–Suicide Severity Rating Scale
The Columbia–Suicide Severity Rating Scale (C-SSRS) is an assessment tool that evaluates 
suicidal ideation and behavior. The following outcomes are C-SSRS categories and have binary 
responses (yes/no). The categories have been re-ordered from the actual scale to facilitate the 
definitions of the composite and comparative endpoints, and to enable clarity in the presentation 
of the results:
Suicidal Ideation
Category 1 
Wish to be dead
Category 2 
Non-specific active suicidal thoughts
Category 3 
Active suicidal ideation with any methods (not plan) without 
intent to act
Category 4 
Active suicidal ideation with some intent to act, without specific 
plan
Category 5 
Active suicidal ideation with specific plan and intent
Suicidal behavior
Category 6 
Preparatory acts or behavior
Category 7 
Aborted attempt
Category 8 
Interrupted attempt
Category 9 
Actual attempt (non-fatal)
Category 10 
Completed suicide
Non-suicidal self-injurious behavior is also a C-SSRS outcome (although not suicide-related) 
and has a binary response (yes/no).
Composite endpoints based on the above categories are defined below:

Suicidal ideation: A “yes” answer at any time during treatment to any one of the five 
suicidal ideation questions (Categories 1-5) on the C-SSRS.

Suicidal behavior: A “yes” answer at any time during treatment to any one of the five 
suicidal behavior questions (Categories 6-10) on the C-SSRS.


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
Suicidal ideation or behavior: A “yes” answer at any time during treatment to any one of 
the ten suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS.
The following outcome is a numerical score derived from the C-SSRS categories. The score is 
created at each assessment for each patient.
Suicidal ideation score: The maximum suicidal ideation category (1-5 on the C-SSRS) present 
at the assessment. Assign a score of 0 if no ideation is present.
Note that missing data should not be imputed.
The incidence of the 11 items (the 10 categories and the ‘Non-suicidal self-injurious behavior’) 
and the 3 composite endpoints will be summarized as frequency distributions at screening and/or 
baseline (combined), and at any of the assessments during treatment (worst score during 
treatment).
The maximum score (from the 10 categories) assigned for each subject will also be summarized 
into one of three broad categories: No suicidal ideation or behavior (0), Suicidal ideation (1 - 5), 
Suicidal behavior (6 - 10). Shifts from the screening/baseline value to the maximum category 
during treatment will be summarized as frequency distributions.
For the suicidal ideation score the shift from screening/baseline to the maximum during treatment 
will be summarized as frequency distributions.
5.7.3.7.
Other Safety Parameters
Not applicable
5.8.
Other Analyses
5.8.1.
Pharmacokinetics
Not applicable
5.8.2.
Immunogenicity
Not applicable
5.8.3.
Pharmacodynamics
Not applicable
5.8.4.
Pharmacokinetic/Pharmacodynamic Relationships
Not applicable
5.8.5.
Biomarkers
Details of the analysis plan and summary of results from both biomarker and pharmacogenomic 
analyses will be reported separately.
5.8.6.
Health Economics
Not applicable


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5.8.7.
Definition of Subgroups
The following subgroups will be used to summarize parameters:
Subgroup
Variant
Definition
Sex
1

Male

Female
Age Group
1

Adult [18-64]

Elderly [>=65]
Number of previous 
treatment failures
1

2

>=3
Class of continued oral AD
1

SNRI

SSRI
The following parameters will be analyzed as described in the respective sections for the 
subgroups:
Selected demographic and disease characteristics;
The primary parameter and the major secondary parameter;
MADRS;
CGI-S and CGI-C;
PHQ-9;
QLDS;
Selected AE parameters (including AEs of special interest).
5.9.
Interim Analyses
Not applicable.
5.10.
Follow-up Phase
The follow-up phase starts when a randomized participant discontinues study intervention. The 
starting visit of the follow-up phase is the visit when the treatment discontinuation occurs, or the 
visit closest to the treatment discontinuation. The follow-up analysis set will be used for all 
analyses. Analyses will be presenting observed data only and uses descriptive methods. For 
continuous parameters the change from starting visit of the follow-up phase will also be 
summarized. Data will be presented by group where to participant was randomized to and overall.
The following parameters will be analyzed as described in the respective sections:
Selected demographic and disease characteristics;
Treatment administered;
Remission and relapse;
MADRS;
CGI-S;


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PHQ-9;
QLDS;
(Serious) Adverse events recorded during a Janssen treatment for depression.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
adverse event
ALT/SGPT
alanine aminotransferase
ANCOVA
analysis of covariance
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic class
BMI
body mass index
CI
confidence interval
CRF
case report form
CSR
Clinical Study Report
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
FDA
Food and Drug Administration
ICH
International Conference on Harmonisation
IWRS
interactive web response system
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SMQs
standardized MedDRA queries
TEAE
treatment-emergent adverse event
TEMA
treatment-emergent markedly abnormal
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
The analysis of time to event endpoints as described in the protocol includes both descriptive 
analysis, log-rank test and Cox proportional hazards model. However, since time to relapse is an 
exploratory endpoint, the analysis of this endpoint will only be descriptive.


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6.3.
Appendix 3 Demographics and Baseline Characteristics
6.3.1.
Demographics
The following demographic variables will be summarized by intervention group:
Continuous Variables
Summary Type
Age (years)
Descriptive statistics (N, mean, standard deviation 
[SD], median and range [minimum and maximum]
Weight (kg) at baseline
Categorical Variables
Age (18-64 years, >=65 years)
Frequency distribution with the number and 
percentage of participants in each category.
Sex (male, female, undifferentiated)
Japanese Ancestry (Yes, No)
Occupational/employment status (full time employed, part 
time employed, casually employed, sheltered work, 
employed, but currently on sick or disability leave, 
unemployed due to depression, but seeking work, 
unemployed for reasons unrelated to depression, but 
seeking work, unemployed due to depression, but not 
seeking work, unemployed for reasons unrelated to 
depression, but not seeking work, retired, housewife or 
dependent husband/partner, student, no information 
available)
The following variables will be summarized for female participants by intervention group:
Continuous Variables
Summary Type
Average length of menstrual cycle (days)
Descriptive statistics (N, mean, standard deviation 
[SD], median and range [minimum and maximum]
Time from last menstrual period to date of assessment
Categorical Variables
Subject's childbearing potential (of childbearing potential, 
permanently sterilized, postmenopausal, not applicable)
Frequency distribution with the number and 
percentage of participants in each category.
Did menstrual period occur since last assessment (Yes, No)
6.3.2.
Nasal examination
The following variables will be summarized for the nasal examination performed at screening by 
intervention group:
Categorical Variables
Summary Type
Condition (Structural/Functional Abnormalities, Septal 
Deviation, Signs of Infections, Obstruction/Functional 
Lesions, Other Findings)
Frequency distribution with the number and 
percentage of participants in each category.
The specifications of the conditions recorded will be listed.


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6.3.3.
Psychiatric history
The following variables will be summarized for the psychiatric history performed at screening by 
intervention group:
Continuous Variables
Summary Type
Subjects age in years when diagnosed with MDD (years)
Descriptive statistics (N, mean, standard deviation 
[SD], median and range [minimum and maximum]
Total number of major depressive episodes to date, 
including current
episode
Duration of Current Episode (weeks)
Categorical Variables
Would the subject be eligible for electroconvulsive therapy, 
had he/she NOT been enrolled in this clinical trial (Yes, 
No)
Frequency distribution with the number and 
percentage of participants in each category.
Does the subject have a family history of psychiatric 
disorders (Yes, No, Unknown)
Psychiatric Disorder (Alcohol Abuse, Anxiety Disorder, 
Bipolar Disorder, Depression, Schizophrenia, Substance, 
Abuse, Other)
Check all family members who have or had the selected 
psychiatric disorder (Father, Mother, Siblings, Other)
The specified Other psychiatric disorders and Family members will be listed.
6.3.4.
Mini International Neuropsychiatric Interview (MINI)
Participants will undergo the MINI (a structured diagnostic interview) to confirm the diagnosis of 
MDD and to determine if there are other psychiatric conditions present.
The following variables will be summarized for the MINI performed at screening by intervention
group:
Categorical Variables
Summary Type
Was the questionnaire completed (Yes, No)
Frequency distribution with the number and 
percentage of participants in each category.
Reason Not Done (Subject too ill, Subject refused, Other)
Major depressive episode, Current (2 weeks) 
Major depressive episode, Past
Major depressive episode, Recurrent
Major depressive disorder, Current (2 weeks) 
Major depressive disorder, Past
Major depressive disorder, Recurrent
Suicidality, Current (Past Month)
Suicidality, Lifetime attempt 
Suicidality level (Low, Moderate, High)


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Suicide behavior disorder, Current
Suicide behavior disorder, In early remission
Manic episode, Current
Manic episode, Past
Hypomanic episode, Current
Hypomanic episode, Past
Hypomanic episode, Not Explored
Bipolar I disorder, Current
Bipolar I disorder, Past
Bipolar I disorder with psychotic features, Current
Bipolar I disorder with psychotic features, Past
Bipolar II disorder, Current
Bipolar II disorder, Past
Other specified bipolar and related disorder, Current
Other specified bipolar and related disorder, Past
Panic disorder, Current (Past Month)
Panic disorder, Lifetime
Agoraphobia, Current
Social anxiety disorder (Social Phobia), Current (Past 
Month)
Obsessive-compulsive disorder, Current (Past Month)
Posttraumatic stress disorder, Current (Past Month)
Alcohol use disorder, Past 12 Months
Substance use disorder (Non-alcohol), Past 12 Months
Any psychotic disorder, Current
Any psychotic disorder, Lifetime
Major depressive disorder with psychotic features, Current
Major depressive disorder with psychotic features, Past
Bipolar I disorder with psychotic features, Current
Bipolar I disorder with psychotic features, Past
Anorexia nervosa, Current (Past 3 Months)
Bulimia nervosa, Current (Past 3 Months)
Binge-eating disorder, Current (Past 3 Months)
Generalized anxiety disorder, Current (Past 6 Months)
Medical, organic, drug cause ruled out (No, Yes, Uncertain)
Antisocial personality disorder, Lifetime
Primary diagnosis (Major depressive episode, …)


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The specified Other reasons for MINI not done will be listed.
6.3.5.
Inventory of Depressive Symptomatology (Clinician-Rated)
The 30 item Inventory of Depressive Symptomatology clinician rated (IDS-C30) is designed to 
assess the severity of depressive symptoms. Each item is interval scaled from 0 to 3; 0 indicates 
absence of the symptom during the last 7 days. The IDS-C30 is scored by summing responses to 
28 of the 30 items to obtain a total score ranging from 0 to 84. Either appetite increase or 
decrease, but not both, are used to calculate the total score. Weight increase or decrease, but not 
both, are used to calculate the total score.
The following variables will be summarized for the IDS-C30 performed at screening by 
intervention group:
Continuous Variables
Summary Type
IDS-C30 total score
Descriptive statistics (N, mean, standard deviation 
[SD], median and range [minimum and maximum]
Categorical Variables
Was the questionnaire completed (Yes, No)
Frequency distribution with the number and 
percentage of participants in each category.
Reason Not Done (Subject too ill, Subject refused, Other)
The specified Other reasons for IDC-C30 not done will be listed.
6.3.6.
Psychotherapy
The following variables will be summarized for the investigator discussion with the participant 
regarding psychotherapy by intervention group:
Categorical Variables
Summary Type
Discussion of initiation/continuation of psychotherapy 
during study has taken place prior to randomization (Yes, 
No)
Frequency distribution with the number and 
percentage of participants in each category.
Psychotherapy recommended based on pre-randomization 
discussion (Yes, No)
Decision by the participant to follow the recommendation 
(prior to randomization) (Decision to follow 
recommendation, Decision to not follow recommendation)
Psychotherapy started (Yes, No)
Category of started psychotherapy (Cognitive–behavioral 
therapy, Nondirective supportive therapy, Behavioral 
activation therapy, Psychodynamic therapy, Systemic 
therapy, Problem-solving therapy, Interpersonal 
psychotherapy, Social skills training, Other)
Reason for starting (Patient's wish/preference, Suggested by 
treating physician, Suggested by third party, Unspecified -
started prior the study, Other)
Frequency (once, infrequent, as necessary, continue, daily, 
twice daily, three times daily, four times daily, every other 
day, weekly, twice weekly, three times weekly, four times 


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weekly, every two weeks, every four weeks, monthly, twice 
per month, every three months, thrice, unknown, other)
Reason for stopping (Patient's decision, Lack of efficacy, 
Lack of tolerability, Lack of cooperation, Other)
Reason for change to another psychotherapeutic 
intervention (Suggested by the therapist, Lack of efficacy, 
Lack of tolerability, Lack of cooperation, Other)
Participant´s adherence to psychotherapeutic intervention
(Good, Moderate, Bad)
The other specifications for psychotherapy, reason for starting, reason for stopping and reason 
for change to another psychotherapeutic intervention will be listed.
6.3.7.
Urine screen for drugs of abuse
The following variables will be summarized for the Urine screen for drugs of abuse performed at 
screening by intervention group:
Categorical Variables
Summary Type
Was the sample collected (Yes, No)
Frequency distribution with the number and 
percentage of participants in each category.
Amphetamine (Positive, Negative)
Barbiturate (Positive, Negative)
Cannabinoids (Positive, Negative)
Cocaine (Positive, Negative)
Methadone (Positive, Negative)
Methamphetamine (Positive, Negative)
Opiate (Positive, Negative)
Phencyclidine (Positive, Negative)
6.3.8.
Preplanned surgeries/procedures
The following variables will be summarized for preplanned surgeries/procedures by intervention
group:
Categorical Variables
Summary Type
Are there any planned/scheduled surgeries/procedures 
which require hospitalization during the course of this trial 
(Yes, No)
Frequency distribution with the number and 
percentage of participants in each category.
Allergic/Immunologic (ongoing yes / no)
Cardiovascular (ongoing yes / no)
Dermatologic (ongoing yes / no)
Ears, Nose and Throat/ (ongoing yes / no)
Endocrine and Metabolic (ongoing yes / no)
Eyes (ongoing yes / no)


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Gastrointestinal (ongoing yes / no)
Genito-urinary (ongoing yes / no)
Hematopoietic/Lymphatic (ongoing yes / no)
Musculoskeletal (ongoing yes / no)
Neurologic (ongoing yes / no)
Psychiatric (ongoing yes / no)
Reproductive/Breast (ongoing yes / no)
Respiratory (ongoing yes / no)
Other (ongoing yes / no)
Indication (Medical History, Prophylaxis, Other)
Details of surgery/procedure and associated medical history/prophylaxis/other will be listed.


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6.4.
Appendix 4 Major Protocol Deviations
In general, major protocol deviations may have the potential to impact participants’ rights, safety 
or well-being, or the integrity and/or result of the clinical study. Participants with major protocol 
deviations will be identified prior to database lock. See the study specific Major Protocol Deviation 
Criteria document.
The participants with major protocol deviations will be summarized by category (“Protocol 
Deviation Coded Term)”. Major protocol deviations will be listed presenting the coded term and 
the description (“PD criterion”).
6.5.
Appendix 5 Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Prior medications are defined as any therapy used before the day of first 
dose (partial or complete) of study intervention. Concomitant medications are defined as any 
therapy used on or after the same day as the first dose of study intervention, including those that 
started before and continue after the first dose of study intervention.
Summaries of concomitant medications will be presented by ATC term and study intervention. 
The proportion of participants who receive each concomitant medication will be summarized as 
well as the proportion of participants who receive at least 1 concomitant medication. In addition, 
concomitant medications of special interest will be presented as administered before the study 
intervention and during the study. These include benzodiazepines and sleeping medications. See 
Appendix 9 for specifications of the medications.
The indication of the concomitant medications will be summarized by study intervention. The 
associated adverse events or medical histories will be summarized. 
Note: the SSRI/SNRI continued during the study in combination with the study drug is 
summarized separately. See section 5.7.1.
Prior medications, meaning the retrospective treatment failures, will be summarized by substance 
class, substance name and study intervention. The number of treatment failures will be summarized 
by study intervention.


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6.6.
Appendix 6 Medical History
The following variables will be summarized for subjects who experienced any past and/ or 
concomitant diseases at screening by intervention group:
Categorical Variables
Summary Type
Allergic/Immunologic (ongoing yes / no)
Frequency distribution with the number and 
percentage of participants in each category.
Cardiovascular (ongoing yes / no)
Dermatologic (ongoing yes / no)
Ears, Nose and Throat/ (ongoing yes / no)
Endocrine and Metabolic (ongoing yes / no)
Eyes (ongoing yes / no)
Gastrointestinal (ongoing yes / no)
Genito-urinary (ongoing yes / no)
Hematopoietic/Lymphatic (ongoing yes / no)
Musculoskeletal (ongoing yes / no)
Neurologic (ongoing yes / no)
Psychiatric (ongoing yes / no)
Reproductive/Breast (ongoing yes / no)
Respiratory (ongoing yes / no)
Other (ongoing yes / no)
The verbatim term for the medical history condition/event will be listed.
6.7.
Appendix 7 Intervention Compliance
Compliance calculation is not applicable for this study.
Relevant deviations from the dosing schedules will be documented through major protocol 
deviations. See the Major Protocol Deviation Criteria document for this study.


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6.8.
Appendix 8 Adverse Events of Special Interest
Adverse events of special interest are defined and grouped in the following MedDRA based 
categories as follows:
Sedation: sedation; somnolence; altered state of consciousness; depressed level of consciousness; 
hypersomnia; stupor
Dissociation: depersonalisation/derealisation disorder; derealisation; dissociative disorder; 
flashback; hallucination; hallucination, auditory; hallucination, visual; hallucination, illusion; 
somatic hallucination; hyperacusis; tinnitus; diplopia; vision blurred; ocular discomfort; 
photophobia; visual impairment; dysesthesia; oral dysesthesia; paraesthesia; paraesthesia oral; 
pharyngeal paraesthesia; time perception altered; daydreaming; delusional perception; feeling hot; 
feeling cold; feeling of body temperature change
Suicidality: completed suicide; depression suicidal; intentional overdose; intentional self-injury; 
multiple drug overdose intentional; poisoning deliberate; self-injurious behavior; self-injurious 
ideation; suicidal behavior; suicidal ideation; suicide attempt; toxicity to various agents
Suggestive of abuse potential: aggression; confusional state; decreased activity; dependence; 
disorientation; dissociation; dissociative disorder; dizziness; drug abuse; drug abuser; drug 
dependence; drug use disorder; drug detoxification; drug diversion; drug rehabilitation; drug 
tolerance; drug tolerance increased; drug withdrawal convulsions; drug withdrawal headache; drug 
withdrawal syndrome; euphoric mood; feeling abnormal; feeling drunk; feeling of relaxation; 
hallucination; hallucination, auditory; hallucination, gustatory; hallucination, olfactory; 
hallucination, synesthetic; hallucination, tactile; hallucination, visual; hallucinations, mixed; 
inappropriate affect; mental impairment; product tampering; psychomotor hyperactivity; psychotic 
disorder; rebound effect; somatic hallucination; somnolence; substance abuser; substance 
dependence; substance use; substance use disorder; substance-induced mood disorder; substance-
induced psychotic disorder; thinking abnormal; withdrawal arrhythmia; withdrawal syndrome
Cystitis: allergic cystitis; chemical cystitis; cystitis; cystitis erosive; cystitis hemorrhagic; cystitis 
interstitial; cystitis noninfective; cystitis ulcer active; cystitis-like symptom; pollakiuria; dysuria; 
micturition urgency; nocturia
Hepatic impairment: cholestasis and jaundice of hepatic origin; hepatic failure; fibrosis and 
cirrhosis; other liver damage-related conditions


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6.9.
Appendix 9 Medications of Special Interest
Concomitant medications of special interest are defined as follows:
Concomitant 
Medication Special 
Interest Category
Selection
Note
benzodiazepines
ATC level 3 class name ANXIOLYTICS 
ATC level 3 code N05B
benzodiazepines
ATC level 3 class name HYPNOTICS AND 
SEDATIVES
ATC level 3 code N05C
sleep medication
quetiapine
Low dose, daily dose ≤50 mg


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6.10.
Appendix 10 Criteria of Markedly Abnormal Laboratory Values
Markedly Abnormal Limits
Laboratory Parameter
Low
High
Alanine aminotransferase (ALT) (SGPT) [U/L]
N/A
200
Alanine aminotransferase (ALT) (SGPT) [U/L]
N/A
>3X ULN
Albumin [g/L]
24
60
Alkaline phosphatase [U/L]
N/A
250
Aspartate aminotransferase (AST) (SGOT) [U/L]
N/A
250
Aspartate aminotransferase (AST) (SGOT) [U/L]
>3X ULN
Basophils [%]
N/A
6
Bicarbonate [mmol/L]
15.1
34.9
Bilirubin, total [mol/L]
N/A
51.3
Blood urea nitrogen [mmol/L]
N/A
17.9
Calcium [mmol/L]
1.5
3
Chloride [mmol/L]
94
112
Creatine kinase (U/L)
N/A
990
Creatinine [mol/L]
N/A
265.2
Eosinophils [%]
N/A
10
Erythrocytes (RBC) [x1012/L] -- female
3.0
5.5
                                                   -- male
3.0
6.4
Gamma glutamyl transferase [U/L]
N/A
300
Glucose [mmol/L]
2.2
16.7
Hemoglobin [g/L]
80
190
Hematocrit [fraction] -- female
0.28
0.50
                                   -- male
0.24
0.55
Lactate Dehydrogenase [U/L]
N/A
500
Leukocytes (WBC) [x109/L]
2.5
15.0
Lymphocytes [%]
10
60
Monocytes [%]
N/A
20
Neutrophils, segmented [%]
30
90
Phosphate [mmol/L]
0.7
2.6
Platelet count [x109/L]
100
600
Potassium [mmol/L]
3.0
5.8
Protein, total [g/L]
50
N/A 
Sodium [mmol/L]
125
155
Urate [mol/L]
89.2
594.8
Urine pH
N/A
8.0
Hy’s Law criteria:
    Alanine aminotransferase (ALT) (SGPT) [U/L] or Aspartate     
aminotransferase (AST) (SGOT) [U/L]
>3X ULN
AND
Bilirubin, total [mol/L]
>2X ULN
Note: The same limits apply to both males and females unless gender is indicated; 
N/A = Not applicable.


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7.
REFERENCES