Clinical trial NCT04599855
Conditions: Depressive Disorder, Treatment-Resistant
Sponsor: Janssen Research & Development, LLC
Start date: 2020-11-04; Completion date: 2024-01-31
Enrollment: 477 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of each individual dose of esketamine nasal spray, 56 milligram (mg) and 84 mg, compared with placebo nasal spray in improving depressive symptoms in participants with treatment resistant depression (TRD), as assessed by the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from Day 1 (prerandomization) to the end of the 4 week double-blind treatment phase (Day 28).

Detailed description:

Arms: arm 1: Participants will receive nasal spray treatment with esketamine 56 mg twice a week for 4 weeks. Participants may participate in an open-label treatment/observation phase, following completion of the double-blind treatment phase assessments (which includes the Day 28 Montgomery-Asberg Depression Rating Scale \[MADRS\] assessment). arm 2: Participants will receive nasal spray treatment with esketamine 84 mg twice a week for 4 weeks. Participants may participate in an open-label treatment/observation phase, following completion of the double-blind treatment phase assessments (which includes the Day 28 MADRS assessment). arm 3: Participants will receive nasal spray treatment with placebo twice a week for 4 weeks. Participants may participate in an open-label treatment/observation phase, following completion of the double-blind treatment phase assessments (which includes the Day 28 MADRS assessment).
Interventions: intervention 1: Esketamine 56 mg intervention 2: Esketamine 84 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Esketamine 56 mg will be self administered as nasal spray. intervention 2: Esketamine 84 mg will be self administered as nasal spray. intervention 3: Matching placebo will be self administered as nasal spray.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date:  14 Jul 2020
Janssen Research & Development *
Clinical Protocol
A Randomized, Double-blind, Multicenter, Placebo-controlled Study to Evaluate the 
Efficacy, Safety, and Tolerability of Esketamine Nasal Spray, Administered as 
Monotherapy, in Adult Participants with Treatment-resistant Depression
Protocol 54135419TRD4005; Phase 4
AMENDMENT 2
JNJ-54135419 (esketamine)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Status:
Approved
Date:
14 Jul 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-194910312, 3.0
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.
NCT04599855


JNJ-54135419   (esketamine)
Clinical Protocol 54135419TRD4005 Amendment 2
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Status: Approved,  Date:  14 Jul 2020
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
14-Jul-2020
Amendment 1
13-Mar-2020
Original Protocol
26-Sep-2019
Amendment 2 (14 Jul 2020)
Overall Rationale for the Amendment:  The amendment updates the protocol to remove post dose TSH 
testing, allow for video teleconferencing of MADRS assessments, and provide updates to the Schedule of 
Activities. 
Section number
and Name
Description of Change
Brief Rationale
Synopsis Efficacy Evaluations; 
Section 1.3.  Schedule of 
Activities – Screening and 
Double-blind Phase; Schedule 
of Activities – For Participants 
Receiving Esketamine: Open-
label Treatment/Observation 
Phase and Follow-up Phase;
Section 8.1. Efficacy 
Assessments
Added that evaluation of Montgomery-
Asberg Depression Rating Scale 
(MADRS) was via video teleconferencing.
In response to the ongoing 
pandemic and continued 
instability across the United 
States (US), this innovative 
approach aligns with 
recommendations to protect all 
parties involved in the study 
conduct, maintain consistency 
and protect study integrity, and 
reduce the potential of missing 
data due to this evolving public 
health emergency.
Section 1.3.  Schedule of 
Activities – Screening and 
Double-blind Phase; Section 8. 
Study Assessments and 
Procedures
Removed thyroid-stimulating hormone 
(TSH) testing post dose and updated blood 
collection volume
Removed to reduce the burden of  
additional blood sampling since 
analyses of TSH data from the 
phase 3 treatment resistant 
depression (TRD) studies did not 
identify an increase in thyroid 
hormone levels with esketamine 
administration.
Section 1.3.  Schedule of 
Activities – Screening and 
Double-blind Phase
Added footnotes g and i regarding 
increased window of assessment for 
MADRS on dosing visits to include 2 days 
before visit and visit window for MADRS 
at Day2 visit.
Increased visit window for 
MADRS assessment since this is 
now being assessed via video 
teleconferencing.
Section 1.3.  Schedule of 
Activities – Screening and 
Double-blind Phase 
Update to reflect all timepoints of 
menstrual cycle tracking (added Day 28 
and screening week 1).
Added assessments to Schedule 
of Activities to align with 
collection times noted in text.
Section 5.1. Inclusion Criteria
Inclusion criterion #2 was modified to 
clarify that the duration of a single episode 
major depressive disorder (MDD) must be 
≥2 years.
Modified to align with inclusion 
criteria in Phase 3 TRD studies.
Section 1.3.  Schedule of 
Activities – Screening and 
Double-blind Phase
Footnotes re-ordered. 
Minor errors were noted. 


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Status: Approved,  Date:  14 Jul 2020
Section number
and Name
Description of Change
Brief Rationale
Section 7.2. Participant 
Discontinuation/Withdrawal 
From the Study
Withdrawal of Consent
Added that less frequent clinical visits 
were only allowed during the open label 
phase.
Clarified options for reduced 
follow-up. 
Section 6.5 Dose Modification,
Section 8.3. Adverse Events, 
Serious Adverse Events, and 
Other Safety Reporting, 
Section 8.6 Biomarkers, 
Section 9.3. Populations for 
Analysis Sets, 10.3. Appendix 
3, 10.4. Adverse Events, 
Serious Adverse Events, 
Product Quality Complaints, 
and Other Safety Reporting: 
Definitions and Procedures for 
Recording, Evaluating, 
Follow-up, and Reporting; 
Section 10.5 Contraceptive and 
Barrier Guidance
Subsequent sections were renumbered 
accordingly, headings were updated, and 
subheadings were numbered.
To align with updated template. 
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.


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Status: Approved,  Date:  14 Jul 2020
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
1.
PROTOCOL SUMMARY ..................................................................................................................... 7
Synopsis........................................................................................................................................... 7
Schema .......................................................................................................................................... 16
Schedule of Activities (SoA)........................................................................................................... 17
2.
INTRODUCTION................................................................................................................................ 23
Study Rationale.............................................................................................................................. 23
Background .................................................................................................................................... 23
2.2.1.
Comparator Drug Combination Therapy .................................................................................... 45
Benefit-Risk Assessment ............................................................................................................... 45
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 45
4.
STUDY DESIGN ................................................................................................................................ 47
Overall Design................................................................................................................................ 47
Scientific Rationale for Study Design............................................................................................. 51
4.2.1.
Participant Input Into Design ...................................................................................................... 54
4.2.2.
Study-Specific Ethical Design Considerations ........................................................................... 54
Justification for Dose...................................................................................................................... 55
End of Study Definition................................................................................................................... 56
5.
STUDY POPULATION ...................................................................................................................... 56
Inclusion Criteria ............................................................................................................................ 57
Exclusion Criteria ........................................................................................................................... 59
Screen Failures .............................................................................................................................. 63
6.
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 64
Study Interventions Administered .................................................................................................. 64
Preparation/Handling/Storage/Accountability ................................................................................ 65
Measures to Minimize Bias: Randomization and Blinding............................................................. 66
Study Intervention Compliance...................................................................................................... 68
Dose Modification........................................................................................................................... 68
6.5.1.
Retreatment Criteria ................................................................................................................... 68
Continued Access to Study Intervention After the End of the Study ............................................. 68
Concomitant Therapy..................................................................................................................... 68
6.7.1.
Rescue Medication ..................................................................................................................... 72
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 72
Discontinuation of Study Intervention ............................................................................................ 72
Participant Discontinuation/Withdrawal From the Study................................................................ 73
7.2.1.
Withdrawal From the Use of Research Samples ....................................................................... 73
Lost to Follow-up............................................................................................................................ 74
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 74
Efficacy Assessments .................................................................................................................... 76
Safety Assessments....................................................................................................................... 77
8.2.1.
Physical Examinations................................................................................................................ 78
8.2.2.
Vital Signs................................................................................................................................... 78
8.2.3.
Electrocardiograms..................................................................................................................... 78
8.2.4.
Clinical Safety Laboratory Assessments .................................................................................... 79


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8.2.5.
Suicidal Ideation and Behavior Risk Monitoring ......................................................................... 79
8.2.6.
Other Evaluations ....................................................................................................................... 79
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 81
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 81
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 82
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 82
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 82
8.3.5.
Pregnancy................................................................................................................................... 83
8.3.6.
Adverse Events of Special Interest............................................................................................. 84
Treatment of Overdose .................................................................................................................. 84
Pharmacokinetics........................................................................................................................... 85
8.5.1.
Evaluations ................................................................................................................................. 85
8.5.2.
Analytical Procedures................................................................................................................. 85
8.5.3.
Pharmacokinetic Parameters and Evaluations........................................................................... 85
Biomarkers ..................................................................................................................................... 85
8.6.1.
Pharmacodynamics .................................................................................................................... 86
8.6.2.
Pharmacogenomic (DNA and RNA) Evaluations ....................................................................... 86
Immunogenicity Assessments ....................................................................................................... 87
Health Economics/Medical Resource Utilization and Health Economics ...................................... 87
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 87
Statistical Hypotheses.................................................................................................................... 87
Sample Size Determination ........................................................................................................... 87
Populations for Analysis Sets ........................................................................................................ 87
Statistical Analyses ........................................................................................................................ 88
9.4.1.
General Considerations.............................................................................................................. 88
9.4.2.
Primary Endpoint ........................................................................................................................ 88
9.4.3.
Key Secondary Endpoint ............................................................................................................ 89
9.4.4.
Other Endpoints.......................................................................................................................... 90
9.4.5.
Safety Analyses .......................................................................................................................... 90
9.4.6.
Other Analyses ........................................................................................................................... 91
Interim Analysis.............................................................................................................................. 91
Data Monitoring Committee or Other Review Board ..................................................................... 91
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 92
Appendix 1: Abbreviations ............................................................................................................. 92
Appendix 2: Clinical Laboratory Tests ........................................................................................... 94
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 96
10.3.1.
Regulatory and Ethical Considerations ...................................................................................... 96
10.3.2.
Financial Disclosure.................................................................................................................... 98
10.3.3.
Informed Consent Process ......................................................................................................... 98
10.3.4.
Data Protection ........................................................................................................................... 99
10.3.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 100
10.3.6.
Committees Structure............................................................................................................... 100
10.3.7.
Publication Policy/Dissemination of Clinical Study Data .......................................................... 100
10.3.8.
Data Quality Assurance............................................................................................................ 102
10.3.9.
Case Report Form Completion................................................................................................. 102
10.3.10.
Source Documents ................................................................................................................... 103
10.3.11.
Monitoring ................................................................................................................................. 103
10.3.12.
On-Site Audits........................................................................................................................... 104
10.3.13.
Record Retention...................................................................................................................... 104
10.3.14.
Study and Site Start and Closure ............................................................................................. 105
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and 
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting............................................................................................................................... 106
10.4.1.
Adverse Event Definitions and Classifications ......................................................................... 106
10.4.2.
Attribution Definitions................................................................................................................ 107


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10.4.3.
Severity Criteria ........................................................................................................................ 107
10.4.4.
Special Reporting Situations .................................................................................................... 107
10.4.5.
Procedures ............................................................................................................................... 108
10.4.6.
Contacting Sponsor Regarding Safety ..................................................................................... 109
10.4.7.
Product Quality Complaint Handling......................................................................................... 109
Appendix 5: Contraceptive and Barrier Guidance ....................................................................... 111
Appendix 6: List of Pharmacological Treatments Commonly Used for Treatment of 
Depression (not all-inclusive)....................................................................................................... 114
Appendix 7: Protocol Amendment History ................................................................................... 115
11.
REFERENCES................................................................................................................................. 123
INVESTIGATOR AGREEMENT ............................................................................................................... 124
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
Volume of Blood to be Collected From Each Participant.......................................................... 75
Table 2:
Patient’s Awareness of Treatment-Arm Assignment Scale...................................................... 79


JNJ-54135419   (esketamine)
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Status: Approved,  Date:  14 Jul 2020
1.
PROTOCOL SUMMARY
Synopsis
A Randomized, Double-blind, Multicenter, Placebo-controlled Study to Evaluate the Efficacy, Safety, and 
Tolerability of Esketamine Nasal Spray, Administered as Monotherapy, in Adult Participants with 
Treatment-resistant Depression.
Esketamine nasal spray (SPRAVATO™) is a nonselective, noncompetitive N-methyl D-aspartate (NMDA) 
receptor antagonist approved in the United States for use in conjunction with an oral antidepressant (AD) 
for the treatment of treatment-resistant depression (TRD) in adults. 
While several definitions of TRD are used in clinical practice, world health authorities, including the Food 
and Drug Administration (FDA) and the European Medicines Agency (EMA), define patients with TRD as 
individuals with major depressive disorder (MDD) who have not responded to at least 2 different 
antidepressant treatments given at an adequate dose for an adequate duration in the current episode of 
depression. This definition was used in the Sponsor’s clinical development program for esketamine nasal 
spray.
The TRD population suffers disproportionately from the morbidity and mortality associated with 
depression, and many patients do not experience relief from depressive symptoms after treatment with 
existing antidepressant medications. Esketamine has demonstrated efficacy in TRD when administered in 
combination with an oral AD. The current study will evaluate the efficacy of esketamine monotherapy in 
the TRD population.
OBJECTIVES AND ENDPOINTS
Primary Objective
The primary objective of this study is to evaluate the efficacy of each individual dose of esketamine nasal 
spray, 56 mg and 84 mg, compared with placebo nasal spray in improving depressive symptoms in 
participants with TRD, as assessed by the change from baseline in the Montgomery-Asberg Depression 
Rating Scale (MADRS) total score from Day 1 (prerandomization) to end of the 4-week double-blind 
treatment phase (Day 28).
Key Secondary Objective
The key secondary objective of this study is to evaluate the efficacy of esketamine nasal spray, 56 mg and 
84 mg, compared with placebo nasal spray in improving depressive symptoms in participants with TRD, as 
assessed by the change from baseline in the MADRS total score from Day 1 (prerandomization) to Day 2.
Other Objectives

To evaluate the efficacy of esketamine nasal spray, 56 mg and 84 mg, compared with placebo nasal 
spray in participants with TRD on:

Depression response and remission rates

Overall severity of depressive illness

Change in MADRS total score over time

Change in Patient Health Questionnaire 9-item (PHQ-9) total score over time


JNJ-54135419   (esketamine)
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Status: Approved,  Date:  14 Jul 2020

To investigate the safety and tolerability of esketamine nasal spray, 56 mg and 84 mg, compared with 
placebo nasal spray in participants with TRD, including the following:

Treatment-emergent adverse events (TEAEs), including adverse events (AEs) of special interest

Effects on heart rate and blood pressure

Potential effects on suicidal ideation/behavior

To assess the pharmacokinetic/pharmacodynamic (PK/PD) relationship of esketamine nasal spray and 
MADRS total score in participants with TRD 

To assess the relationship of biomarkers with response/nonresponse to esketamine nasal spray in 
participants with TRD
Primary Endpoint
The primary efficacy endpoint is the change from baseline in MADRS total score from Day 1 
(prerandomization) to end of the 4-week double-blind treatment phase (Day 28).
Key Secondary Endpoint
The key secondary efficacy endpoint is the change from baseline in MADRS total score from Day 1 
(prerandomization) to Day 2.
Other Endpoints
The other efficacy endpoints are as follows:

MADRS total score 

Proportion of responders (≥50% reduction from baseline in MADRS total score) over time to the 
end of the 4- week double-blind treatment phase (Day 28)

Proportion of participants in remission (MADRS ≤10) over time to the end of the 4-week double-
blind treatment phase (Day 28)

Change from baseline in MADRS total score over time to the end of the 4-week double-blind 
treatment phase

Change from baseline in Clinical Global Impression – Severity (CGI-S) over time to the end of the 
4-week, double-blind treatment phase (Day 28)

PHQ-9 total score

Proportion of responders (reduction in PHQ-9 score of 6 points) over time to the end of the 
double-blind treatment phase (Day 28)

Change from baseline in PHQ-9 total score over time to the end of the 4-week double-blind 
treatment phase (Day 28)
Hypothesis
The hypothesis of this study is that esketamine nasal spray, 56 mg or 84 mg, when used as monotherapy, is 
superior to placebo nasal spray in improving depressive symptoms in participants with TRD.
OVERALL DESIGN
This is a randomized, double-blind, placebo-controlled, multicenter study in male and female participants 
with TRD to evaluate the efficacy, safety, and tolerability of esketamine nasal spray, 56 mg and 84 mg, 
administered as monotherapy. 


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Status: Approved,  Date:  14 Jul 2020
This study has 4 phases: screening, double-blind treatment, open-label treatment/observation, and follow-
up.
A target of approximately 446 participants will be randomized in a 2:1:1 ratio to placebo, esketamine 56 mg, 
or esketamine 84 mg. A minimum of 356 participants meeting predefined nonresponse criteria will be 
randomized for the primary efficacy analysis set.
The maximum duration of study participation is 24 weeks.
Screening Phase (up to 7 weeks)
Evaluations that will be performed at the screening visits are outlined in the Schedule of Activities (SoA).
The study population will include men and women, 18 years of age (or older if the minimum legal age of 
consent in the country in which the study is taking place is >18) or older, who meet the Diagnostic and 
Statistical Manual of Mental Disorders (5th Edition; DSM-5) diagnostic criteria for single episode MDD 
or recurrent MDD, without psychotic features, based upon clinical assessment, and confirmed by the Mini 
International Neuropsychiatric Interview (MINI). In addition, the participant must have an Inventory of 
Depressive Symptomatology-Clinician rated, 30-item (IDS-C30) total score of ≥34, which corresponds to 
moderate to severe depression. 
Participants can be screened for study participation whether or not they are currently taking an 
antidepressant medication.
At the start of screening, participants must have had nonresponse to ≥2 different oral AD treatments in the 
current episode of depression, as assessed by the Massachusetts General Hospital-Antidepressant Treatment 
Response 
Questionnaire 
(MGH-ATRQ), 
and 
confirmed 
by 
documented 
records 
(eg, medical/pharmacy/prescription records or a letter from treating physician).
The participant’s current major depressive episode, depression symptom severity, and AD treatment 
response in their current depressive episode must be deemed valid for participation in the clinical study 
based on the “State vs. Trait, Assessibility, Face Validity, Ecological Validity, Rule of Three P’s” (SAFER) 
Interview, which is a site-independent qualification assessment.
If clinically indicated, a participant’s current AD medication(s), including adjunctive treatment for MDD, 
should be tapered and discontinued during this phase per the local prescribing information, guidelines or 
clinical judgement. Tapering/discontinuation of any antidepressant medication(s) should not be started until 
the SAFER Interview is completed and the site has received confirmation that the participant has “passed” 
the SAFER Interview. 
All participants will have a minimum of 2 weeks in the Screening Phase without any AD medication(s) just 
prior to randomization. 
For participants not taking any AD medication at study entry (screening), the mandatory 2-week 
antidepressant-free period may start at entry. However, the screening phase will be at least 3 weeks to 
ensure required procedures are completed.
Participants taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of 
lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, zaleplon) during the 
screening phase can continue these medications. Temporary dose increases of benzodiazepines beyond the 
equivalent of 6 mg/day lorazepam or initiation of new benzodiazepines are permitted during the screening 
phase if needed to assist with AD taper/discontinuation and/or the antidepressant-free period. However, the 
dose of the current benzodiazepines is to be less than or equal to the equivalent of 6 mg/day of lorazepam 
before randomization in the double-blind treatment phase.


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Potential participants will be excluded from participating in the study if they have used 
ketamine/esketamine (lifetime); previously demonstrated nonresponse of depressive symptoms to an 
adequate course of treatment with electroconvulsive therapy (ECT) in the current major depressive episode, 
defined as at least 7 treatments with unilateral/bilateral ECT; if they have received vagal nerve stimulation 
(VNS) or deep brain stimulation (DBS) in the current major depressive episode; if they have a current or 
prior DSM-5 diagnosis of a psychotic disorder or MDD with psychosis, 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; 
if they have homicidal ideation/intent or suicidal ideation with some intent to act within 6 months prior to 
the start of the screening phase per the investigator’s clinical judgment and/or based on the Columbia 
Suicide Severity Rating Scale (C-SSRS) or suicidal behavior in the last year; or if they have a history of 
moderate or severe substance or alcohol use disorder according to DSM-5 criteria. 
Participants meeting the inclusion/exclusion criteria are eligible to proceed to the double-blind treatment 
phase.
Double-blind Treatment Phase (4 weeks)
Eligible participants will be randomly assigned at a 2:1:1 ratio to receive double-blind nasal spray treatment 
with either placebo, esketamine 56 mg, or esketamine 84 mg, twice a week for 4 weeks.
The participant will self-administer nasal spray treatment (esketamine or placebo) under the direct 
supervision of a healthcare provider during a treatment session at all treatment visits. A treatment session 
consists of nasal administration of the study medication and post-administration observation. On all dosing 
days, all participants must remain at the clinical site for post-administration observation for at least 2 hours 
postdose, until the patient is safe to leave. 
After receiving a treatment session, instruct participants not to engage in potentially hazardous activities, 
such as driving a motor vehicle or operating machinery, until the next day after a restful sleep.
Evaluations that will be performed during this phase are outlined in the Schedule of Activities.
Participants taking benzodiazepines and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, 
zaleplon) during the screening phase can continue these medications during the double-blind treatment 
phase (at dosages equal to or less than the equivalent of 6 mg/day of lorazepam), however they may not be 
used within 12 hours prior to the start of each nasal spray treatment session. No dose increases beyond the 
equivalent of 6 mg/day of lorazepam, or new benzodiazepine medications, are permitted during the double-
blind treatment phase, except for the use of permitted benzodiazepine rescue medication.
Missing data in clinical trials can lead to problems that undermine the scientific credibility of causal 
conclusions. The most common reason for missing data is participants who discontinue the assigned 
treatment because of AEs, lack of tolerability, lack of efficacy, or inconvenience. In order to reduce missing 
data in this study, if a participant discontinues double-blind study medication for reasons other than 
withdrawal of consent, the participant should complete the remaining scheduled visits (without study 
medication dosing) through the end of the phase (Day 28). For participants remaining in the double-blind 
treatment phase without study medication dosing, standard-of-care treatment may be initiated. Participants 
who complete the double-blind treatment phase (ie, including the Day 28 visit) may be eligible to proceed 
to the open-label treatment/observation phase.
If a participant discontinues from the study in the double-blind treatment phase (ie, prior to completion of 
the Day 28 visit), an Early Withdrawal visit should be conducted within 1 week of the date of 
discontinuation. Participants that discontinue early from the double-blind treatment phase (ie, prior to 
completion of the Day 28 visit) are not eligible to participate in the open-label treatment/observation phase 
and will proceed to the follow-up phase. 


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Open-label Treatment/Observation Phase (up to 3 months)
On Day 28, following completion of the double-blind treatment phase assessments (which includes the 
Day 28 MADRS assessment), participants may participate in an open-label treatment/observation phase. 
The Investigator needs to assess and confirm in source documentation that, based on clinical judgment, it 
is in the participant’s best interest to participate in this phase. 
During the open-label treatment/observation phase, for a duration of up to 3 months, participants can: 

receive open-label esketamine nasal spray 

If clinically indicated based on the investigator’s judgment, participants receiving open-label 
esketamine nasal spray treatment can also receive standard-of-care treatment for depression. 
The decision to receive open-label esketamine must be made at the start of the open-label 
treatment/observation phase, participants who chose to not receive esketamine (to be observed
only) will not be allowed to start open-label esketamine treatment during this phase.

choose to be observed only (ie, no nasal spray treatment sessions) and receive standard-of-care 
treatment for depression. Participants who choose to be observed only will not be allowed to switch to 
the open-label esketamine nasal spray arm during the open-label treatment/observation phase.
Participants in this phase who have opted to receive open-label esketamine will receive 56 mg on Day 28 
regardless of the participant's study drug/dose assignment in the double-blind phase. Subsequent doses can 
remain the same or be adjusted (56 mg or 84 mg) based on efficacy and tolerability. The recommended 
dosing frequency is as follows:

Weeks 5 to 8: twice weekly (maximum)

Weeks 9 to 12: once weekly 

Weeks 13 to 16: weekly or every other week. Dosing frequency will be based on clinical judgment 
and should be individualized to the least frequent dosing to maintain remission/response. 
The participant will self-administer esketamine nasal spray under the direct supervision of a healthcare 
provider during a treatment session at all treatment visits. A treatment session consists of nasal 
administration of the study medication and post-administration observation. On all dosing days, all
participants must remain at the clinical site for post-administration observation until at least 2 hours 
postdose until the patient is safe to leave. 
After receiving a treatment session, instruct participants not to engage in potentially hazardous activities, 
such as driving a motor vehicle or operating machinery, until the next day after a restful sleep.
If a participant discontinues the open-label treatment/observation phase for reasons other than withdrawal 
of consent, the participant will proceed to the follow-up phase. 
Evaluations that will be performed during this phase are outlined in the Schedule of Activities.
Follow-up Phase
All participants who have received at least 1 dose of nasal spray medication in the study will complete a 
follow up visit in the follow-up phase. 
Further clinical/standard of care for the treatment of depression will be arranged by the study investigator 
and/or the participant’s treating physician.
NUMBER OF PARTICIPANTS
A target of approximately 446 participants will be randomized in a 2:1:1 ratio to placebo, esketamine 56 mg, 
or esketamine 84 mg. A minimum of 356 participants meeting predefined nonresponse criteria will be 
randomized for the primary efficacy analysis set.


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INTERVENTION GROUPS AND DURATION
This Phase 4 study will randomize approximately 446 participants into 1 of 3 treatment groups in the 
double-blind treatment phase:
Double-blind treatment phase:

Placebo nasal spray, twice a week for 4 weeks

Esketamine 56 mg nasal spray, twice a week for 4 weeks

Esketamine 84 mg nasal spray, twice a week for 4 weeks
Participants who complete the double-blind treatment phase may be eligible to participate in an open-label 
treatment/observation phase.
Open-label treatment/observation phase:

Esketamine nasal spray flexible dosing (56 and 84 mg). Recommended frequency of twice a week for 
4 weeks (Weeks 5 to 8), once a week for the next 4 weeks (Weeks 9 to 12), and once a week or every 
other week for the last 4 weeks (Weeks 13 to 16), based on clinical judgment. Dosing frequency should 
be individualized to the least frequent dosing to maintain remission/response. Esketamine treatment 
can be used as monotherapy or with standard-of-care treatment for depression.

Standard-of-care treatment for depression for 12 weeks. Participants who choose to be observed only 
will not be allowed to switch to the open-label esketamine nasal spray arm during the open-label 
treatment/observation phase.
EFFICACY EVALUATIONS
The primary efficacy evaluation will be the MADRS total score. 
The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to 
antidepressant treatment. It 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 assessment will be performed by site-based raters via video teleconferencing assessment
during the study using the Structured Interview Guide for the MADRS. To minimize the risk of unblinding 
the treatment assignment, different site raters will perform efficacy and safety assessments; clinicians who 
perform the MADRS assessments will be different from those who evaluate safety assessments (eg, vital 
signs) and AEs. Raters for the MADRS will not be allowed to access or to review participant safety records 
or supervise/observe study drug administration; therefore, they will not provide clinical care for 
participants.
The Clinical Global Impression – Severity (CGI-S) scale will be used to assess severity of depressive 
illness. 
The Patient Health Questionnaire 9-item (PHQ-9) is a participant-reported outcome measure that will be 
used to assess severity of depressive symptoms. 
PHARMACOKINETIC EVALUATIONS
Plasma samples will be used to evaluate the PK of esketamine. The concentrations of esketamine and 
noresketamine or other metabolites (if warranted) will be measured in plasma. 


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PHARMACODYNAMIC AND BIOMARKER EVALUATIONS 
Blood samples will be collected to explore biomarkers related to immune system activity, hypothalamic-
pituitary-adrenal (HPA) axis activation, and neurotropic factors. 
Biomarker samples will be collected to:

evaluate the mechanism of action of esketamine or 

help explain inter-individual variability in clinical outcomes or 

help identify population subgroups that respond differently to a drug
At the conclusion of the biomarker analyses, these findings will be presented in a separate study report.
PHARMACOGENOMIC (DNA and RNA) EVALUATIONS
A pharmacogenomic blood sample will be collected from participants who consent separately to this 
component of the study to allow for pharmacogenomic research, as necessary. Whole blood samples for 
DNA and RNA analyses will be collected at the time points indicated in the Schedule of Activities. 
Participation in pharmacogenomic research is optional.
The goal of the pharmacogenomic component is to collect DNA and RNA to allow the identification of 
genetic, epigenetic, and transcription factors that may influence the pharmacokinetics (PK), 
pharmacodynamics (PD), efficacy, safety, or tolerability of esketamine and to identify factors associated 
with MDD. 
SAFETY EVALUATIONS
Safety evaluations will include:

Monitoring of TEAEs, including TEAEs of special interest, pregnancy testing (for women of 
childbearing potential), and vital signs. 

Columbia Suicide Severity Rating Scale (C-SSRS), to assess potential suicidal ideation and behavior.
STATISTICAL METHODS
Populations for Analyses

Efficacy analyses for the double-blind treatment phase will be performed on the full efficacy analysis 
set, which is defined as all randomized participants who meet nonresponse criteria and have received 
at least one dose of double-blind study medication. Participants who do not meet nonresponse criteria 
will be summarized separately for efficacy.

Safety analyses for the double-blind treatment phase will be performed on the safety analysis set, 
which is defined as all randomized participants (both participants who meet and do not meet 
nonresponse criteria) who receive at least one dose of double-blind study medication.

The safety and efficacy analyses for the open-label treatment phase will be based on all participants 
who receive at least one dose of open-label esketamine study medication.

The safety and efficacy analyses for the observational phase will be based on all participants who enter 
the observational phase but do not receive open-label esketamine study medication.
Sample size determination
The sample size is calculated for the full efficacy analysis set, which includes all randomized patients who 
meet predefined nonresponse criteria (based on MADRS assessments performed during the screening 
phase). A standardized treatment effect for the primary endpoint at Day 28 compared to the placebo arm of 


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0.45 (a treatment difference of 5.4 points for the change from baseline [Day 1 prerandomization] in MADRS 
total score with a standard deviation of 12) and the Hochberg procedure, with the truncation parameter 
equal to 1 (which results in the conventional Hochberg method with respect to the primary endpoint) to 
control the overall familywise error rate of 0.05 (two-sided) were used for the calculation. A 2:1:1 
randomization scheme requires 71 participants per active treatment arm and 142 for the placebo arm to 
complete 4 weeks of treatment to achieve 85% power for each dose and 93% power to correctly reject at 
least one null hypothesis. Taking into consideration a 20% drop-out rate, 356 patients who meet the 
predefined nonresponse criteria (based on MADRS assessments performed during the screening phase) will 
need to be randomized in the study. The treatment discontinuation rate will be closely monitored in a 
blinded fashion throughout the trial. 
Efficacy Analyses
The multiplicity, with regard to testing multiple endpoints (the primary [Day 28] and the key secondary 
[Day 2]) and multiple doses (esketamine 84 mg vs placebo and esketamine 56 mg vs placebo), will be 
controlled by a sequential gatekeeping method using the Hochberg procedure, a familywise error rate of 
0.05 and a truncation parameter of 1. For the primary hypothesis (Day 28), if the largest p-value of the two 
dose comparisons of esketamine 84 mg vs placebo and esketamine 56 mg vs placebo is less than two-sided 
0.05 level, both esketamine 56 mg and esketamine 84 mg will be declared statistically significantly different 
from placebo. If the largest p-value of primary endpoint tests is greater than or equal to 0.05, the comparison 
associated with this p-value will be declared not statistically significant and the smaller p-value will be 
compared to the 0.025 level. The key secondary hypothesis (Day 2) will be tested using the Hochberg 
procedure only after the null hypothesis for the primary endpoint is rejected for both doses.
Primary Endpoint
The primary efficacy variable, change from baseline in MADRS total score at Day 28, will be analyzed 
using a Mixed-Effect Model for Repeated Measures (MMRM) model based on observed case data. The 
model will include factors for treatment (esketamine 56 mg, esketamine 84 mg, placebo), center, 
antidepressant treatment status (on- or off-treatment) at screening entry, day, day-by-treatment interaction, 
and baseline MADRS total score as a covariate. The within-participant covariance between visits will be 
estimated via an unstructured variance-covariance matrix. Comparisons of the esketamine groups versus 
placebo will be performed using the appropriate contrast.
Key Secondary Endpoint
The key secondary efficacy variable, change from baseline in MADRS total score at Day 2 in the double-
blind treatment phase, will be analyzed using the same MMRM model as described for the primary 
endpoint.
Other Endpoints
Change from baseline in MADRS total score over time will be analyzed using the same MMRM model as 
described for the primary endpoint. Response and remission rates based on the MADRS total score will be 
summarized at each visit. Frequency distributions of the CGI-S scores at each scheduled timepoint will be 
provided. Change from baseline in PHQ-9 total score over time in the double-blind treatment phase will be 
analyzed using the same MMRM model as described for the primary endpoint. Response rates based on the 
PHQ-9 will be summarized at each visit. Descriptive summaries of efficacy data will be provided for the 
double-blind phase for participants who do not meet nonresponse criteria and for the open 
label/observational phase.


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Safety Analyses
Adverse Events
Safety data will be analyzed separately for each phase. Adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). All reported adverse events with onset during the 
treatment phase (ie, TEAEs and AEs that have worsened since baseline) 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 treatment group. 
The TEAEs of special interest will be examined separately; AEs of special interest will be further listed in 
the statistical analysis plan (SAP). Participants who discontinue treatment due to an AE and serious AEs 
(SAEs) will be summarized separately. Narratives will be provided for deaths, SAEs, and participants who 
discontinue due to an AE. 
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, body weight measurements, and blood pressure 
(systolic and diastolic) values and changes from baseline will be summarized at each scheduled time point. 
The percentage of participants with values beyond clinically important limits will be summarized.
C-SSRS
A frequency distribution of C-SSRS scores at each scheduled timepoint by treatment will be provided. 
Shifts from the baseline visit to the most severe/maximum score during each study phase will be 
summarized by treatment. The maximum score assigned for each participant will also be summarized into 
one of three categories: no suicidal ideation or behavior (0), suicidal ideation (1-5), suicidal behavior (6-10).
Other Analyses
Pharmacokinetic Analyses 
The plasma concentrations of esketamine and noresketamine or other metabolites (if warranted) will be 
listed for all participants and summarized descriptively.
Patient’s Assessment of Treatment-arm Assignment
Descriptive statistics will be reported.


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Schema








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period. During tapering/discontinuation, a clinic visit or telephone contact for collection of C-SSRS, adverse events and concomitant therapies should be performed 
weekly. If the additional weeks are not required, the applicable visit (ie, Visit 1.3, 1.4, 1.5) should be omitted.
b.
All participants must have a 2-week (±2 days) antidepressant free period in the Screening Phase just prior to randomization at Visit 2.1. For participants not taking 
any antidepressant medications at the start of screening, the mandatory 2-week antidepressant free period may start at entry. However, the screening phase will be 
at least 3 weeks in duration to ensure required procedures are completed.
c.
For participants not taking any antidepressant medications at study entry (the start of screening), the mandatory antidepressant free period may start at entry 
(Visit 1.1). In this scenario only, the following visits would be required: Visits 1.1, 1.2, 1.6, and 2.1.
d.
Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Source Documentation in Appendix 3, Regulatory, 
Ethical, and Study Oversight Considerations. Verify inclusion/exclusion criteria before randomization of each participant.
e.
Predose (if applicable) and at the actual dosing day. On Day 1 performed pre-randomization.
f.
Must be completed prior to start of tapering or discontinuation of current antidepressant treatment.
g.
The MADRS should be administered no more than 2 days prior to the subject’s targeted (not actual) clinic visit date (except Visit 2.1, which is within 1 day prior). 
If performed on the day of the scheduled clinic visit with an intranasal treatment session, the MADRS must be performed prior to the intranasal treatment session.
h.
If Visit 1.7 and Visit 2.1 are performed on the same day, Visit 1.7 procedure can be omitted (ie, will be performed only as part of Visit 2.1).
i.
The Day 2 MADRS assessment must be administered within the Day 2 to Day 4 window and prior to Day 4 intranasal treatment session.
j.
Performed at t = 40 minutes and t =1.5 hours postdose, t = 0 is the time of the first spray of nasal spray study medication. 
k.
Collected at t = 40 minutes and t = 2 hours postdose, where t = 0 is the time of the first spray of nasal spray study medication.
l.
The pharmacogenomic samples (DNA and RNA) should be collected at the specified time point predose under fasting condition, however, if necessary the sample 
may be collected at a later visit (predose, fasting) without constituting a protocol deviation.






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2.
INTRODUCTION 
Esketamine nasal spray (SPRAVATO™) is a nonselective, noncompetitive N-methyl D-aspartate 
(NMDA) receptor antagonist approved in the United States for use in conjunction with an oral 
antidepressant for the treatment of treatment-resistant depression (TRD) in adults.
While several definitions of TRD are used in clinical practice, world health authorities, including 
the Food and Drug Administration (FDA) and the European Medicines Agency, define patients 
with TRD as individuals with major depressive disorder (MDD) who have not responded to at 
least 2 different antidepressant treatments given at an adequate dose for an adequate duration in 
the current episode of depression. This definition is used in the Sponsor’s clinical development 
program for esketamine nasal spray.
The TRD population suffers disproportionately from the morbidity and mortality associated with 
depression, and many patients do not experience relief from depressive symptoms after treatment 
with existing antidepressant medications. Esketamine provides clinically meaningful, rapid, and 
sustained improvement in depressive symptoms for this population. The efficacy results, combined 
with a well-characterized safety profile and comprehensive risk mitigation program, highlight the 
potential for esketamine to improve the treatment landscape for adult patients suffering from TRD.
For the most comprehensive nonclinical and clinical information regarding the study intervention 
esketamine, refer to the latest edition of the Investigator's Brochure5 and SPRAVATO United 
States Prescribing Information (USPI)11.
The term “study intervention” throughout the protocol, refers to esketamine/placebo nasal spray.
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
Study Rationale 
The Phase 3 esketamine TRD studies all administered esketamine in conjunction with a 
newly-initiated, oral antidepressant (AD), or as adjunctive to prior oral antidepressants in the phase 
2 studies. Accordingly, esketamine is indicated for use in patients with TRD along with a 
concomitant oral AD. As there is no conclusive data yet to support the efficacy of esketamine apart 
from the use of a concomitant AD, this study is being conducted to evaluate the efficacy of 
esketamine as monotherapy for TRD. In addition, two esketamine treatment groups will allow for 
assessment of the efficacy and safety of the 84 mg and the 56 mg doses. 
Background
Nonclinical Studies
Nonclinical Pharmacology
Through N methyl D aspartate receptor (NMDAR) antagonism, esketamine produces a transient 
increase in glutamate release leading to increases in α-amino 3 hydroxy 5 methyl-4-isoxazole 


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propionic acid receptor (AMPAR) stimulation and subsequently increase neurotrophic signaling 
that restores synaptic function in the brain regions involved with the regulation of mood and 
emotional behavior. Unlike other AD therapies, esketamine’s primary AD action does not directly 
involve monoamine, γ-amino butyric acid-ergic (GABA), or opioid receptors. Thus, as a 
noncompetitive, subtype nonselective, activity dependent glutamate receptor modulator, 
esketamine offers a novel mechanism of action that provides important advantages not previously 
available to patients with TRD. 
Esketamine decreased IKr (human ether-à-go-go-related gene) with a 50% inhibition 
concentration (IC50) of 214 μM. Given that the maximum mean human plasma concentration of 
total esketamine produced by 84 mg esketamine nasal spray is 174 ng/mL (or 0.73 μM esketamine 
base, MW 237.7) (TRD1001), the IC50-based safety margin is approximately 400-fold based on 
free esketamine concentration assuming 40% protein binding. In dog, increases in heart rate and 
blood pressure were noted at clinically relevant exposures of esketamine.
Pharmacokinetics and Product Metabolism in Animals
Across species, fast absorption occurred following intranasal administration of esketamine, with 
peak plasma concentrations generally reached within 30 minutes for esketamine and shortly 
thereafter for its active metabolite noresketamine (M10). Following nasal dosing in mice and rats, 
Cmax values of esketamine and noresketamine were comparable whereas the area under the 
concentration-time curve (AUC) values were higher for noresketamine than for the parent. In the 
dog, the AUC of noresketamine was lower than that of esketamine. Sublingual oral thin film (OTF) 
formulations resulted in fast systemic absorption in dogs, yielding high plasma exposure and 
almost complete bioavailability.
The tissue distribution of esketamine is characterized by a fast equilibrium between plasma and 
well perfused tissues leading to a rapid tissue uptake. Total brain concentrations of esketamine 
were 4- (rat) to 7-(human) fold higher compared to those in the systemic circulation. In general, 
the brain uptake of the more polar metabolites was less efficient than the parent drug.
The unbound fraction of esketamine in healthy participants was ~56%, and ~60% for 
noresketamine (M10). 
Based on a human mass balance study, noresketamine (M10) is a major circulating metabolite, 
accounting for ~13% of the total drug-derived material. All other major phase-1 and all phase-2 
metabolites individually represented <10% of the total-drug related material in plasma. 
N-Demethylation of esketamine to noresketamine (M10) is the initial metabolic pathway, followed 
by metabolization to numerous downstream metabolites via hydroxylation at the cyclohexanone 
ring, hydroxylamine formation, keto reduction, dehydrogenation or aromatic hydroxylation.
Most esketamine-derived metabolites were excreted in urine (rats, humans). Very low levels of 
unchanged drug were present in urine (<1% of the dose), indicating that esketamine is 
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Cytochrome P450 (CYP) 2B6 was the main enzyme involved in esketamine metabolism in human 
liver microsomes with a contribution close to 60%, while the contribution of CYP3A4 was 
estimated at 35 to 40%. CYP2A6 and CYP2B6 were the major enzymes involved in the 
downstream metabolism of noresketamine to hydroxy-noresketamine metabolites. 
Esketamine and its major circulating metabolites had no clinically relevant inducing effect on 
CYP1A2, CYP3A4 or CYP2B6. In vitro, only a weak reversible inhibition of noresketamine on 
CYP3A4 was observed. 
Esketamine and noresketamine were not substrates of transporters (P-glycoprotein [P-gp], breast 
cancer resistance protein [BCRP], organic anion-transporting polypeptide [OATP] OATP1B1, 
OATP1B3 for esketamine, and P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, organic cation 
transporter [OCT]1, OCT2 for noresketamine [M10]). Esketamine and its major circulating 
phase 1 metabolites were found not to be inhibitors of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, 
OAT3, OCT2, multidrug and toxin extrusion MATE1, or MATE2K transporters.
Toxicology
Following intranasal esketamine dosing of up to 6 months in rats and up to 9 months in dogs, 
clinical signs were noted reflecting the (exaggerated) pharmacological action of the test article. No 
notable lesions were noted in the nasal cavity or any peripheral organ. The No Observed Adverse 
Effect Levels (NOAELs) were 9 mg/day or ~27 mg/kg/day in rats, and 72 mg/day or ~10 
mg/kg/day in dogs, respectively. Upon 3 months of daily dosing in rats and dogs, the AUC-based 
exposure ratios for esketamine compared to the 84 mg intranasal human dose were ~0.7- to 0.9-
fold.
The maximum tolerated dose (MTD) for single oral administration of esketamine to rats was 
160 mg/kg for male and 40 mg/kg for female rats. Repeated oral dosing with esketamine was 
tolerated for 14 days at these levels with clinical observations in line with those after intranasal 
dosing. Liver and kidney were identified as target organs.
In single dose tolerability studies in dogs, sublingual and buccal OTF formulations containing 
esketamine at ~24 mg and 28 mg, respectively, were well tolerated, with expected pharmacology-
related signs, no oral cavity changes and no effects on electrocardiography. 
Esketamine poses no genotoxic risk to humans. Esketamine was not carcinogenic in rat and mouse 
bioassays.
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 
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.


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Esketamine is known for their abuse potential in animals and humans. In single dose and 14-day 
repeated-dose neurotoxicity studies with intranasally administered esketamine in adult rats, no 
histopathological brain lesions were noted. Furthermore, in the 6-month rat and 9-month dog 
repeat dose toxicology studies with intranasally administered esketamine, and in the pre- and 
postnatal developmental toxicity study in rats, no evidence of neurotoxicity was found. There were 
no histopathological brain lesions after single or 14-day repeated subcutaneous dosing of 
esketamine to juvenile rats. The risk of neurotoxicity associated with nasal administration of 
esketamine to adult and adolescent patients is considered to be low.
Clinical Studies
Human Pharmacokinetics 
Healthy Participants
Esketamine is rapidly absorbed through the nasal mucosa following administration as a nasal spray 
and can be measured in plasma within 7 minutes following a 28-mg dose. The time to reach 
maximum concentrations (tmax) of esketamine is typically observed at approximately 20 to 40 
minutes after the last nasal spray of a given dose. The maximum concentrations (Cmax) and AUC 
from time 0 to the last measurable concentration (AUClast) of esketamine 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 84 mg. The mean terminal half-life (t1/2) 
ranged from approximately 7 to 12 hours. The pharmacokinetics (PK) of esketamine was similar 
after single and repeated (ie, twice a week) dose administration of nasal esketamine. No 
accumulation in plasma is observed when esketamine is administered twice a week (TRD1010).
The absolute bioavailability of esketamine nasal spray (84 mg) administered to healthy participants 
was approximately 48% (TRD1009).
In human mass balance Study TRD1016, esketamine was mainly excreted in urine as metabolites 
following oral and IV administration. 
For the detailed PK results within subpopulations, see the latest edition of the Investigator’s 
Brochure5. 
Participants with TRD
At corresponding esketamine nasal spray 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 from healthy participants who enrolled in 
the Phase 1 studies.
Effects of Esketamine on Probes of Hepatic Cytochrome P450
Administration of 84 mg esketamine nasal spray twice a week for 2 weeks reduced the mean 
plasma AUC∞produced by oral midazolam, a probe of hepatic CYP3A4 activity, by approximately 


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16% (TRD1010). The same regimen of esketamine nasal spray did not affect the mean plasma 
AUC∞produced by oral bupropion, a probe of hepatic CYP2B6 activity.
Effects of Potent Inducers of Hepatic Cytochrome P450
In Study TRD1008, mean esketamine Cmax and AUC∞values were approximately 17% and 28% 
lower, respectively, when 56-mg esketamine nasal spray was administered by participants 
pretreated with rifampin, an inducer of CYP3A4 and CYP2B6 activity, compared to esketamine 
administration without rifampin pretreatment. 
Effects of Potent Inhibitors of Hepatic Cytochrome P450
In Study TRD1009, pretreatment with oral clarithromycin, an inhibitor of CYP3A4 activity, 
produced small effects (ie, <11% increase) on the Cmax and AUC∞of intranasal esketamine. 
Furthermore, the decline in plasma concentrations (ie, half-life) of esketamine was not affected by 
clarithromycin pretreatment. 
In Study TRD1020, pretreatment with oral ticlopidine, an inhibitor of hepatic CYP2B6 activity, 
had no effect on the Cmax of intranasally administered esketamine. The AUC∞of esketamine was 
increased by approximately 29%. The terminal half-life was not affected by ticlopidine 
pretreatment.
Effects of Nasal Mometasone and Nasal Oxymetazoline
The results of Study TRD1007 demonstrated that daily intranasal administration of mometasone 
furoate had no effects on the pharmacokinetics of intranasal esketamine (56 mg dose) in healthy 
participants. Furthermore, the pharmacokinetics of intranasal esketamine was similar with and 
without intranasal administration of oxymetazoline HCl in participants experiencing symptoms of 
nasal rhinitis. 
Efficacy Studies in Participants with TRD
Phase 2 Studies (TRD2003)
The results of Phase 2 double-blind, placebo-controlled study in TRD population demonstrated a 
rapid onset and significant antidepressant effect for esketamine. In this adjunctive delayed start 
design Study TRD2003, consisting of a 2-week double-blind phase that included two 1-week 
treatment periods, twice weekly esketamine significantly improved depressive symptoms in adults 
with TRD, as measured by the change from baseline in MADRS total scores. Efficacy was dose-
related, with doses of 56 mg and 84 mg demonstrating significantly greater efficacy than placebo. 
The 28 mg dose had a shorter duration of response, and the 14 mg dose was ineffective. The clinical 
effect was observed as early as 2 hours after the first dose. In the open-label phase (Days 15-74) 
following the double-blind period, in which the frequency of esketamine dosing was reduced to 
once weekly for 2 weeks and then to every 2 weeks, the antidepressant response appeared to persist 
for approximately 2 months after the last dose of esketamine.


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Short-term Phase 3 Studies: TRD3001, TRD3002 and TRD3005
Phase 3 studies TRD3001, TRD3002, and TRD3005 were randomized, double-blind, multicenter, 
active controlled studies that evaluated the efficacy, safety, and tolerability of esketamine nasal 
spray plus an oral AD in participants with TRD. The efficacy of esketamine nasal spray was 
assessed at fixed dose (56 mg or 84 mg) in adult participants in Study TRD3001, at flexible-dose 
(56 mg or 84 mg) in adult participants in Study TRD3002 and at flexible-dose (28 mg, 56 mg or 
84 mg) in elderly participants (65 years and older) in Study TRD3005.
Since the primary endpoints for these 3 short-term studies were the same, the results for the 
primary efficacy endpoint (mixed-effects model using repeated measures [MMRM] analyses) are 
presented together. 
Change in MADRS Total Scores From Baseline to the End of the 4-Week Double-blind Induction 
Phases:
Across the 3 studies (TRD3001, TRD3002 and TRD3005), treatment group differences 
consistently showed larger improvements with esketamine + oral AD compared with oral AD + 
placebo. Moreover, results for each study were similar when analyzed using MMRM. 

For Study TRD3002, a statistical superiority of flexibly dosed esketamine 56 / 84 mg + oral 
AD vs oral AD + placebo nasal spray in improving symptoms of depression in a TRD
population after 4 weeks of treatment was shown, with least-squares (LS) mean treatment 
differences (95% CI) of -4.0 (-7.31, -0.64) based on MMRM (2-sided p=0.020).

For Study TRD3001, while treatment effects for esketamine + oral AD were not statistically
significant relative to the oral AD + placebo nasal spray control, the median unbiased 
estimated treatment differences (based on MMRM analysis, 95% CI) of  -4.1 (-7.53,-0.60) for 
the esketamine 56 mg dose group and  -3.2 (-6.88,0.45) for the esketamine 84 mg dose group 
support a clinically meaningful benefit for both fixed-dose regimens in adults with TRD. 

For Study TRD3005, while the treatment effect for esketamine + oral AD was not statistically 
significant relative to the oral AD + placebo nasal spray control, the estimated treatment 
difference of -3.6 (-7.20,0.07) (MMRM, 95% CI) suggests a clinically meaningful benefit in 
the 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.
The key secondary endpoints for studies TRD3002 and TRD3001 were the onset of clinical 
response by Day 2, and changes from baseline in Sheehan Disability Scale (SDS) and Patient 
Health Questionnaire 9 item (PHQ-9) total scores at Day 28. In Study TRD3005 with elderly 
participants, the onset of clinical response by Day 2 was not evaluated because all participants 
received a low-dose (28 mg) for tolerability as the initial dose. 


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For the key secondary endpoints analyses at the end of the Double-blind Induction Phase:

Results for the rigorously-defined endpoint of onset of clinical response by Day 2 in studies 
TRD3002 and TRD3001 showed odds ratios numerically favoring the esketamine + oral AD 
groups compared to the oral AD + placebo nasal spray groups; however, the treatment group 
differences were not statistically significant for Study TRD3002 (2-sided p=0.321) and could 
not be tested statistically for Study TRD3001 due to the truncated fixed-sequence testing 
hierarchy. 

Treatment group differences in participant reported outcomes related to functional impairment 
and associated disability (SDS total score) and depressive symptoms (PHQ-9 total score) 
could not be tested statistically for TRD3002 and TRD3001 due to the fixed-sequence testing 
hierarchy and were not planned to be evaluated statistically for Study TRD3005. However, 
results in all 3 short-term studies numerically favored esketamine + oral AD treatment for 
both endpoints. The consistent advantages in these participant-reported outcomes supported 
the meaningfulness of the clinician-rated improvements in the primary endpoints.

For the 3 short-term studies, remission rates at Day 28 (observed case) based on MADRS total 
score ≤12 in the esketamine + oral AD group among adult participants were 53% in Study 
TRD3002 and 36% to 39% in both dose groups in Study TRD3001 (vs 31% for oral AD + 
placebo nasal spray groups of both studies), and were 17.5% in the elderly population in Study 
TRD3005 (vs 7% in elderly oral AD + placebo nasal spray group). These remission rates 
indicate a treatment benefit in a treatment-resistant population, including the elderly 
population. 

For the 3 short-term studies, response rates (defined as ≥50% improvement from baseline in 
MADRS total score) in the adult studies after the first dose ranged from 16% to 19% in the 
esketamine + oral AD group compared with 8% to 11% for the oral AD + placebo nasal spray 
group. At Day 28, response rates in the esketamine + oral AD groups were 69% in Study 
TRD3002 (vs 52% for oral AD + placebo nasal spray) and 53% to 54% in both dose groups 
of Study TRD3001 (vs 39% for oral AD + placebo). In the elderly population in Study 
TRD3005, the response rate at the end of the induction phase was 27% in the esketamine + 
oral AD group (vs 13% for oral AD + placebo nasal spray). All these differences met the 
clinically meaningful threshold of 10 percentage points of difference between esketamine + 
oral AD and oral AD + placebo nasal spray. For elderly participants, these response rates 
indicate a treatment benefit. 
Long-term Phase 3 Studies: TRD3003 and TRD3004
TRD3003
Study TRD3003 was a randomized, double-blind, multicenter, active-controlled efficacy study of 
esketamine nasal spray at flexible-dose (56 mg or 84 mg) plus an oral AD for relapse-prevention 
in adult participants with TRD. 
Primary Efficacy Endpoint: Time to Relapse for Participants in Stable Remission After Treatment 
With Esketamine in Earlier Phases


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Based on the weighted combination log-rank test, the difference between treatment groups for the 
time to relapse was statistically significant (2-sided p=0.003). Relapse events occurred in 26.7% 
of the esketamine group and 45.3% of the oral AD + placebo group. 
Secondary Efficacy Endpoint: Time to Relapse for Participants With Stable Response (But Not 
Stable Remission) After Treatment With Esketamine in Earlier Phases
Relapse events occurred in 25.8% of the esketamine group and 57.6% of the oral AD + placebo 
nasal spray group. Participants randomized to continue esketamine showed a statistically 
significantly longer time to relapse compared to those randomized to discontinue esketamine 
(2-sided p<0.001).
TRD3004
Study TRD3004, was an open-label, long-term, safety and efficacy study of esketamine nasal spray 
at flexible-dose (28 mg, 56 mg or 84 mg) in adult participants with TRD. 
Since this was an open-label study with no comparator group, efficacy was considered a secondary 
objective of this study. Only descriptive summaries of efficacy rating scales are presented. 
Secondary Efficacy Endpoint:
MADRS total score 

The mean (SD) change from baseline in the MADRS total score at end point of the 4-week 
induction phase of -16.4 (8.76) remained largely unchanged throughout the 48-week 
optimization (OP)/maintenance (MA) phase for those participants who entered that phase, 
with the mean (SD) change from the baseline to end point of the OP/MA phase being 
0.3 (8.12).
MADRS response and remission

At the induction endpoint, the response rate (defined as ≥50% reduction in the MADRS total 
score from baseline) was 78.4% (593/756) and the remission rate (defined as a MADRS total 
score ≤12) was 47.2% (357/756). Of the participants proceeding to the OP/MA phase, 76.5% 
(461/603) had met the criteria for response and 58.2% (351/603) were in remission at end 
point (OP/MA).
Studies in Participants with MDSI
Esketamine was also studied in 3 completed Phase 2 and Phase 3 studies in participants with MDD 
who had active suicidal ideation with intent (assessed to be at imminent risk for suicide per the 
study protocols; referred to hereafter as MDSI). The Phase 3 studies (SUI3001 and SUI3002) and 
the Phase 2 study (SUI2001) were double-blind, randomized, placebo-controlled studies designed 
to evaluate the efficacy, safety, and tolerability of esketamine nasal spray 84 mg compared with 
placebo nasal spray in the treatment of participants with MDSI.
Safety findings from these studies are presented in the following sections.


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Pharmacodynamic Studies
Evaluation of Effects on Cognitive Function
Phase 1 Studies
Study TRD1005 evaluated the effect of esketamine nasal spray (total dose of 84 mg) on cognitive 
functioning in healthy participants using the CogState computerized test battery. Esketamine was 
associated with an early, transient decline in cognitive function compared with placebo, which was 
restored to comparable levels in participants receiving esketamine or placebo by 2 hours postdose. 
The transient reductions in cognitive function in participants receiving esketamine were associated 
with early postdose sedation, as assessed by the Karolinska Sleepiness Scale (KSS), and the greater 
level of effort required to complete the CogState computerized test battery, as assessed using the 
Mental Effort Scale. The increases in sleepiness (at 40 minutes and 2 hours postdose) and the 
mental effort required (at 40 minutes postdose) returned to levels comparable to placebo by 4 and 
2 hours postdose, respectively. 
The on-road driving Study TRD1006 evaluated the effect of 84 mg esketamine nasal spray 
compared to placebo on sleepiness using KSS. Maximal increases in sleepiness were observed at 
1- and 2-hour postdose while there was little change in the placebo group.
Phase 2 Studies
In Study TRD2003, cognitive data were collected in 9 participants in Panel A. Small changes in 
score on the Cogstate and Hopkins Verbal Learning Test-Revised (using a 12-item word list recall 
test) measures were observed throughout the study, consistent with typical, individual fluctuation 
over time and not suggestive of clinically meaningful change. 
Phase 3 Studies
In the short-term Phase 3 studies (TRD3001, TRD3002, and TRD3005), treatment with esketamine 
+ oral AD 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. 
Similarly, in the long-term relapse-prevention Study TRD3003, comparison of the results for the 
double-blind MA phase suggested no evidence for deterioration of cognitive performance with 
repeated, longer-term intermittent esketamine dosing. 
In the long-term open-label safety Study TRD3004, 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 attentional impairment. 
Performance on all other cognitive tests remained stable in elderly participants in this study. 


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On-the-road Driving Test
Two studies were conducted to assess the effects of esketamine on driving skills; one study in adult 
patients with major depressive disorder (TRD1019) and one study in healthy participants 
(TRD1006). On road driving performance was assessed by the mean standard deviation of the 
lateral position, a measure of driving impairment.
Results from these 2 studies guided recommendations in the esketamine product labeling that 
patients not engage in potentially hazardous activities such as driving and operating machinery 
after esketamine dosing until the next day following a restful sleep.
Abuse Potential
Study TRD1015 assessed the abuse potential of esketamine nasal spray in recreational users of 
perception altering drugs. The results were consistent with expected findings and showed that 
single doses of esketamine nasal spray (84 mg and 112 mg) and the positive control drug, IV 
ketamine (0.5 mg/kg infused over 40 minutes), produced significantly higher scores than placebo 
on subjective ratings of “drug liking” and on other measures of subjective drug effects in this 
population.
Cardiac Electrophysiology
A thorough corrected QT interval (QTc) study (TRD1013) was conducted in healthy participants. 
Participants were randomly assigned to receive placebo, oral moxifloxacin (positive control), or 
84 mg esketamine nasal spray in the first 3 periods (ie, 1 treatment per period). They received 
0.8 mg/kg esketamine as a 40-minute IV infusion in the fourth open-label period. No evidence of 
QT interval prolongation (based on a study-specific power model and Fridericia’s correction 
methods) was found in participants treated with intranasal or intravenous esketamine. 
Moxifloxacin demonstrated QTc prolongation and established assay sensitivity.
Safety and Tolerability Findings Across Indications
Exposure to Esketamine Nasal Spray in Phase 2 and Phase 3 studies across indications
In 6 completed Phase 2 and 3 studies in TRD, 1,708 participants received esketamine [611 patient-
years of exposure] and 486 participants received placebo [107 patient-years of exposure]). In the 
ongoing open-label extension safety study TRD3008, 1,140 adult and elderly participants who 
previously participated in the Phase 3 TRD studies received esketamine [1,198 patient-years of 
exposure]).
In 3 completed Phase 2 and Phase 3 studies in MDSI, 262 participants received at least 1 dose of 
esketamine (15.8 patient-years of exposure) and 256 received at least 1 dose of placebo 
(15.7 patient-years of exposure).


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Analysis of Common Treatment-Emergent Adverse Events
Phase 1 Studies
In a pooled analysis (n=577) of 18 Phase 1 studies (TRD1001, TRD1002, TRD1003, TRD1004, 
TRD1005, TRD1006, TRD1007, TRD1008, TRD1009, TRD1010, TRD1011, TRD1012, 
TRD1013, TRD1014, TRD1015, TRD1016, TRD1018, and TRD1020), in the total esketamine 
group, TEAEs (at least 10% of the participants) were reported in 89.3% of participants. For the 
total esketamine group, frequently reported TEAEs (≥20%), were dizziness (38%), dysgeusia 
(30.4%), somnolence (26.4%), vertigo (21.5%), headache (21.3%), and feeling drunk (21%). 
In the on-road driving Study TRD1019 in participants with MDD, all participants reported at least 
1 or more TEAEs. The highest incidence of TEAEs during Part A of the study in the esketamine 
nasal spray 84 mg + oral placebo treatment group was dissociation (80.8%), in the placebo nasal 
spray + oral alcohol treatment group was headache (34.6%), and in the placebo nasal spray + oral 
placebo treatment group was fatigue (23.1%). The highest incidence of TEAEs during Part B of 
the study in the esketamine nasal spray treatment group was dissociation (96.0%), whereas in the 
placebo nasal spray treatment group, 3 participants (12.0%) each reported a TEAE of headache.
Studies in Participants with TRD
Phase 2 Study (TRD2003)
In Study TRD2003, for Panels A and B combined, 78.6% participants in the total esketamine nasal 
spray group and 61.1% participants in the placebo group experienced at least 1 TEAE during the 
double-blind phase. The most common TEAEs (in at least 10% of participants) were dizziness, 
headache, dysgeusia, dissociation, nausea, hypoesthesia, feeling abnormal, and somnolence. 
Common TEAEs that occurred more frequently in the placebo group than in the esketamine group 
were dysgeusia (20.4% vs 16.7%) and somnolence (13.0% vs 10.7%). During the open-label 
phase, 88.5% of participants experienced at least 1 TEAE. The most commonly reported TEAEs 
(≥10% of participants across panels) were generally similar to those reported by participants who 
received esketamine during the double-blind phase.
Phase 3 Short-term Studies (TRD3001, TRD3002, and TRD3005)
In studies TRD3001 and TRD3002, the most common TEAEs (reported by ≥10% of participants) 
in the total esketamine nasal spray + oral AD group were: nausea, dissociation, dizziness, vertigo, 
headache, dysgeusia, somnolence, paraesthesia, hypoaesthesia, hypoaesthesia oral; and in the oral 
AD + placebo nasal spray group: headache and dysgeusia. All of the most common TEAEs were 
observed more frequently (with a difference of at least 3%) in the total esketamine + oral AD group 
vs the oral AD + placebo nasal spray group: nausea (28.3% vs 8.6%), dissociation (26.6% vs 3.6%) 
dizziness (23.7% vs 6.8%), vertigo (22.5% vs 2.3%), headache (20.2% vs 17.1%), dysgeusia 
(18.8% vs 13.5%), somnolence (17.3% vs 9.0%), paraesthesia (12.4% vs 1.8%), hypoaesthesia 
(11.0% vs 1.4%), hypoaesthesia oral (10.7% vs 1.4%).


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In Study TRD3005, most common TEAEs (reported by ≥10% participants) observed more 
frequently in the esketamine nasal spray + oral AD group vs the oral AD + placebo nasal spray 
group were: dizziness (20.8% vs 7.7%), nausea (18.1% vs 4.6%), headache (12.5% vs 3.1%), 
fatigue (12.5% vs 7.7%), BP increased (12.5% vs 4.6%), dissociation (12.5% vs 1.5%), and vertigo 
(11.1% vs 3.1%). The most common TEAE (reported by ≥5% participants) observed more 
frequently in the oral AD + placebo nasal spray group was anxiety (7.7% vs 2.8% in the esketamine 
nasal spray + oral AD group).
Phase 3 Long-term Studies (TRD3003 and TRD3004)
In Study TRD3003, in the double-blind MA phase, the most common TEAEs (≥10% participants) 
in the esketamine + oral AD group included dysgeusia, vertigo, dissociation, somnolence, 
dizziness, headache, nausea, vision blurred, and hypoaesthesia oral. No TEAEs were reported at 
this rate in the oral AD + placebo nasal spray group. Of the TEAEs reported in at least 5% of 
participants, all except viral upper respiratory tract infection were reported at higher rates in 
esketamine + oral AD group than in oral AD + placebo nasal spray group (with a difference of 3% 
or more).
Overall, of those participants treated in either of the treatment phases (induction and/or 
optimization/maintenance), most reported TEAEs (90.1%) and the most common TEAEs (≥10% 
of participants) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), headache (24.9%), 
somnolence (16.7%), dysgeusia (11.8%), hypoaesthesia (11.8%), vertigo (11.0%), vomiting 
(10.8%), and viral upper respiratory tract infection (10.2%).
Studies in Participants with MDSI 
As observed in the TRD program, most TEAEs reported during esketamine treatment, including 
those that were most common, were mild or moderate in severity, were observed post dose on the 
day of dosing, and resolved the same day. In the pooled Phase 3 studies (SUI3001/3002), 89.9% 
of the participants in the esketamine + standard of care (SOC) group (n=227) and 75.6% in the 
placebo + SOC group (n=225) experienced at least 1 TEAE during the 4-week double-blind phase. 
The most common TEAEs (reported by ≥10% participants) observed more frequently in the 
esketamine + SOC group versus placebo + SOC group during the double-blind phase were: 
dizziness (38.3% versus 13.8%), dissociation (33.9% versus 5.8%), nausea (26.9% versus 13.8%), 
somnolence (20.7% versus 10.2%), dysgeusia (19.8% versus 12.9%), vision blurred (11.9% versus 
4.9%), paresthesia (11.5% versus 3.1%), vomiting (11.5% versus 5.3%), blood pressure increased 
(11.5% versus 4.0%), sedation (10.1% versus 2.2%), and anxiety (10.1% versus 7.6%). Headache 
was observed in similar proportion of participants in both groups (20.3% vs. 20.4%). A similar 
pattern of results was observed in the Phase 2 study SUI2001.


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Deaths, Serious Adverse Events and Other Significant Adverse Events
Deaths
Overall, across all completed and ongoing Phase 1, Phase 2, and Phase 3 studies with esketamine 
in the MDSI and TRD indications, 8 deaths have been reported up to 2 October 2019. 
Participants with TRD:

Completed Phase 2 and 3 TRD studies: There were 4 deaths reported among the 
1,708 participants who had received treatment with esketamine + oral AD in the completed 
Phase 2 and 3 studies in TRD (611 patient-years exposure). The deaths included 2 completed 
suicides; 1 of which occurred during the follow-up phase of TRD2003 (20 days after last dose 
of esketamine) and the other occurred during the OP/MA phase of TRD3004 (last esketamine 
dose 12 days prior to death). Other causes of death in the completed TRD studies were 
multiple injuries sustained during a road traffic accident during the double-blind phase of 
TRD3002 and death as a result of acute cardiac and respiratory failure during the OP/MA 
phase of TRD3004.

Ongoing Long-term open-label (OL) Extension Study TRD3008: 3 deaths were reported 
among the 1,140 participants treated with esketamine in the ongoing extension study 
TRD3008: 1 death due to
 1 death due to myocardial infarction, and 1 death 
due to multiple injuries (accidental polytrauma).
Participants with MDSI
In the completed Phase 2 and 3 MDSI studies, 1 death was reported in 262 participants who had 
been assigned to esketamine + SOC treatment in the double-blind treatment phase. This death 
(completed suicide) occurred during the follow-up phase of SUI3001
Serious Adverse Events
Participants with TRD
Three participants (<1% of those exposed to any formulation of esketamine) experienced serious 
adverse events (SAEs) in the 19 Phase 1 studies. One participant each reported an SAE of severe 
tooth abscess (TRD1004), an SAE of blighted ovum (TRD1013), and an SAE of substance induced 
psychotic disorder (TRD1015). All the events resolved after treatment, and only the SAE of 
blighted ovum was considered to be doubtfully related to esketamine nasal spray.
In the controlled Phase 3 TRD studies, SAEs were reported in participants receiving esketamine + 
oral AD at rates that were low and generally similar to those in participants receiving oral AD + 
placebo nasal spray (pooled TRD3001/3002: 0.9% [vs 0.5% for oral AD + placebo]; double-blind 
MA phase of Study TRD3003: 2.6% [vs 0.7% for oral AD + placebo nasal spray]; Study 
TRD3005: 4.2% [vs 3.1% for oral AD + placebo nasal spray]). Across both phases of the OL long-
term safety study (TRD3004), 6.9% of participants experienced serious TEAEs. Across all studies, 
the most frequently reported SAEs were in the psychiatric disorders category and were associated 
with the underlying disease state.
PPD


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SAEs in the esketamine + oral AD groups assessed by the investigator as related to study treatment 
included 1 participant each with depression, headache, blood pressure increased, and anxiety 
disorder across the Phase 3 short term studies; 1 participant each with disorientation, suicidal 
ideation, sedation, autonomic nervous system imbalance and simple partial seizures, lacunar 
stroke, and hypothermia in the relapse-prevention Study TRD3003 (all reported in induction 
phase); and 1 participant each with delirium, anxiety and delusion, suicidal ideation, and suicidal 
attempt in the long-term safety Study TRD3004.
Participants with MDSI
In the double-blind phase of the pooled Phase 3 studies SUI3001/3002, SAEs were reported for 
4.0% participants in the esketamine + SOC group (suicide attempt, depression suicidal, 
depersonalization/derealization disorder, depression, suicidal ideation, and diabetic ketoacidosis) 
and 5.3% participants in the placebo + SOC group (suicide attempt, depression suicidal, 
depression, suicidal ideation, aggression, arrhythmia, pericardial effusion, hypertransaminasemia, 
and pneumothorax). After discontinuation from the double-blind phase, 1.3% participants in the 
esketamine + SOC group experienced SAEs (suicidal ideation and acute psychosis) versus 0.9% 
participants in the placebo + SOC group (depression suicidal, major depression, and suicide 
attempt). During the follow-up phase, SAEs were observed at similar rates in participants who 
were treated with esketamine + SOC during the double-blind phase and participants who were 
treated with placebo + SOC during the double-blind phase (11.6% and 11.9%, respectively). In the 
Phase 2 study SUI2001, SAEs were observed in 11.4% participants in the esketamine + SOC group 
and 0 participants in the placebo + SOC group during the double-blind phase, and in 3.7% 
participants and 22.7% participants, respectively, during the follow-up phase.
Adverse Events Leading to Discontinuation
Across the 19 Phase 1 studies, TEAEs led to withdrawal of 18 participants from study treatment 
in studies TRD1018 (6 participants); TRD1013 (4 participants); TRD1001 (2 participants); 
TRD1004, TRD1006, TRD1007, TRD1009, TRD1015 and TRD1020 (1 participant each). 
Participants with TRD
In the Phase 2 Study TRD2003, 4 participants experienced TEAEs which led to withdrawal of 
study medication: 3 participants due to at least 1 TEAEs of syncope, headache or dissociative 
disorder in double-blind phase and 1 participant due to an SAE of ectopic pregnancy in the open-
label phase. Except for ectopic pregnancy, all other events were considered as possibly or very 
likely related to the study drug. 
TEAEs leading to discontinuation of esketamine were reported in approximately 5% to 6% of 
participants in the Phase 3 short-term studies in both adult and elderly participants, although rates 
were higher than for the oral AD + placebo groups (pooled TRD3001/TRD3002: 4.6% [vs 1.4% 
for oral AD + placebo]; Study TRD3005: 5.6% [vs 3.1% for oral AD + placebo]). 
After longer-term exposure to esketamine in Study TRD3003, discontinuation rates for nasal study 
drug during the double-blind MA phase were similar for the esketamine + oral AD (2.6%) and oral 


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AD + placebo (2.1%) groups. The overall discontinuation rate due to TEAEs observed in the Phase 
3 uncontrolled, open-label safety study (TRD3004) with long-term esketamine treatment 
(exposure of up to 1 year) was 9.5%.
Across the Phase 3 short term studies (TRD3001, TRD3002, and TRD3005), TEAEs leading to 
esketamine discontinuation in more than 2 participants (>0.1%) were: anxiety, depression, blood 
pressure increased, dizziness, suicidal ideation, dissociation, nausea, vomiting, headache, 
muscular weakness, vertigo, hypertension, panic attack, and sedation. 
The rates of discontinuations of esketamine treatment due to TEAEs were generally highest 
immediately after treatment initiation. In the Phase 3 short-term studies in adults (TRD3001, 
TRD3002), nearly all discontinuations due to TEAEs in esketamine-treated participants occurred 
within the first 2 weeks of the double-blind phase. In the Phase 3 relapse-prevention (TRD3003) 
and open-label long term safety (TRD3004) studies, discontinuations due to TEAEs in esketamine-
treated participants occurred in higher rates in the induction phase compared to the OP and/or MA 
phases (Study TRD3003: 5.0% vs 1.1% [OP] and 2.6% [MA]; Study TRD3004: 6.8% vs 3.8% 
[OP/MA combined]).
Participants with MDSI
In the pooled Phase 3 studies SUI3001/3002, 6.2% participants in the esketamine + SOC group 
and 3.6% participants in the placebo + SOC group experienced TEAEs leading to discontinuation 
of nasal spray study medication. TEAEs that led to discontinuation in >1 participant in the 
esketamine + SOC group were: dissociation (3 participants), depersonalization/derealization 
disorder, nausea, and blood pressure increased (2 participants each). In the Phase 2 study SUI2001, 
14.3% participants in the esketamine + SOC group had a TEAE leading to discontinuation of study 
medication (dizziness, dysgeusia, aggression, agitation, ventricular extrasystoles, nausea, and 
dyspnea) versus 1 (3.2%) participant in the placebo + SOC group (dissociative disorder and panic 
attack).
Adverse Events of Clinical Interest/Special Safety Topics
Abuse Potential
Across all Phase 1, 2, and 3 studies of esketamine across indications, TEAEs suggestive of abuse 
potential, most commonly associated with esketamine were dizziness, somnolence, and 
dissociation. These symptoms were predominantly reported shortly after dosing on the day of 
esketamine administration, were transient and self-limiting, and mild or moderate in severity. 
Other events, such as euphoric mood, confusional state, feeling drunk or abnormal, and 
hallucinations, were also observed but occurred at lower rates. After up to 1 year of repeated 
intermittent dosing with esketamine in the open-label long-term safety study, the reporting 
frequencies of these other TEAEs were below 4%, while TEAEs of hallucinations were reported 
at rates not exceeding 1%.
Across Phase 3 TRD studies, the changes in withdrawal symptoms assessed by the 20-item 
Physician Withdrawal Checklist after cessation of treatment with esketamine + oral AD were 


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consistent with observed changes in symptoms of depression and anxiety. Based on these results, 
there was no evidence suggestive of a distinct withdrawal syndrome after cessation of treatment 
with esketamine + oral AD in Study TRD3003 or at 1, 2 or 4 weeks after cessation of treatment 
with esketamine + oral AD in Study TRD3004.
Suicidal Ideation and Behavior
In the Phase 1 studies, no postbaseline occurrences of suicidal ideation and/or suicidal behavior 
have been reported with the exception of 1 participant from Cohort 1 in Study TRD1012, which 
was conducted in healthy participants. This participant reported suicidal ideation throughout the 
study (ie, at screening, on Day 1, Day 2, and end-of-study) without any plan or intent to act, and 
without suicidal behavior. One other participant reported non-specific suicidal thoughts, which 
were not present at the end-of-study visit. No TEAEs related to suicidal ideation/behavior were 
observed in the Phase 1 studies.
Participants with TRD
Across all Phase 2 and 3 studies, suicidal ideation, assessed using the Columbia Suicide Severity 
Rating Scale (C-SSRS), showed a decrease from baseline to the endpoint in the esketamine 
treatment groups. Most participants reported no suicidal ideation or behavior during any of the 
completed TRD studies.
Most participants stayed within the same suicidality category throughout the duration of the Phase 
3 studies. For participants with no suicidal ideation or behavior at baseline, the rates of reported 
suicidal ideation (based on C-SSRS) at least once during the treatment phase were similar for the 
esketamine + oral AD groups and the oral AD + placebo groups in the short term double-blind 
studies (TRD3001/3002: 10.2% vs 12.3%, respectively; TRD3005: 13.8% vs 16.7%) and in the 
double-blind MA phase of the relapse-prevention Study TRD3003 (2.4% vs 4.5%). Only a small 
number of participants with no suicidal ideation or behavior at baseline, all of whom had 
esketamine exposure, had suicidal behavior at any time postbaseline (1 [0.3%] participant in the 
induction phase of Study TRD3003; 2 [0.3%] participants in induction phase of Study TRD3004, 
and 2 [0.4%] in the OP/MA Phase of Study TRD3004).
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 TEAEs were reported at a low incidence (<1% for individual PTs) in each of the Phase 2 
and 3 studies. Clinical review of suicidality-related TEAEs indicated that most of these events 
were likely associated with the underlying disease.


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Participants with MDSI
The MDSI studies enrolled participants with MDD who had active suicidal ideation with intent 
(assessed to be at imminent risk for suicide per the study protocols). Study inclusion criteria 
corresponded with the level of severity of suicidal ideation considered to be predictive of suicidal 
behavior over the short term, and, in the physician’s opinion, acute psychiatric hospitalization of 
the participant was to be clinically warranted due to imminent risk for suicide. In the pooled Phase 
2 and 3 MDSI studies, the frequency of adverse events potentially related to suicidality occurring 
during the double-blind phase was similar in the 2 treatment groups (7.6% in the esketamine + 
SOC group and 6.6% in the placebo + SOC group). During the follow-up phase, the incidence of 
these events was similar in participants previously exposed to esketamine (10.6%) or placebo 
(11.6%). The reported frequencies of suicide attempts and completed suicides during the double-
blind phase (1.5% in the esketamine + SOC group and 1.6% in the placebo + SOC group) and 
follow-up phase (3.7 in the esketamine + SOC group and 2.9% in the placebo + SOC group) for 
the pooled Phase 2 and 3 studies was similar in the 2 treatment groups. Across these studies, there 
were no completed suicides during the double-blind treatment phase, and 1 completed suicide 
during the follow-up phase.
Overall, the rate of suicide-related AEs observed in the ~3-month MDSI studies was not 
unexpected in light of reported findings in the literature in this high-risk population.
Clinician-Administered Dissociative States Scale (CADSS)
In all the reported studies, the majority of participants who were administered esketamine 
experienced dissociative symptoms as assessed by the CADSS. The symptoms peaked at around 
40 minutes from the time of study drug administration and typically resolved by 2 to 4 hours after 
dosing. 
Across completed Phase 2 and 3 studies across indications, consistent with the observations 
captured in the CADSS rating scale, median duration of the TEAEs 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 not exceeding 4% across studies, was not considered 
serious for any participants in completed Phase 2 and 3 studies, and rarely led to discontinuation 
of study drug. 
Transient dissociative/perceptual changes (based on the CADSS scores, the overall TEAE 
incidence rates, and the severe TEAE incidence rates) were more pronounced in participants 
receiving higher doses of esketamine. 
Brief Psychiatric Rating Scale – 4-Item Positive Symptom Subscale (BPRS+)
In the Phase 1 studies (TRD1001, TRD1002, TRD1003, TRD1004, TRD1005, TRD1006, 
TRD1007, TRD1009, TRD1010, and TRD1012), the majority of participants had total BPRS+ 
scores of 0.0, which remained unchanged during each study. When postdose increases in BPRS+ 
total scores were noted, they were generally seen at 40 minutes postdose and returned to baseline 


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levels by 2 hours postdose. Few participants experienced any increase in suspiciousness, 
hallucinatory behavior or unusual thought content. However, the Japanese participants showed 
higher mean BPRS+ total scores than the Caucasians. Results in elderly participants were similar 
to those in younger adults.
Across the Phase 2 and Phase 3 TRD studies, a small mean increase in BPRS+ total score from 
baseline was observed at 40‑minute postdose assessment in esketamine + oral AD treatment groups 
(mean maximum values of <1, indicating symptoms were ‘very mild’). After this transient, 
minimal worsening, mean scores generally returned to predose values at the 1.5-hour postdose 
assessment. Based upon review of TEAE data and BPRS+ data, treatment with esketamine nasal 
spray does not appear to be associated with development of potential psychotic-like symptoms. 
No TEAEs of psychosis were reported across the Phase 2 and 3 studies in TRD. In the MDSI 
studies, 1 participant in SUI3001 had a mild TEAE of psychotic symptom (mild severity) 2 days 
after his last esketamine dose, followed by an SAE of acute psychosis 2 days later; the investigator 
considered both events as not related to the study drug. Another participant in SUI2001 had a 
TEAE of psychotic disorder (moderate severity). As MDD (including TRD) with psychosis 
represents a more vulnerable population in whom esketamine may cause psychotomimetic 
symptoms, the product labeling for esketamine recommends that this drug product should be used 
with caution in patients with a presence or history of psychosis.
Anxiety
Across all Phase 2 and 3 studies across indications, TEAEs related to anxiety were primarily mild 
or moderate in severity, transient and self-limited. Most of these events occurred on the day of 
dosing and resolved spontaneously the same day. Anxiety was reported as severe in intensity in 
esketamine-treated participants at incidences below 2% across studies/study phases. Isolated cases 
of anxiety were reported as serious. Most of these events were considered by the investigator to be 
either not related to or doubtfully related to esketamine. Discontinuation of study drug due to 
anxiety was reported in under 2% of participants. 
Transient Dizziness or Vertigo
Across all Phase 2 and 3 studies across indications, TEAEs related to dizziness or vertigo were 
primarily mild or moderate in severity, transient and self-limited. Most of these events occurred 
on the day of dosing and resolved spontaneously the same day, with the median duration not 
exceeding 2 hours across dosing sessions. Dizziness and vertigo were reported as severe in 
intensity at incidences under 3% across studies/study phases. No SAEs of dizziness or vertigo were 
reported in esketamine treated participants. Discontinuations of study drug due to dizziness or 
vertigo were reported at low rates (less than 1% of participants for each PT). 
Sedation and Somnolence
Adverse effects of sedation were assessed using data based on the Modified Observer’s 
Assessment of Alertness/Sedation (MOAA/S) rating scale (measured each day of nasal spray 
dosing at 15-minute intervals from predose until 1.5 hours postdose or longer if necessary until the 


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participant had a score of 5 [awake]), as well as via review of the incidence, type, and severity of 
sedation related AEs. Across the Phase 1 studies, when sedation was reported it was limited in 
duration and generally returned to baseline levels within 1 to 2 hours after dosing. Results in 
elderly participants were similar to those in younger adults. The majority of the participants across 
all of the study cohorts experienced mild or no sedation (few participants had a MOAA/S score of 
less than 3, indicating at least moderate sedation) and remained alert after dosing with esketamine. 
Based on the pattern of responses on the MOAA/S in the Phase 2 and 3 studies across indications, 
sedative effects of esketamine were generally mild, had an onset shortly after the nasal spray 
dosing peaking at 30 to 45 minutes postdose, and typically resolved by 1 to 1.5 hours postdose. 
Among esketamine treatment groups, 10% or fewer participants across the Phase 3 studies/study 
phases had a MOAA/S score of 3 or less (corresponding to moderate or greater sedation), although 
the occurrence of these scores was higher than that for the oral AD + placebo group. Across the 
Phase 3 studies in TRD, 10 of the 1,601 participants treated with esketamine + oral AD (and 1 of 
the 432 participants who received oral AD + placebo), had a MOAA/S score of 0 (no reaction to 
painful stimulus [trapezius squeeze]) and/or 1 (response to trapezius squeeze, including purposeful 
and reflexive withdrawal). Across the Phase 2 and 3 MDSI studies, 1 of 262 participants who 
received esketamine + SOC (and 0 of 256 participants who received placebo + SOC) had a 
MOAA/S score of 0. These isolated instances of severe sedation generally did not repeat with 
subsequent dosing. Among participants with a MOAA/S score of ≤3 (including those with a score 
of 0) across the Phase 3 studies, no symptoms of respiratory distress were observed, and 
hemodynamic parameters (including vital signs and oxygen saturation) remained within normal 
ranges.
The most commonly reported individual PTs (≥5%) related to sedation symptoms in the Phase 2 
and 3 TRD studies were somnolence and sedation, and these events were reported at higher rates 
following treatment with esketamine + oral AD compared to oral AD + placebo in controlled Phase 
3 studies/study phases (pooled TRD3001/TRD3002 studies: 17.3% vs 9.0%, respectively, for 
somnolence; 5.5% vs 0.9%, respectively, for sedation; Study TRD3003 double-blind MA phase: 
21.1% vs 2.1% for somnolence; 6.6% vs 0.7% for sedation. However, in Study TRD3005, 
somnolence was reported at a higher rate in oral AD + placebo compared to esketamine + oral AD 
(4.6% vs 1.4%) [no TEAEs of sedation]). There were no TEAEs of respiratory depression among 
esketamine-treated participants across the Phase 1, 2, or 3 studies across indications.
Effects on Cognition
For the Phase 2 study (TRD2003), none of the participants experienced TEAE of impaired 
cognition. No TEAEs related to cognitive impairment (ie, preferred terms, cognitive disorder, 
minor cognitive motor disorder) were reported in the Phase 3 studies in TRD.
Based on the interim analysis of the ongoing long-term open-label extension study TRD3008 in 
1,131 participants up to Week 76 an assessment of cognitive function based on a computerized 
cognitive test battery and the Hopkins Verbal Learning Test-Revised indicated that long-term 
treatment with esketamine was not associated with negative cognitive effects in the overall study 
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Nasal Tolerability and Nasal Examination
Across all Phase 1 studies, most participants did not report any nasal tolerability symptoms. Where 
nasal tolerability symptoms were reported, most were rated by the patient as mild. Abnormal 
findings during the nasal examination were generally mild. The results in Japanese participants 
were similar to those in Caucasian participants (TRD1002), and the results in elderly Japanese 
participants were similar to those in younger Japanese adults (TRD1018).
In the Phase 2 and 3 TRD studies 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. 
Cardiovascular Effects
Blood Pressure Measurements
For many participants in the Phase 1 clinical studies (TRD1001, TRD1002, TRD1003, TRD1004, 
TRD1005, TRD1006, TRD1007, TRD1008, TRD1009, TRD1010, TRD1011, TRD1013, 
TRD1015, and TRD1020) there was a dose-dependent increase in systolic blood pressure (SBP) 
and diastolic blood pressure (DBP) which typically peaked at around 30 to 50 minutes and resolved 
at approximately 2 hours after esketamine administration. These changes generally returned to 
baseline within 2 to 4 hours postdose. Results in elderly participants ≥65 years of age were similar 
to those in younger adult participants, and results in Japanese participants were similar to those in 
Caucasian participants in these Phase 1 studies. For the majority of participants, no clinically 
relevant changes were observed in the mean blood pressure and HR.
Across all Phase 2 and 3 studies in participants with TRD transient, primarily asymptomatic, 
increases in systolic and diastolic BP were observed following esketamine administration, with 
maximum mean changes typically observed within 40 minutes of dosing and mean BP values 
subsequently returning to, or close to, predose values within the 1.5-hour postdose timepoint.
Pulse Rate Measurements
In Study TRD2003, abnormal increases in pulse rate were observed in no more than 2 participants 
in any treatment sequence and period. Across the Phase 3 studies/study phases, the rates of 
treatment-emergent abnormal decreases or increases in pulse rate relative to baseline at any time 
were less than 9%. Similar rates were reported for the esketamine + oral AD and oral AD + placebo 
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Cardiovascular TEAEs
In the QT Study TRD1013, 2 participants had an AE of palpitations (mild in intensity) that was 
considered very likely and possibly (1 participant each) related to the study treatment. No other 
TEAEs related to cardiac disorders were reported. No clinically meaningful effects in 
electrocardiogram (ECG) parameters (PR, RR, QRS, QT, QTcB, and QTcF intervals, heart rate 
[HR], and P-wave) were observed.
Across all Phase 2 and 3 TRD studies, TEAEs of increased BP in esketamine-treated participants 
were reported at the rates ranging from 6.6% to 13.9% across studies/study phases (based on the 
total esketamine + oral AD group in the pooled 3001/3002 studies), while TEAEs of increased HR 
occurred at lower incidences (all rates below 1.6%).
In the double-blind phases of Phase 2 Study TRD2003, the reporting rate for TEAEs related to 
increased blood pressure was 13.1% across all esketamine groups and 7.4% for the placebo group; 
no TEAEs related to increased heart rate were reported in the double-blind phases of this study. 
TEAEs related to increased heart rate occurred at low incidence rates (<2%) across the Phase 3 
studies/study phases. By comparison, TEAEs related to increased blood pressure were reported at 
higher frequencies following treatment with esketamine + oral AD compared to oral AD + placebo 
in the controlled Phase 3 studies/study phases (pooled TRD3001/TRD3002 studies: 10.1% vs 
2.7%, respectively; TRD3005: 13.9% vs 6.2%: double-blind MA phase of TRD3003: 8.6% vs 
3.4%). Across the open-label long-term safety Study TRD3004, TEAEs related to increased blood 
pressure were reported for 12.8% of participants receiving esketamine + oral AD).
In the pooled Phase 3 MDSI studies (SUI3001/3002), TEAEs related to increased BP were 
reported at higher rates in the esketamine + SOC group than in the placebo + SOC group (15.0% 
vs. 6.2%). In the Phase 2 study SUI2001, TEAEs of increased BP were reported at low rates in 
both treatment arms (2 [5.7%] participants in the esketamine + SOC group and 1 [3.2%] participant 
in the placebo + SOC group).
Among esketamine-treated participants in the Phase 3 studies, very few of the TEAEs (individual 
preferred terms) of blood pressure increased or tachycardia were severe (≤0.2% in all study/study 
phases except Study TRD3005 where incidence of severe increased blood pressure TEAEs was 
1.4% [representing 1 participant]). Further, TEAEs of increased blood pressure or tachycardia 
were reported as serious in only isolated cases, and discontinuation of esketamine treatment for 
these events occurred in <2% of participants across studies/study phases.
Between 90% and 100% of the reported TEAE preferred term of increased blood pressure occurred 
on the day of dosing in the Phase 3 studies/study phases and of these, >93% resolved spontaneously 
the same day.
Serious cerebrovascular TEAEs were reported in 2 of the 1,601 esketamine-treated participants 
across the Phase 3 studies (lacunar stroke after day of first esketamine dose with plausible 
mechanism of microatheroma; cerebrovascular accident occurring in follow-up phase 25 days after 
last esketamine dose in a participant with vasculitis).


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Electrocardiogram
For most participants in the Phase 1 clinical studies (TRD1001, TRD1002, TRD1003, TRD1004, 
TRD1005, TRD1006, TRD1007, TRD1008, TRD1009, TRD1010, TRD1011, TRD1012, 
TRD1014, TRD1015, TRD1016, TRD1018, TRD1019, and TRD1020) no clinically relevant 
changes in ECG parameters or clinically meaningful treatment-related trends were observed. 
Across Phase 1 studies, there were no cardiovascular SAEs reported. Two participants 
discontinued due to AEs from the Cardiac Disorders SOC (1 in Study TRD1006 for AE of atrial 
fibrillation and 1 in Study TRD1007 for AE of Wolff-Parkinson-White syndrome); the investigator 
did not consider these events to be related to the study agents.
In the thorough QT study (TRD1013), no clinically significant changes in ECG parameters were 
observed.
Across the completed Phase 2 and 3 studies across indications, there were no clinically relevant 
mean changes in ECG parameters (heart rate, PR duration, QRS duration, QTcB and QTcF 
intervals, QT duration, and RR duration) from average predose values over time in any group.
Bladder Pain/Interstitial Cystitis Symptom Score
The Phase 2 and 3 studies included monitoring for symptoms of cystitis or lower urinary tract 
symptoms using the BPIC-SS, a participant reported outcome measure developed to identify a 
bladder pain syndrome/interstitial cystitis population for clinical studies evaluating new treatments 
for bladder pain syndrome. Overall, there were no cases of interstitial cystitis or ulcerative cystitis 
in any of the esketamine studies across indications.
Other Safety Observations
Overall, no clinically relevant changes were observed in vital signs, clinical laboratory evaluations 
or clinically meaningful treatment related trends.
Safety in Participants with Hepatic Impairment (TRD1011)
Study TRD1011 evaluated the PK of esketamine nasal spray (28 mg) in participants with mild or 
moderate hepatic impairment in comparison to participants with normal hepatic function. Most of 
the observed TEAEs were mild and were reported to be resolved by the end of the study. There 
were no deaths, SAEs, persistent AEs, or discontinuations due to AEs. None of the laboratory 
abnormalities were considered clinically significant or reported as a TEAE. The safety profile in 
participants with hepatic impairment was similar to participants with normal hepatic function. 
Phase 2 and 3 Findings
Elevations in ALT/AST >3xULN were reported at low rates across studies, were primarily 
asymptomatic, transient, and resolved spontaneously without worsening while treatment with 
esketamine and oral AD continued. No cases in any Phase 1, 2, or 3 esketamine studies across 
indications met the criteria for severe drug induced hepatocellular injury as defined by Hy’s law.


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2.2.1.
Comparator Drug Combination Therapy 
Not applicable.
Benefit-Risk Assessment
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 assessments estimate that between 5 and 21 more patients 
per 100 treated achieve remission of depression symptoms after 4 weeks of treatment with 
esketamine + oral AD compared to initiating treatment with an oral AD alone. Further, once 
remission has been achieved on esketamine, continued maintenance treatment with esketamine + 
oral AD is estimated to result in 19 to 32 fewer relapses per 100 patients relative to those who 
discontinue esketamine. The safety experience with esketamine 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 (HCP), and resolve the same day. In 
addition, certain adverse events such as dissociation, dizziness/vertigo, and nausea/vomiting tend 
to lessen in frequency with continued dosing. The benefits of esketamine are considered to 
outweigh the risks of the infrequent severe or treatment-limiting side effects in the TRD 
population. While the potential for abuse exists with esketamine, there were no TEAEs of drug 
abuse or overdose and no reports of confirmed diversion in clinical trials. Several risk mitigation 
initiatives are in place to lessen the potential for abuse and misuse. Patient preference study 
findings indicate that patients with TRD, both with and without esketamine treatment experience, 
place a higher value on improved depression symptoms over those of short-term unusual post dose 
sensations and drug administration logistics or hypothesized extreme safety risks associated with 
ketamine abuse.
More detailed information about the known and expected benefits and risks of esketamine may be 
found in the latest edition of the Investigator’s Brochure5 and USPI11.
Taking into account the measures taken to minimize risk to participants of this study, the potential 
risks identified in association with esketamine are justified by the anticipated benefits that may be 
afforded to participants with TRD.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of each individual dose of esketamine 
nasal spray, 56 mg and 84 mg, compared with placebo nasal spray in improving depressive 
symptoms in participants with TRD, as assessed by the change from baseline in the MADRS total 
score from Day 1 (prerandomization) to the end of the 4-week double-blind treatment phase (Day 
28).


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Key Secondary Objective
The secondary objective of this study is to evaluate the efficacy of esketamine nasal spray, 56 mg 
and 84 mg, compared with placebo nasal spray on improving depressive symptoms in participants 
with TRD, as assessed by the change from baseline in the MADRS total score from Day 1 
(prerandomization) to Day 2.
Other Objectives

To evaluate the efficacy of esketamine nasal spray, 56 mg and 84 mg, compared with placebo
nasal spray in participants with TRD on:

Depression response and remission rates

Overall severity of depressive illness

Change in MADRS total score over time

Change in PHQ-9 total score over time

To investigate the safety and tolerability of esketamine nasal spray, 56 mg and 84 mg, 
compared with placebo nasal spray in participants with TRD, including the following:

Treatment-emergent adverse events (TEAEs), including AEs of special interest

Effects on heart rate and blood pressure

Potential effects on suicidal ideation/behavior

To assess the pharmacokinetic/pharmacodynamic (PK/PD) relationship of esketamine nasal 
spray and MADRS total score in participants with TRD 

To assess the relationship of biomarkers with response/nonresponse to esketamine nasal 
spray in participants with TRD
Endpoints
Primary Endpoint
The primary efficacy endpoint is the change from baseline in MADRS total score from Day 1 
(prerandomization) to the end of the 4-week double-blind treatment phase (Day 28).
Key Secondary Endpoint
The key secondary efficacy endpoint is the change from baseline in MADRS total score from Day 
1 (prerandomization) to Day 2.
Other Endpoints
The other efficacy endpoints are as follows:

MADRS total score 

Proportion of responders (≥50% reduction from baseline in MADRS total score) over 
time to the end of the 4- week double-blind treatment phase (Day 28)


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
Proportion of participants in remission (MADRS ≤10) over time to the end of the 4-week 
double-blind treatment phase (Day 28)

Change from baseline in MADRS total score over time to the end of the 4-week double-
blind treatment phase

Change from baseline in Clinical Global Impression – Severity (CGI-S) over time to the end 
of the 4-week, double-blind treatment phase (Day 28)

PHQ-9 total score

Proportion of responders (reduction in PHQ-9 score of 6 points) over time to the end of 
the double-blind treatment phase (Day 28)

Change from baseline in PHQ-9 total score over time to the end of the 4-week double-
blind treatment phase (Day 28)
HYPOTHESIS 
The hypothesis of this study is that esketamine nasal spray, 56 mg or 84 mg, when used as 
monotherapy, is superior to placebo nasal spray in improving depressive symptoms in participants 
with TRD.
4.
STUDY DESIGN
Overall Design
This is a randomized, double-blind, placebo-controlled, multicenter study in male and female 
participants with TRD to evaluate the efficacy, safety, and tolerability of esketamine nasal spray, 
56 mg and 84 mg, administered as monotherapy.
This study has 4 phases: screening, double-blind treatment, open-label treatment/observation, and 
follow-up.
A target of approximately 446 participants will be randomized in a 2:1:1 ratio to placebo, 
esketamine 56 mg, or esketamine 84 mg. A minimum of 356 participants meeting predefined 
nonresponse criteria will be randomized for the primary efficacy analysis set.
The maximum duration of study participation is 24 weeks.
Screening Phase (up to 7 weeks)
This phase will assess the participant’s eligibility for study participation. 
Evaluations that will be performed at the screening visits are outlined in Section 1.3, Schedule of 
Activities (SoA).
The study population will include men and women, 18 years of age (or older if the minimum legal 
age of consent in the country in which the study is taking place is >18) or older,  who meet the 
Diagnostic and Statistical Manual of Mental Disorders (5th Edition; DSM-5) diagnostic criteria 
for single episode MDD or recurrent MDD, without psychotic features, based upon clinical 


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assessment, and confirmed by the Mini International Neuropsychiatric Interview (MINI). In 
addition, the participant must have an Inventory of Depressive Symptomatology-Clinician rated, 
30-item (IDS-C30) total score of ≥34, which corresponds to moderate to severe depression. 
Participants can be screened for study participation whether or not they are currently taking an 
antidepressant medication.
At the start of screening, participants must have had nonresponse to ≥2 different oral antidepressant 
treatments in the current episode of depression, as assessed by the Massachusetts General Hospital-
Antidepressant Treatment Response Questionnaire (MGH-ATRQ), and confirmed by documented 
records (eg, medical/pharmacy/prescription records or a letter from treating physician).
The participant’s current major depressive episode, depression symptom severity, and AD 
treatment response in their current depressive episode must be deemed valid for participation in 
the clinical study based on the “State vs. Trait, Assessibility, Face Validity, Ecological Validity, 
Rule of Three P’s” (SAFER) Interview, which is a site-independent qualification assessment.
If clinically indicated, a participant’s current AD medication(s), including adjunctive treatment for 
MDD, should be tapered and discontinued during this phase per the local prescribing information, 
guidelines6 or clinical judgement. Tapering/discontinuation of any antidepressant medication(s) 
should not be started until the SAFER Interview is completed and the site has received 
confirmation that the participant has “passed” the SAFER Interview. 
All participants will have a minimum of 2 weeks in the Screening Phase without any AD 
medication(s) just prior to randomization. 
For participants not taking any AD medications at study entry (screening), the mandatory 2-week 
antidepressant-free period may start at entry. However, the screening phase will be at least 3 weeks 
to ensure required procedures are completed.
Participants taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of 
lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, zaleplon) 
during the screening phase can continue these medications. Temporary dose increases of 
benzodiazepines beyond the equivalent of 6 mg/day lorazepam or initiation of new 
benzodiazepines are permitted during the screening phase if needed to assist with AD 
taper/discontinuation and/or the antidepressant-free period. However, the dose of the current 
benzodiazepines is to be less than or equal to the equivalent of 6 mg/day of lorazepam before 
randomization in the double-blind treatment phase.
Potential participants will be excluded from participating in the study if they have used 
ketamine/esketamine (lifetime); previously demonstrated nonresponse of depressive symptoms to 
an adequate course of treatment with electroconvulsive therapy (ECT) in the current major 
depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT; if they have 
received vagal nerve stimulation (VNS) or deep brain stimulation (DBS) in the current major 
depressive episode; if they have a current or prior DSM-5 diagnosis of a psychotic disorder or 


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MDD with psychosis, 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; if they have homicidal 
ideation/intent or suicidal ideation with some intent to act within 6 months prior to the start of the 
screening phase per the investigator’s clinical judgment and/or based on the C-SSRS or suicidal 
behavior in the last year; or if they have a history of moderate or severe substance or alcohol use 
disorder according to DSM-5 criteria. 
Participants meeting the inclusion/exclusion criteria (Section 5) are eligible to proceed to the 
double-blind treatment phase.
Double-blind Treatment Phase (4 weeks)
Eligible participants will be randomly assigned at a 2:1:1 ratio to receive double-blind nasal spray 
treatment with either placebo, esketamine 56 mg, or esketamine 84 mg, twice a week for 4 weeks.
The participant will self-administer nasal spray treatment (esketamine or placebo) under the direct 
supervision of a healthcare provider during all treatment sessions. A treatment session consists of 
nasal administration of the study medication and post-administration observation. On all dosing 
days, all participants must remain at the clinical site for post-administration observation until at 
least 2 hours postdose until the patient is safe to leave. See Section 6, Study Intervention 
Administered, for blood pressure monitoring guidance on nasal spray treatment session days.
After receiving a treatment session, instruct participants not to engage in potentially hazardous 
activities, such as driving a motor vehicle or operating machinery, until the next day after a restful 
sleep.
Evaluations that will be performed during this phase are outlined in Section 1.3, Schedule of 
Activities.
Participants taking benzodiazepines and/or permitted non-benzodiazepine sleep medications 
(eg, zolpidem, zaleplon) during the screening phase can continue these medications during the 
double-blind treatment phase (at dosages equal to or less than the equivalent of 6 mg/day of 
lorazepam), however they may not be used within 12 hours prior to the start of each nasal spray 
treatment session. No dose increases beyond the equivalent of 6 mg/day of lorazepam, or new 
benzodiazepine medications are permitted during the double-blind treatment phase, except for the 
use of permitted benzodiazepine rescue medication.
Missing data in clinical trials can lead to problems that undermine the scientific credibility of 
causal conclusions. The most common reason for missing data is participants who discontinue the 
assigned treatment because of AEs, lack of tolerability, lack of efficacy, or inconvenience. In order 
to reduce missing data in this study, if a participant discontinues double-blind study medication 
for reasons other than withdrawal of consent, the participant should complete the remaining 
scheduled visits (without study medication dosing) through the end of the phase (Day 28). For 
participants remaining in the double-blind treatment phase without study medication dosing, 


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standard-of-care treatment may be initiated. Participants who complete the double-blind treatment 
phase (ie, including the Day 28 visit) may be eligible to proceed to the open-label 
treatment/observation phase.
If a participant discontinues from the study in the double-blind treatment phase (ie, prior to 
completion of the Day 28 visit), an Early Withdrawal visit should be conducted within 1 week of 
the date of discontinuation. Participants that discontinue early from the double-blind treatment 
phase (ie, prior to completion of the Day 28 visit) are not eligible to participate in the open-label 
treatment/observation phase and will proceed to the follow-up phase. 
Open-label Treatment/Observation Phase (up to 3 months)
On Day 28, following completion of the double-blind treatment phase assessments (which includes 
the Day 28 MADRS assessment), participants may participate in an open-label 
treatment/observation phase. The Investigator needs to assess and confirm in the source 
documentation that, based on clinical judgment, it is in the participant’s best interest to participate 
in this phase.
During the open-label treatment/observation phase, for a duration of up to 3 months, participants 
can: 

receive open-label esketamine nasal spray 

If clinically indicated based on the investigator’s judgment, participants receiving open-
label esketamine nasal spray treatment can also receive standard-of-care treatment for 
depression. The decision to receive open-label esketamine must be made at the start of 
the open-label treatment/observation phase, participants who chose to not receive 
esketamine (to be observed only) will not be allowed to start open-label esketamine 
treatment during this phase.

choose to be observed only (ie, no esketamine nasal spray treatment sessions) and receive 
standard-of-care treatment for depression. Participants who choose to be observed only will 
not be allowed to switch to the open-label esketamine nasal spray arm during the open-label 
treatment/observation phase.
Evaluations that will be performed during this phase are outlined in the Schedule of Activities. 
Participants in this phase who have opted to receive open-label esketamine will receive 56 mg on 
Day 28 regardless of the participant's study drug/dose assignment in the double-blind phase. 
Subsequent doses can remain the same or be adjusted (56 mg or 84 mg) based on efficacy and 
tolerability. The recommended dosing frequency is as follows:

Weeks 5 to 8: twice weekly (maximum)

Weeks 9 to 12: once weekly 

Weeks 13 to 16: weekly or every other week. Dosing frequency will be based on clinical 
judgment and should be individualized to the least frequent dosing to maintain 
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The participant will self-administer esketamine nasal spray under the direct supervision of a 
healthcare provider during a treatment session at all treatment visits. A treatment session consists 
of nasal administration of the study medication and post-administration observation. On all dosing 
days, all participants must remain at the clinical site for post-administration observation until at 
least 2 hours postdose. After receiving a treatment session, participants are not to engage in 
potentially hazardous activities, such as driving a motor vehicle or operating machinery, until the 
next day after a restful sleep. See Section 6, Study Intervention Administered, for blood pressure 
monitoring guidance on nasal spray treatment session days.
If a participant discontinues the open-label treatment/observation phase for reasons other than 
withdrawal of consent, the participant will proceed to the follow-up phase.
Evaluations that will be performed during this phase are outlined in Section 1.3, Schedule of 
Activities.
Follow-up Phase
All participants who have received at least 1 dose of nasal spray medication in the study will 
complete a follow up visit in the follow-up phase.
Further clinical/standard of care for the treatment of depression will be arranged by the study 
investigator and/or the participant’s treating physician.
A diagram of the study design is provided in Section 1.2, Schema.
Scientific Rationale for Study Design
The sponsor has recently completed a phase 3 clinical program assessing the efficacy and safety 
of esketamine nasal spray used together with an oral antidepressant for the treatment of patients 
with TRD. Based on this program, esketamine nasal spray was registered by US FDA for this 
indication. However, there was insufficient information to confirm whether esketamine nasal spray 
is also effective in the treatment of participants with TRD when used as monotherapy. This 
protocol was designed in cooperation with FDA to provide the required data. In order to enable 
the comparison of results from this study with results from the phase 3 program, the study 
population, entry criteria, and study design were defined similarly to the phase 3 studies. This 
study will assess an onset of treatment effect on Day 2 and a durability of the treatment effect after 
4 weeks of treatment with esketamine nasal spray used as monotherapy.
Study Phases
The screening phase (up to 7 weeks) will provide adequate time to assess participant eligibility 
according to the study entry criteria and to complete a mandatory 2-week antidepressant drug-free 
period prior to the start of a double-blind treatment phase. Participants taking antidepressant 
medications (for a complete list of antidepressant medications, please refer to Section 10.6, 
Appendix 6: Medications Used for the Treatment of Depression to be Discontinued During the 
Screening Phase) at entry will have these medications tapered (if applicable) and discontinued 
during this phase, per the local prescribing information or clinical judgment. This method of 


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recruitment allows for entry of participants being treated with various antidepressant medications 
or treatment regimens in the current depression episode. The mandatory 2-week antidepressant 
drug-free period will reduce any impact of the prior antidepressant medication(s) on the evaluation 
of the efficacy and safety of esketamine used as monotherapy in the double-blind treatment phase.  
After the 2-week antidepressant drug-free period and assessment of nonresponse, there will be two 
groups of patients entering the double-blind treatment phase:

Participants who meet the predefined nonresponse criteria: These participants will be 
randomized to receive nasal spray treatment with either placebo, esketamine 56 mg, or 
esketamine 84 mg.

Participants who do not meet the predefined nonresponse criteria: For ethical reasons, these 
participants will also be randomized to receive nasal spray treatment with either placebo, 
esketamine 56 mg, or esketamine 84 mg, however they will not be included in the primary 
efficacy analysis set (ie, a separate randomization list will be used). 
Previous studies have shown onset of efficacy with esketamine within a day, and durability of an 
antidepressant effect with repeated dosing. Based on the completed phase 2 and 3 studies, the 
treatment duration of 4 weeks was selected to demonstrate the treatment effect of esketamine 
(primary endpoint). To demonstrate an early onset of efficacy with esketamine treatment, Day 2 
was selected as the key secondary endpoint.
The open label treatment/observation phase was designed to provide an opportunity for TRD 
patients completing the double-blind treatment phase to receive esketamine nasal spray, an 
effective treatment for TRD. This phase will have a recommended dosing frequency that allows 
for induction and stabilization of treatment with esketamine nasal spray. Participants not willing 
to receive esketamine can also enter this phase to be observed only, while receiving standard-of-
care treatment for depression. A 3-month duration is provided to help participants receiving 
esketamine transition to available long-term care, if appropriate.
For participants entering the follow-up phase, the one-week duration following the last visit of the 
double-blind or open-label treatment phase will allow sufficient time to assess safety and 
tolerability after cessation of nasal spray study medication, including potential withdrawal 
symptoms.
Treatment Groups and Dose Selection
The 3 treatment groups in the double-blind treatment phase are:

Esketamine nasal spray (56 mg)

Esketamine nasal spray (84 mg)

Placebo nasal spray
The treatment groups will allow for an evaluation of the efficacy, safety, and tolerability of 2 fixed 
doses of esketamine nasal spray as compared with placebo nasal spray in participants with TRD. 


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Study Drug
The data from Study ESKETINTRD2003 Panel A, phase 3 studies and MDSI studies support the 
hypotheses that both the 56-mg and 84-mg doses are effective as a treatment for depression in 
participants with TRD, that they have a rapid onset of effect, and that 2 treatment sessions per 
week can sustain the response throughout the 4 week duration of the double-blind treatment phase. 
In addition, the 56-mg and 84-mg dosages were generally well tolerated by participants.
The dosing frequencies selected for the open-label treatment/observation phase are based on the 
data from the completed phase 3 studies, ESKETINTRD3003 and ESKETINTRD3004. The 
dosing frequency reduced from twice a week to weekly for a duration of 4 weeks, and then 
individualized to either weekly or every other week based on clinical judgment, can stabilize and 
maintain the response throughout the long-term treatment.
Blinding, Control, Study Phase, Intervention Groups
A placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of active intervention. 
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. 
Blinded intervention will be used to reduce potential bias during data collection and evaluation of 
clinical endpoints.
Blinded, site-based MADRS raters will be used to minimize the risk of unblinding the treatment 
assignment. Different site raters will perform efficacy and safety assessments; clinicians who 
perform the MADRS assessments will be different from those who evaluate safety assessments 
(eg, vital signs) and AEs. Raters for the MADRS will not be allowed to access or to review 
participant safety records, supervise administration of study medication nor observe patients in the 
2-hour post dose observation period; therefore, they will not provide clinical care for participants.
Pharmacokinetic Assessments
PK samples will be obtained during the study for measurement of the plasma concentrations of 
esketamine, noresketamine, and/or additional metabolites, if warranted.
Pharmacogenomic (DNA & RNA) Evaluations
It is recognized that genetic variation and variations in transcription can be important contributory 
factors to inter-individual differences in drug distribution and response and can also serve as a 
marker for disease susceptibility and prognosis. Pharmacogenomic research may help to explain 
inter-individual variability in clinical outcomes and may help to identify population subgroups that 
respond differently to a drug. 


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The goal of the pharmacogenomic component is to collect DNA and RNA to allow the 
identification of genetic, epigenetic, and transcription factors that may influence the PK, PD, 
efficacy, safety, or tolerability of esketamine and to identify factors associated with MDD. 
4.2.1.
Participant Input Into Design 
Not applicable
4.2.2.
Study-Specific Ethical Design Considerations
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. 
Pharmacogenomic sample testing is optional and requires additional consent of the participant.
Clinical Study in Treatment-resistant Major Depression
Major depressive disorder is a common, severe, chronic, and often life-threatening illness. It is 
now the leading cause of disability worldwide. While there are a number of antidepressants 
approved for the treatment of depression, the response to them in patients who do not benefit after 
the first two antidepressants is much lower, which is often referred to as TRD. There is a clear 
need to develop novel and improved therapeutics for TRD. 
Esketamine nasal spray was recently approved by the FDA for treatment of TRD in adults used in 
conjunction with an oral antidepressant. There is no systematic data available on use of esketamine 
as monotherapy. As patients may often not tolerate or discontinue the oral antidepressant for safety 
or tolerability, its necessary to know whether esketamine is efficacious when used as monotherapy.
Justification for Using Placebo 
To assess the potential efficacy of a new compound for the treatment of major depression requires 
adequate and well-controlled clinical studies. For a new compound, this can be achieved either 
through a placebo-controlled study or through a study comparing it to an active comparator 
through a noninferiority design. For non-inferiority studies, previous placebo-controlled studies 
have to show consistently the superiority of the active standard drug to placebo. Nearly half of the 
studies with antidepressants fail even with previously proven antidepressants, making assay 
sensitivity difficult to establish and thus, a noninferiority design invalid.8 Recent analyses have 
shown response to placebo varies considerably from 10% to 55%. Therefore, randomized, 
controlled studies that rely on comparison with standard antidepressants alone will generate 
unreliable results with limited assay sensitivity.
The completed phase 3 studies of esketamine in TRD all initiated esketamine with a newly initiated 
oral AD. This was done in part due to concerns about randomizing patients with a serious condition 
like TRD to placebo treatment. However, patients with TRD in the phase 3 studies showed an 
unexpectedly strong response to placebo nasal spray and oral AD, even at earlier timepoints where 


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oral AD was unlikely to have taken effect and appeared similar to that seen with other oral AD 
monotherapy studies. 
Therefore, the use of a placebo-controlled study remains the gold standard for assessment of 
efficacy of new compound to allow for scientifically meaningful results. There is no known risk 
of irreversible harm in short term placebo-controlled studies. In a meta-analysis7 of drug studies 
conducted in major depression, it was reported that participants did not have higher rates of suicide 
behaviors or attempts in the placebo group compared with those receiving an active AD. These 
studies show annual suicide rates of 0.8% on the investigational drug, 0.7% on the active 
comparator, and 0.4% on placebo. Placebo-controlled studies in major depression are ethically and 
scientifically justifiable.1,8,13
Precautions to Ensure Participant Safety in the Study 
Participants may participate in the study only if they have adequate capacity to give consent and 
after fully understanding the potential risks and giving an informed consent. The probability of 
receiving placebo and the concept of random assignment will be explained to the participant. Only 
participants who have not adequately responded to their antidepressant medications and continue 
to have moderate to severe depression where a clinician would consider changing it for lack of 
response or poor tolerability, in addition to meeting the severity criteria for the study, will be 
enrolled. Current antidepressant medications will need to be tapered and discontinued prior to 
starting a mandatory 2-week antidepressant drug-free period prior to randomization. Withdrawal 
and/or discontinuation symptoms may be challenging for some patients. However, there are a 
number of strategies including use of rescue medications that may be used to minimize discomfort 
to participants.6
The duration of the study is short, minimizing the time on placebo. Participants in the study will 
be monitored very closely with in-person visits at least twice a week during the double-blind phase. 
Safety evaluations will include evaluation of suicidal ideation/behavior at each clinic visit. At any 
point in the study, the participant may withdraw consent, discontinue study intervention and 
receive standard-of-care therapy for depression, or be removed from the study by the investigator 
if there are any clinical concerns and provisions for appropriate and immediate clinical triage as 
necessary. A short-term placebo-controlled study may be conducted with reasonable expectation 
of patient safety.
Esketamine nasal spray is made available through an open label phase for all eligible participants 
who complete the 4-week double-blind treatment phase.
The total blood volume to be collected is considered to be within the normal range allowed for this 
participant population over this time frame. The approximate blood volume to be collected is 
93.5 mL, which will be less than a Red Cross blood donation.
Justification for Dose
Doses selected (56 mg and 84 mg) are based on the United States Prescribing Information (FDA 
approved label)11 for SPRAVATO™.


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End of Study Definition
End of Study Definition
The end of study is considered as the last scheduled study assessment shown in the Schedule of 
Activities 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.
Phase and Study Completion Definitions
A participant will be considered to have completed the double-blind treatment phase of the study 
if the Day 28 study visit is completed. Note: If all scheduled study procedures for the Day 28 visit 
are not performed, at least the MADRS for this visit must be completed for the participant to be 
considered as having completed the double-blind treatment phase.
A participant will be considered to have completed the open-label treatment/observation phase of 
the study if the Week 16 study visit is completed. 
A participant will be considered to have completed the study if he/she completed the double-blind 
treatment phase and the follow up visit (if the subject did not enroll in the open-label phase) or 
completed the double-blind, open-label phases and the follow-up visit.
5.
STUDY POPULATION
Screening procedures for eligible participants will be performed per Section 1.3, Schedule of 
Activities. Refer to Section 5.3, 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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Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study: 
1.
At the time of signing the informed consent form (ICF), participant must be a man or 
woman 18 years of age (or older if the minimum legal age of consent in the country in 
which the study is taking place is >18) or older.
2.
Criterion modified per Amendment 2
2.1. Participant must meet the DSM-5 diagnostic criteria for single-episode MDD (if 
single episode MDD, the duration of the episode must be ≥2 years) or recurrent MDD, 
without psychotic features, based upon clinical assessment and confirmed by the MINI. 
Participants 65 years of age or older must have had the first onset of depression prior to 
55 years of age.
3.
Participant must have had nonresponse (≤25% improvement) to ≥2 oral antidepressant 
treatments in the current episode of depression, assessed using the MGH-ATRQ, and 
confirmed by documented records (eg, medical/pharmacy/prescription records or a letter 
from a treating physician).
4.
Participant must have an IDS-C30 total score of ≥34.
5.
The participant’s current major depressive episode, depression symptom severity, and 
antidepressant treatment response in the current depressive episode, must be confirmed 
by the SAFER Interview.
6.
Participant must be medically stable on the basis of physical examination, medical 
history, vital signs (including blood pressure), and 12-lead ECG performed in the 
screening phase. If there are any abnormalities that are not specified in the inclusion and 
exclusion criteria, the determination of their clinical significance must be determined by 
the investigator and recorded in the participant's source documents and initiated by the 
investigator.
7.
Participant must be medically stable on the basis of clinical laboratory tests performed in 
the screening phase. If the results of the serum chemistry panel, hematology, or urinalysis 
are outside the normal reference ranges, the participant may be included only if the 
investigator judges the abnormalities or deviations from normal to be not clinically 
significant or to be appropriate and reasonable for the population under study. This 
determination must be recorded in the participant's source documents and initialed by the 
investigator.

Participants with a pre-existing history of thyroid disease/disorder who are 
treated with thyroid hormones must be on a stable dosage for 3 months prior to 
the start of the screening phase.


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
For any participant (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.
8.
Participant must be comfortable with self-administration of nasal spray medication and 
be able to follow the nasal spray administration instructions provided.
9.
Criterion modified per Amendment 1
9.1. A woman of childbearing potential must have a negative highly sensitive serum 
(β-human chorionic gonadotropin [β-hCG]) at the start of screening and a negative urine 
pregnancy test must be obtained before the first dose of study drug on Day 1, prior to 
randomization.
10.
Criterion deleted per Amendment 1
11.
Criterion modified per Amendment 1
11.1. A woman must be (as defined in Section 10.5, Appendix 5: Contraceptive and 
Barrier Guidance and Collection of Pregnancy Information)
a.
Not of childbearing potential
b.
Of childbearing potential and
Practicing a highly effective, user-independent (preferably) or user-
dependent 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 6 weeks after last dose. Examples 
of highly effective methods of contraception are located in Section 10.5, 
Appendix 5 Contraceptive and Barrier Guidance and Collection of Pregnancy 
Information. 
12.
Criterion deleted per Amendment 1
13.
Criterion modified per Amendment 1
13.1. A male participant must agree not to donate sperm for the purpose of reproduction 
during the study and for a minimum of 90 days after receiving the last dose of study 
intervention.
A male participant who is sexually active with a woman of childbearing potential must 
be practicing a highly effective method of contraception with his female partner (for 
examples of highly effective methods of contraception, please refer to Section 10.5, 
Appendix 5: Contraceptive and Barrier Guidance and Collection of Pregnancy 
Information) during the study (ie, from Day 1 of the double-blind treatment phase prior 


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to administration of the first dose of study intervention) and for a minimum of 90 days 
after receiving the last dose of the study intervention.
14.
Criterion modified per Amendment 1
14.1. Participant must be willing and able to adhere to the requirements and restrictions 
specified in this protocol.
15.
Each participant must be able to read and write. The participant 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.
16.
Participant must sign a separate informed consent form if he or she agrees to provide 
optional samples for pharmacogenomic research. Refusal to give consent for the optional 
pharmacogenomic research samples does not exclude a participant from participation in 
the study.
Exclusion Criteria 
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study: 
1.
The participant has used ketamine/esketamine (lifetime).
2.
The participant’s depressive symptoms have previously demonstrated nonresponse to 
an adequate course of treatment with ECT in the current major depressive episode, 
defined as at least 7 treatments with unilateral/bilateral ECT.
3.
Participant has received vagal nerve stimulation (VNS) or has received deep brain 
stimulation (DBS) in the current episode of depression.
4.
Participant 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.


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5.
Participant has homicidal ideation/intent, per the investigator’s clinical judgment, or 
has suicidal ideation with some intent to act within 6 months prior to the start of the 
screening phase, per the investigator’s clinical judgment or based on the C-SSRS, 
corresponding to a response of “Yes” on Item 4 (active suicidal ideation with some 
intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan 
and intent) for suicidal ideation on the C-SSRS, or a history of suicidal behavior within 
the past year prior to the start of the screening phase. Participants reporting suicidal 
ideation with intent to act or suicidal behavior prior to the start of the double-blind 
treatment phase should be excluded.
6.
Participant has a history of moderate or severe substance or alcohol use disorder 
according to DSM-5 criteria, except nicotine or caffeine, within 6 months before the 
start of the screening phase.
a.
A history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid
diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) 
hallucinogen-related use disorder is exclusionary.
7.
Participant has a current or history of seizures (uncomplicated childhood febrile 
seizures with no sequelae are not exclusionary).
8.
Criterion modified per Amendment 1
8.1. Participant has one of the following cardiovascular-related conditions:
a.
Cerebrovascular disease with a history of stroke, transient ischemic attack or 
history of intracerebral hemorrhage.
b.
Aneurysmal vascular disease (including intracranial, thoracic, or abdominal 
aorta, or peripheral arterial vessels) or arteriovenous malformation.
c.
Coronary artery disease with myocardial infarction, unstable angina, or 
revascularization procedure (eg, coronary angioplasty or bypass graft surgery) 
within 12 months before the start of the screening/prospective observational 
phase. 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.
d.
Hemodynamically significant valvular heart disease such as mitral 
regurgitation, aortic stenosis, or aortic regurgitation.
e.
New York Heart Association (NYHA) Class III-IV heart failure of any 
etiology (details will be provided in an attachment to the full protocol).
9.
Participant has a history of uncontrolled hypertension despite diet, exercise, or 
antihypertensive therapy at the start of the screening phase or any past history of 
hypertensive crisis or ongoing evidence of uncontrolled hypertension defined as a 
supine SBP >140 mmHg or DBP >90 mmHg during screening phase which continues 
to be above this range with repeated testing during this phase. Note: On Day 1 of the 


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double-blind treatment phase prior to randomization a supine SBP >140 mmHg or DBP 
>90 mmHg is exclusionary.
a.
A potential participant may have his/her current antihypertensive 
medication(s) adjusted during the screening phase and be re-evaluated to 
assess their blood pressure control. 
10.
Criterion modified per Amendment 1
10.1. Participant has a history of, or symptoms and signs suggestive of, liver cirrhosis 
(eg, esophageal varices, ascites, and increased prothrombin time) OR alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) values ≥3× the upper limit 
of normal (ULN) or total bilirubin >1.5× the ULN in the screening phase.
a.
Repeat of screening test for abnormal ALT and AST is permitted during the 
screening period provided per investigator discretion and provided there is an 
alternative explanation for the out of range value.
b.
For elevations in bilirubin if, in the opinion of the investigator and agreed upon 
by the sponsor’s medical officer, the elevation in bilirubin is consistent with 
Gilbert’s disease, the participant may participate in the study.
11.
Criterion modified per Amendment 1
11.1. Participant has positive test result(s) for drugs of abuse (eg, barbiturates, 
methadone, 
opiates, 
cocaine, 
phencyclidine 
(PCP), 
MDMA, 
and 
amphetamine/methamphetamine) at the start of the screening phase or Day 1 of 
the double-blind treatment phase prior to randomization.
a.
Participants who have a positive test result at screening due to prescribed 
psychostimulants (eg, amphetamine, methylphenidate) taken for any 
indication must discontinue the medication at least 2 weeks before Day 1 of 
the double-blind treatment phase (prior to randomization) in accordance with 
Section 6.5, Concomitant Therapy. The result of the Day 1 (prior to 
randomization) test for drugs of abuse must be negative for the participant to 
be randomized.
b.
Otherwise, participants who have a positive test result at screening due to 
prescribed/over-the-counter opiates or barbiturates may be permitted to 
continue in the screening phase if the medication is discontinued at least 
1 week or 5 half-lives, whichever is longer, before Day 1 of the double-blind 
treatment phase (prior to randomization) in accordance with Section 6.5, 
Concomitant Therapy. The result of the Day 1 (prior to randomization) test for 
drugs of abuse must be negative for the participant to be randomized.

Retesting is not permitted for positive test result(s), except for reasons 
stated above.
c.
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. A positive test for cannabinoids at the start of the screening phase 


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is not exclusionary; however, a positive test result for cannabinoids predose 
on Day 1 of the double-blind treatment phase is exclusionary.
12.
Participant has uncontrolled diabetes mellitus, as evidenced by HbA1c >9% in the 
screening phase or history in the prior 3 months prior to the start of the screening phase 
of diabetic ketoacidosis, hyperglycemic coma, or severe hypoglycemia with loss of 
consciousness.
13.
Participant has any anatomical or medical condition that, per the investigator’s clinical 
judgment based on assessment, may impede delivery or absorption of nasal spray study 
drug.
14.
Participant has a history of malignancy within 5 years before the start of the screening 
phase (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in 
situ of the cervix, or malignancy that, in the opinion of the investigator, with 
concurrence with the sponsor's medical monitor, is considered cured with minimal risk 
of recurrence).
15.
Participant has known allergies, hypersensitivity, intolerance, or contraindications to 
esketamine/ketamine and/or its excipients.
16.
Participant has taken any prohibited therapies that would not permit dosing on Day 1, 
as noted in Section 6.5, Concomitant Therapy.
17.
Participant is taking a total daily dose of benzodiazepines greater than the equivalent of 
6 mg/day of lorazepam at the start of the screening phase.

Note: Temporary dose increases of benzodiazepines beyond the equivalent of 
6 mg/day lorazepam, or initiation of new benzodiazepines, are permitted during 
the screening phase if needed to assist with antidepressant taper/discontinuation 
and/or the antidepressant-free period. However, the dose must be reduced to 
less than or equal to the equivalent of 6 mg/day of lorazepam before 
randomization in the double-blind treatment phase. 
18.
Participant 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 has participated in 2 or more MDD or other psychiatric condition 
clinical interventional studies (with different investigational medication) in the previous 
1 year before the start of the screening phase, or is currently enrolled in an 
investigational interventional study.
19.
Participant is a woman who is pregnant, breastfeeding, or planning to become pregnant 
while enrolled in this study or within 6 weeks after the last dose of nasal spray study 
drug.


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20.
Participant plans to father a child while enrolled in this study or within 90 days after the 
last dose of study intervention.
21.
Participant has a diagnosis of acquired immunodeficiency syndrome. Human 
immunodeficiency virus testing is not required for this study.
22.
Participant has any condition or situation/circumstance 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.
23.
Participant is an employee of the investigator or study site, with direct involvement in 
the proposed study or other studies under the direction of that investigator or study site, 
as well as family members of the employees or the investigator.
24.
Participant has severe renal impairment (creatinine clearance <30 mL/min).
25.
Participant has not completed the mandatory 2-week antidepressant drug-free period 
prior to Day 1 of the double-blind treatment phase.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening 
and/or Day 1 prior to randomization (as applicable). 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 the participant no longer meets all 
eligibility criteria, then the participant should be excluded from participation in the study. 
Section 5.3, Screen Failures, describes options for retesting. The required source documentation 
to support meeting the enrollment criteria are noted in Section 10.3, Appendix 3, Regulatory, 
Ethical, and Study Oversight Considerations.
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.
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. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened only after Sponsor's approval as assessed on a case by case basis. 


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6.
STUDY INTERVENTION AND CONCOMITANT THERAPY
Study Interventions Administered
Esketamine will be supplied as a nasal spray device. Each device contains 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 two sprays (one to each nostril) 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).
Placebo will be supplied as in matching nasal spray devices. Each device contains a solution of 
water for injection with a bittering agent (0.001 mg/mL denatonium benzoate) added to simulate 
the taste of the nasal spray esketamine solution. Each nasal spray device contains 2 sprays of 
placebo solution.
Instructions for use documents (participant and healthcare provider versions) for nasal spray study 
drug administration will be provided as separate documents. Details regarding study drug 
administration will be recorded in the source documents and the eCRF.
If the participant has nasal congestion on the dosing day, an intranasal decongestant can be used 
to reduce congestion, or the dosing day can be delayed (per the permitted visit window; see the 
Schedule of Activities table). If an intranasal decongestant is used to reduce congestion, it cannot 
be used within 1 hour prior to nasal spray study drug dosing.
Food will be restricted for at least 2 hours before each administration of study drug. Drinking of 
any fluids will be restricted for at least 30 minutes before the first nasal spray. Participants must 
abstain from using alcohol within 24 hours before and after each nasal spray treatment session. If 
a participant appears intoxicated, dosing should not occur on that day.
Prior to the first nasal spray dose on Day 1, participants will practice spraying (into the air, not 
intranasally) a demonstration nasal spray device that is filled with a placebo solution.
Participants will be dosed as described in Section 4 under “Double-blind Treatment Phase 
(4 weeks)” and “Open-label Treatment/Observation Phase (up to 3 months)”. 
Guidance for Blood Pressure Monitoring on Nasal Spray Treatment Session Days:
Given the potential for treatment-emergent transient elevation in systolic and diastolic blood 
pressure, the following guidance should be followed on dosing days:

If subsequent to fulfilling the inclusion and exclusion criteria on Day 1 (ie, applicable for all 
other nasal spray treatment session days after Day 1), a participant’s predose SBP is 
>140 mmHg and/or DBP is >90 mmHg, it is recommended to repeat the blood pressure 
measurement after the participant rests in sitting or recumbent position. If after rest and 
repeated measurements, predose SBP is >140 mmHg and/or DBP is >90 mmHg, then dosing 
should be postponed, and the participant scheduled to return on the following day or within 
the given visit window. If the blood pressure elevation persists on the next visit, the participant 


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will be scheduled for a consultation by cardiologist, other specialist, or primary care physician, 
prior to further dosing.

If at any postdose time point on the dosing day, the SBP is 180 mmHg but <200 mmHg 
and/or the DBP is 110 mmHg but <120 mmHg, further nasal spray dosing should be 
interrupted and the participant should be referred to a cardiologist, other specialist, or primary 
care physician for a follow-up assessment.

After the assessment by a cardiologist, other specialist, or primary care physician, if 
recommended by the referring doctor and considered appropriate according to the clinical 
judgment for the participant to continue in the study, then the participant may continue 
with nasal spray dosing if the predose blood pressure at the next scheduled visit is within 
the acceptable range (see bullet point above).

If at any postdose time point on the dosing day the SBP is 200 mmHg and/or the DBP is 
120 mmHg, the participant must discontinue from further dosing and the participant should 
be referred to a cardiologist, other specialist, or primary care physician for a follow-up 
assessment.

At 1.5 hours postdose, if the SBP is 160 mmHg and/or the DBP 100 mmHg, assessments 
should continue every 30 minutes until:

the blood pressure is <160 mmHg SBP and <100 mmHg DBP, or 

in the investigator’s clinical judgment, the participant is clinically stable and can be 
discharged from the study site, or 

the participant is referred for appropriate medical care, if clinically indicated.

If the blood pressure remains ≥180 mmHg SBP and/or ≥110 mmHg DBP, 2 hours after 
dosing, the participant should be referred for immediate medical treatment.
Study intervention administration must be captured in the source documents and the CRF.
Esketamine nasal spray will be manufactured and provided under the responsibility of the sponsor. 
Refer to the Investigator's Brochure5 for a list of excipients.
For details on rescue medications, refer to Section 6.7.1, Rescue Medication. For a definition of 
study intervention overdose, refer to Section 8.4, Treatment of Overdose.
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study intervention must be stored at controlled room temperatures ranging from 59°F to 86°F
(15°C to 30°C). 
Refer to the study site investigational product and procedures manual (IP manual) for additional 
guidance on study intervention preparation, handling, and storage.


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Accountability
The investigator is responsible for ensuring that all study intervention received at the site is 
inventoried and accounted for throughout the study. The dispensing of study intervention to the 
participant, and the return of study intervention from the participant must be documented on the 
intervention accountability form. Participants must be instructed to return all original containers, 
whether empty or containing study intervention. The study intervention administered to the 
participant must be documented on the intervention accountability form. All study intervention 
will be stored and disposed of according to the sponsor's instructions. Study-site personnel must 
not combine contents of the study intervention containers.
Study intervention 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 as per local 
requirements for Schedule III controlled substances, under appropriate environmental conditions. 
Unused study intervention, and study intervention 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, or used returned study intervention for destruction, will 
be documented on the intervention return form. When the study site is an authorized destruction 
unit and study intervention supplies are destroyed on-site, this must also be documented on the 
intervention return form.
Study intervention should be dispensed under the supervision of the investigator or a qualified 
member of the study-site personnel. Study intervention will be supplied only to participants 
participating in the study. Returned study intervention must not be dispensed again, even to the 
same participant. Study intervention may not be relabeled or reassigned for use by other 
participants. The investigator agrees neither to dispense the study intervention from, nor store it 
at, any site other than the study sites agreed upon with the sponsor. Further guidance and 
information for the final disposition of unused study interventions are provided in the IP manual.
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 3 intervention groups based on a computer-generated randomization schedule prepared 
before the study by or under the supervision of the sponsor. The randomization will be balanced 
by using randomly permuted blocks and will be stratified by study site and antidepressant 
treatment status (on- or off-treatment) at screening entry (refer to Section 10.6 for a list of 
applicable treatments). Two separate randomization lists will be generated, a list for those 
participants who meet the predefined nonresponse criteria and a list for those participants do not 
meet the nonresponse criteria. The interactive web response system (IWRS) will assign a unique 
intervention code, which will dictate the intervention assignment and matching study intervention 
kit for the participant. The requestor must use his or her own user identification and personal 


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identification number when contacting the IWRS and will then give the relevant participant details 
to uniquely identify the participant.
Blinding
To maintain the study blind during the double-blind phase, the study intervention container will 
have a label containing the study name, study intervention number, and reference number. 
However, if it is necessary for a participant's safety, the study blind may be broken and the identity 
of the study intervention ascertained. The study intervention number will be entered in the CRF 
when the study intervention is dispensed. The study interventions will be identical in appearance 
and will be packaged in identical containers.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual participant.
Conditions to maintain the blind of MADRS raters are specified in Section 8.1.
Data that may potentially unblind the intervention assignment (ie, study drug concentrations, study 
drug preparation/accountability data, treatment allocation, and biomarker or other specific 
laboratory data) will be handled with special care to ensure that the integrity of the blind is 
maintained and the potential for bias is minimized. This can include making special provisions, 
such as segregating the data in question from view by the investigators, clinical team, or others as 
appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until all participants have completed 
the study and the database is finalized. The investigator may in an emergency determine the 
identity of the intervention by contacting the IWRS. While the responsibility to break the 
intervention code in emergency situations resides solely with the investigator, it is recommended 
that the investigator contact the sponsor or its designee if possible, to discuss the particular 
situation, before breaking the blind. Telephone contact with the sponsor or its designee will be 
available 24 hours per day, 7 days per week. In the event the blind is broken, the sponsor must be 
informed as soon as possible. The date, time, and reason for the unblinding must be documented 
by the IWRS in the appropriate section of CRF, and in the source document. The documentation 
received from the IWRS indicating the code break must be retained with the participant's source 
documents in a secure manner.
Participants who have had their intervention assignment unblinded should continue to return for 
scheduled evaluations, but the nasal spray treatment would be discontinued.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. 


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Study Intervention Compliance
Participants will self-administer nasal spray treatment under the direct supervision of a healthcare 
provider to be compliant with study intervention administration. During the course of the study, 
the investigator or designated study-site personnel will be responsible for providing additional 
instruction to reeducate any participant who is not compliant with taking the study intervention.
Dose Modification
No dose modifications are allowed during the double-blind treatment phase.
Participants in the open-label treatment/observation phase, who have opted to receive open-label 
esketamine will receive 56 mg on Day 28 regardless of the participant's study drug/dose 
assignment in the double-blind phase. Subsequent doses can remain the same or be adjusted 
(56 mg or 84 mg) based on efficacy and tolerability. There will be a recommended dosing 
frequency of twice weekly (maximum) for Weeks 5 to 8, followed by once weekly dosing from 
Weeks 9 to 12. From Week 13 to Week 16, the dosing frequency (weekly or every other week) 
will be based on clinical judgment. Dosing frequency should be individualized to the least frequent 
dosing to maintain remission/response.
6.5.1.
Retreatment Criteria 
If applicable, a need for retreatment must be discussed with the sponsor medical monitor and a 
decision will be taken on a case by case basis.
Continued Access to Study Intervention After the End of the Study
There is no study intervention following the end of the study.
Participants will be instructed that study intervention will not be made available to them after they
have completed/discontinued study intervention and that they should return to their primary 
physician to determine standard of care.
Concomitant Therapy
Prestudy therapies administered up to 30 days before entering screening phase must be recorded 
at the start of screening.
All antidepressant treatment(s) (pharmacological, including adjunctive treatments and/or 
non-pharmacological eg ECT, VNS, DBS, psychotherapy) taken during the current depressive 
episode (ie, including those taken more than 30 days prior to the start of the screening phase) will 
be recorded at the start of the screening phase. All antidepressant treatments listed on the MGH-
ATRQ, as well as any not listed on the MGH-ATRQ, used as antidepressant treatment in the 
current depressive episode must be recorded in "Concomitant Therapy" eCRF.
Participants should continue to take their permitted concomitant medications (eg, antihypertensive 
medications) at their regular schedule; however, restrictions as outlined in this section under 
Prohibited Medications (table below) should be taken into account. Of note, if a participant has 


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routinely taken oral antihypertensive medications in the morning on dosing days, the morning dose 
should be taken prior to nasal spray dosing.
Concomitant therapies (including psychotherapy) must be recorded throughout the study 
beginning with signing of the informed consent and continuing up to the last visit. 
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens, or other specific categories of interest) different from the study 
intervention must be recorded in the CRF. Recorded information will include a description of the
type of therapy, duration of use, dosing regimen, route of administration, and indication.
Modification of an effective preexisting therapy should not be made for the explicit purpose of 
entering a participant into the study.
The following concomitant medications are allowed within the study.

Participants who were taking benzodiazepines and/or permitted non-benzodiazepine sleep 
medications (eg, zolpidem, zaleplon) during the screening phase can continue these 
medications (at dosages equal to or less than the equivalent of 6 mg/day of lorazepam) during 
the double-blind treatment phase. No dose increases beyond the equivalent of 6 mg/day of 
lorazepam, or new benzodiazepine medications are permitted during the double-blind 
treatment phase, with the exception of the use of permitted benzodiazepine rescue medication. 
Benzodiazepines and non-benzodiazepine sleeping medication (eg, zolpidem, zaleplon, 
eszopiclone, and ramelteon) are prohibited within 12 hours prior to the start of each nasal 
spray treatment session. Close monitoring for sedation is necessary when used with 
esketamine.

ECT, DBS, transcranial magnetic stimulation, and VNS are prohibited from study entry 
through the end of the double-blind treatment phase.

Participants receiving psychotherapy (including cognitive behavioral therapy) can continue 
receiving psychotherapy; however, psychotherapy must have been ongoing for the last 
3 months prior to the start of the screening phase. Any form of new psychotherapy is 
prohibited during the screening and double-blind phase of this study.
Prohibited Concomitant Medications With Nasal Spray Study Medication (esketamine or 
placebo)
This list of medications is not all-inclusive; if necessary, please contact the medical monitor for 
any questions regarding a medication(s).
Please refer to the local prescribing information of the participant’s non-study medications for 
information regarding prohibited concomitant medications. 
Except where specifically noted, the prohibited medications listed in the following table are 
prohibited from 1 week (or 5 half-lives, whichever is longer) prior to the first dose of nasal spray 
study medication until after the last dose of nasal spray study medication.


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Note in the following table: N, Prohibited; Y, Permitted, with restrictions (please refer to the 
column labeled “Comments” for additional guidance).
Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for Prohibition
ADHD medications (eg, 
atomoxetine, guanfacine); 
psychostimulants (eg, 
amphetamines, 
methylphenidate)
N
N
Not allowed during the 2-week 
mandatory antidepressant-free period 
prior to randomization and during the 
double-blind phase. Allowed for 
patients switched to standard-of care 
treatment during the double-blind 
treatment phase and during the open-
label treatment/observation phase, but 
must not be taken within 12 hours 
prior to the intranasal treatment 
session.
Safety
Potential impact on 
efficacy
Anorexiants 
(eg, phentermine, 
phendimetrazine)
N
N
Safety
Anticholinesterase 
inhibitors
N
N
Participant population is 
excluded
Anticonvulsants  
Y
Y
Participants with seizures are 
excluded. 
Note: Anticonvulsants used for 
indications other than seizures may 
be allowed (eg, valproate for 
migraine; pregabalin)
Safety and PD interaction
Antidepressants and 
medications used for 
treatment of depression
N
N
Not allowed within 2 weeks of 
mandatory antidepressant-free period 
prior to randomization and during the 
double-blind phase. Allowed for 
patients switched to standard-of care 
treatment during the double-blind 
treatment phase and during the open-
label treatment/observation phase. 
Refer to Section 10.6 for a list of 
applicable medications.
Potential impact on 
efficacy
Antipsychotics
N
N
Not allowed within 2 weeks of 
mandatory antidepressant-free period 
prior to randomization and during the 
double-blind phase
Allowed for patients switched to 
standard-of care treatment during the 
double-blind treatment phase and 
during the open-label 
treatment/observation phase.
Potential impact on 
efficacy
Benzodiazepines (at 
dosages equal to or less 
than the equivalent of 
6 mg/day lorazepam 
except of temporary 
increases allowed during 
taper and antidepressant-
free screening periods) 
and non-benzodiazepine 
sleeping medication 
(including: zolpidem, 
zaleplon, eszopiclone, and 
ramelteon)
Y
Y
Prohibited within 12 hours prior to 
the start of each nasal spray treatment 
session or cognition testing. Close 
monitoring for sedation is necessary 
when used as concomitant medication 
with esketamine.
Safety and PD interaction
Benztropine
Y
N
Prohibited if use is continuous and 
prohibited within 12 hours prior to 
the start of cognition testing
Safety and PD interaction


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Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for Prohibition
Chloral hydrate, valerian
N
N
Safety and PD interaction
Clonidine
Y
Y
Use for blood pressure control is 
allowed.
Corticosteroids (systemic)
Y
N
Inhaled, intranasal, topical, and
ophthalmic steroids are not 
prohibited.
Intermittent IM/IV/PO corticosteroids 
are permitted with sponsor approval 
(chronic use prohibited).
Intranasally-administered 
corticosteroids should not be used 
from 1 hour prior to each nasal spray 
study medication administration.
PD interaction
Cough/cold 
preparations/nasal 
solutions containing 
vasoconstrictors, 
decongestants
Y
Y
Intranasally-administered 
decongestants (vasoconstrictors) 
should not be used from 1 hour prior 
to each nasal spray study medication 
administration.
Pseudoephedrine- containing 
products should not be used within 
12 hours prior to a nasal spray 
treatment session.
Safety and PD interaction
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 nasal spray study 
medication until at least 24 hours 
after the last dose of nasal spray study 
medication.
Examples (not all-inclusive): 
Efavirenz, nevirapine, barbiturates, 
carbamazepine, glucocorticoids, 
modafinil, oxcarbazepine, 
phenobarbital, phenytoin, rifabutin, 
rifampin, and St. John's wort
PK
Diphenhydramine
Y
N
Prohibited within 12 hours prior to 
the start of each nasal spray treatment 
session
Safety
Ketanserin
N
N
Safety
Memantine
N
N
PD interaction
Methyldopa
N
N
Safety and PD Interaction
Metyrosine
N
N
Safety and PD interaction
Non-vitamin K antagonist 
oral anticoagulation 
agents (eg, dabigatran, 
rivaroxaban, apixaban)
N
N
Safety
Opioids
N
N
With Sponsor approval, brief 
treatment with opiates may be 
allowed for treatment of acute 
injuries, etc.
Safety
Reserpine
N
N
PD interaction
Thyroid hormone 
supplement for treatment 
of thyroid condition only 
(not for depression)
N
Y
Safety


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Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for Prohibition
Thyroxine/ 
triiodothyronine (T3), 
thyroid hormone 
prescribed for depression
N
N
Potential impact on 
efficacy
Abbreviations: ADHD: attention deficit hyperactivity disorder; IM: intramuscular; IV: intravenous; N: Prohibited; PD: 
pharmacodynamics; PK: pharmacokinetics; PO: oral; Y: Permitted, with restrictions (please refer to the column labeled 
“Comments” for additional guidance).
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
6.7.1.
Rescue Medication 
The study site will supply rescue medication that will be obtained locally. The following rescue 
medications may be used:

For agitation or anxiety: As required, short-acting benzodiazepines, eg, lorazepam, 
alprazolam, midazolam. 

For nausea: As required, ondansetron 8 mg sublingually, metoclopramide (10 mg orally or IV 
or IM) or dimenhydrinate (25 to 50 mg, IV or IM) 

Transient increase in blood pressure should not be treated, as the blood pressure returns to 
predose values typically in 1.5-4 hours. The effect of any treatment may result in hypotension.
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
Discontinuation of Study Intervention
A participant's study intervention must be discontinued if:

The participant withdraws consent to receive study intervention

The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the participant to discontinue study intervention

The participant becomes pregnant Refer to Section 10.5, Appendix 5, Contraceptive Guidance 
and Collection of Pregnancy Information.

Major protocol deviation (to be assessed on a case by case basis)

Blind broken
If a participant discontinues study intervention for any reason (other than withdrawal of consent) 
before the end of the double-blind phase a participant should continue with the scheduled visits 
until end of the double-blind phase (Day 28). Completion of the double-blind treatment phase is 
required to enter the open-label treatment/observation phase of the study. For any participant who 
has not completed this phase (Day 28 visit or at least Day 28 MADRS assessment), an Early 
Withdrawal visit should be conducted within 1 week of the date of discontinuation. 


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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 to participate in the study

Death

Major protocol deviation (to be assessed on a case by case basis)

Positive Urine Drug Screen for PCP or cocaine at any time point during the study
When a participant withdraws before study completion, the reason for withdrawal is to be 
documented in the CRF and in the source document. If the reason for withdrawal from the study 
is withdrawal of consent, then no additional assessments are allowed.
Withdrawal of Consent
In the situation where a participant may be at risk for withdrawal of consent and is unable to return 
for scheduled visits at the protocol-defined frequency, the investigator may consider options for 
reduced follow-up. These may include (as local regulations permit):

Less frequent clinical visits (OL phase only)

Telephone, email, letter, social media, fax, or other contact with:

participant

relatives of the participant

participant’s physicians (general or specialist)

Review of any available medical records
Details regarding these contacts must be properly documented in source records including 
responses by participants.
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:

The collected samples will be retained and used in accordance with the participant's original 
informed consent for research samples.

The participant may withdraw consent for research samples, in which case the samples 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 
research samples and to request sample destruction. The sponsor study site contact will, in 
turn, contact the biomarker representative to execute sample destruction. If requested, the 
investigator will receive written confirmation from the sponsor that the samples have been 
destroyed.


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Withdrawal From the Optional Research Samples While Remaining in the Main Study
The participant may withdraw consent for optional research samples while remaining in the study. 
In such a case, the optional research samples 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 samples for research (refer to Long-term 
Retention of Samples for Additional Future Research in Section 10.3, Appendix 3, Regulatory, 
Ethical, and Study Oversight Considerations). In such a case, samples will be destroyed after they 
are no longer needed for the clinical study. Details of the sample retention for research are 
presented in the main ICF.
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization 
attempts should be made to obtain contact information from each participant, eg, home, work, and 
mobile telephone numbers and email addresses for both the participant as well as appropriate 
family members.
A participant will be considered lost to follow-up if the participant 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. Locator agencies may also be used as local regulations permit. 
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.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot 
reach the participant to inform them, their contact information will be transferred to another study 
site.
8.
STUDY ASSESSMENTS AND PROCEDURES 
Overview
The Schedule of Activities summarizes the frequency and timing of efficacy, PK, PD, biomarker, 
pharmacogenomic, safety, and other measurements applicable to this study.


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All participant-reported outcomes assessments should be conducted/completed before any tests, 
procedures, or other consultations to prevent influencing participant perceptions.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures 
be performed in the following sequence: MADRS, PHQ-9, CGI-S, C-SSRS, vital signs (predose), 
ECG, lab sampling, dosing of study medication, postdose vital signs and observation. Blood 
collections for PK and PD assessments should be kept as close to the specified time as possible. 
Actual dates and times of assessments will be recorded in the source documentation.
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.
The total blood volume to be collected from each participant will be approximately 93.5 mL 
(Table 1).
Table 1:
Volume of Blood to be Collected From Each Participant
Type of Sample
Volume per 
Sample (mL)
No. of Samples 
per Participant
Total Volume of 
Blood (mL) a
Screening Phase
TSH
2.5
1
2.5
Hematology, Chemistry b, c
3.5
1
3.5
Double-blind Treatment Phase
Hematology, chemistry
2.5
2
5.0
Pharmacokinetics
2.0
2
4.0
Biomarker: Protein  
30.0
2
60.0
Pharmacogenomics DNA d
6.0
1
6.0
Pharmacogenomics: RNA d
2.5
1
2.5
Open Label Treatment/Observational Phase
Hematology, chemistry
2.5
3
7.5
Follow-up Phase
Hematology, chemistry
2.5
1
2.5
Approximate volume of blood collected during the study
93.5 mL
Abbreviations: DNA, deoxyribonucleic acid; RNA, ribonucleic acid; TSH, thyroid-stimulating hormone
a)
Calculated as number of samples multiplied by amount of blood per sample.
b) Hematology, chemistry includes serum -hCG pregnancy tests (for women of childbearing potential), HbA1c, and lipid 
panel.
c)
As needed, HbA1c will be measured from the sample collected for hematology.
d) Blood samples will be collected only from participants who have consented to provide optional samples for research.
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 laboratory requisition 
form. If blood samples are collected via an indwelling cannula, an appropriate amount (1 mL) of 
serosanguineous fluid slightly greater than the dead space volume of the lock will be removed 
from the cannula and discarded before each blood sample is taken. After blood sample collection, 


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the cannula will be flushed with 0.9% sodium chloride, United States Pharmacopeia (or equivalent) 
and charged with a volume equal to the dead space volume of the lock. If a mandarin (obturator) 
is used, blood loss due to discard is not expected.
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: 

Protocol

Investigator’s Brochure

Pharmacy manual/study site investigational product and procedures manual

Procedural documents for SAFER Interview

Practice nasal spray devices

Instructions for Use documents (participant and healthcare provider version) for nasal spray 
study medication

Rater training procedural documents for select clinician administered assessments

MGH-ATRQ guidance document

Laboratory manual

Clinician and patient reported outcome questionnaires

Patient Reported Outcomes Completion Guidelines

IWRS Manual

ECG equipment and associated materials (eg, manual)

Electronic data capture (eDC) Manual

eSource Manual

Device and instructions for conducting and recording of remote interviews

Sample ICF
Efficacy Assessments 
The primary efficacy evaluation will be the MADRS total score. 
The MADRS is a clinician-rated scale designed to measure depression severity and detects changes 
due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 
(item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total 


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possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates 
apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability 
to feel (interest level), pessimistic thoughts, and suicidal thoughts. The test exhibits high interrater 
reliability. 
The MADRS will be performed by site-based raters via video teleconferencing during the study 
using the Structured Interview Guide for the MADRS. To minimize the risk of unblinding the 
treatment assignment, different site raters will perform efficacy and safety assessments; clinicians 
who perform the MADRS assessments will be different from those who evaluate safety 
assessments (eg, vital signs) and adverse events. Raters for the MADRS will not be allowed to 
access or to review participant safety records or supervise/observe study drug administration; 
therefore, they will not provide clinical care for participants. 
All MADRS assessments will be recorded for the purpose of quality monitoring.
The Clinical Global Impression – Severity (CGI-S) scale will be used to assess severity of 
depressive symptoms. The CGI-S provides an overall clinician-determined summary measure of 
the severity of the participant’s illness that takes into account all available information, including 
knowledge of the participant’s history, psychosocial circumstances, symptoms, behavior, and the 
impact of the symptoms on the participant’s ability to function.
The Patient Health Questionnaire 9-item (PHQ-9) is a participant-reported outcome measure that 
will be used to assess depressive symptoms. 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 recall period is 2 weeks.
Safety Assessments 
Adverse events will be reported and followed by the investigator as specified in Section 8.3, 
Adverse Events and Serious Adverse Events and Section 10.4, Appendix 4, Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event 
section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be 
followed by the investigator until resolution or until a clinically stable condition is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in Section 1.3, Schedule of Activities:

Monitoring of TEAEs, including TEAEs of special interest, pregnancy testing (for women of 
childbearing potential), and vital signs. 


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
C-SSRS, to assess potential suicidal ideation and behavior.
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS will be used to assess potential suicidal ideation and behavior. 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters 
Study to assess severity and track suicidal events through any treatment.9 It is a clinical interview 
providing a summary of both ideation and behavior that can be administered during any evaluation 
or risk assessment to identify the level and type of suicidality present. The C-SSRS can also be 
used during treatment to monitor for clinical worsening.
Two versions of the C-SSRS will be used in this study, the Baseline/Screening version, and the 
Since Last Visit version. The Baseline/Screening version of the C-SSRS will be used in the 
screening/prospective observational phase. In this version, suicidal ideation will be assessed at 
2 timepoints: “lifetime” and “in the past 6 months,” and suicidal behavior will be assessed at 
2 timepoints: “lifetime” and “in the past year.” All subsequent C-SSRS assessments in this study 
will use the Since Last Visit version, which will assess suicidal ideation and behavior since the 
participant’s last visit.
8.2.1.
Physical Examinations
A full physical examination, including body weight will be carried out at screening, double-blind 
treatment phase, open-label treatment/observational phase and follow-up phase as specified in the 
Schedule of Activities. Height will be measured at screening as specified in the Schedule of 
Activities.
8.2.2.
Vital Signs
Vital Signs (Temperature, Pulse/Heart Rate, Blood Pressure)
Blood pressure and pulse/heart rate measurements will be assessed supine with a completely 
automated device or using manual techniques.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest 
in a quiet setting without distractions (eg, television, cell phones).
For further details regarding blood pressure, see Section 6.1 under the subheading entitled 
"Guidance for Blood Pressure Monitoring on Nasal Spray Treatment Session Days."
Tympanic temperature is recommended.
8.2.3.
Electrocardiograms
Single, 12-Lead ECGs
During the collection of 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.


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All ECG tracings will be sent to a central ECG laboratory. The ECGs will be read at the scheduled 
time points and summarized by a central ECG laboratory. The central ECG laboratory will send 
the sponsor an electronic copy of the data for inclusion in the clinical database. In addition, the 
investigator or subinvestigator is required to review all ECGs at the study visit to assess for any 
potential safety concerns or evidence of exclusionary conditions prior to dosing.
8.2.4.
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will 
be collected as noted in Section 10.2, Appendix 2, Clinical Laboratory Tests. The investigator must 
review the laboratory results, document this review, and record any clinically relevant changes 
occurring during the study in the adverse event section of the CRF. The laboratory reports must be 
filed with the source documents.
8.2.5.
Suicidal Ideation and Behavior Risk Monitoring 
Treatment resistant depression is associated with higher risk of suicide attempt than that with major 
depression. Esketamine is considered to be an antidepressant. There has been some concern that 
antidepressants may be associated with an increased risk of suicidal ideation or behavior when 
given to some participants with TRD. Although this study intervention or other similar treatments 
in this 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 or during this clinical study. In the completed esketamine programs there 
were 4 cases of completed suicide, but the overall trend was in reduction of suicidal ideation.
Participants being treated with esketamine should be monitored appropriately and observed closely 
for suicidal ideation and behavior or any other unusual changes in behavior. 
Baseline assessment of suicidal ideation and behavior and intervention-emergent suicidal ideation 
and behavior will be assessed during the study using C-SSRS and adverse event reporting.
8.2.6.
Other Evaluations
Patient’s Awareness of Treatment-Arm Assignment Scale
To assess participants assessment of blinding, they will be asked to respond to the question “Which 
medication did you receive?” Their responses will be captured and scored as indicated in Table 2
and used to determine whether the participants can differentiate between the 2 treatments they may 
receive (esketamine nasal spray or placebo nasal spray).
Table 2:
Patient’s Awareness of Treatment-Arm Assignment Scale
Question: Which medication did you receive?
Response:
Code as:
Strongly believe the nasal spray treatment is esketamine
1
Somewhat believe the nasal spray treatment is esketamine
2
Don’t know 
3
Somewhat believe the nasal spray treatment is placebo
4
Strongly believe the nasal spray treatment is placebo
5


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Menstrual Cycle Tracking
Menstrual cycle tracking (start date of last menstrual period) is captured only for women with a 
menstrual cycle at the study visits specified in the Schedule of Activities.
Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire 
(MGH-ATRQ)
The MGH-ATRQ is used to determine treatment resistance in MDD.3
The MGH-ATRQ evaluates the adequacy of duration and dose of all antidepressant medications 
used for the current major depressive episode. In addition, the MGH-ATRQ assesses the degree of 
improvement on a scale from 0% (not improved at all) to 100% (completely improved). The MGH-
ATRQ will be completed by the clinician in collaboration with the participant.
Inventory of Depressive Symptomatology - Clinician-rated, 30-item (IDS-C30)
The 30-item IDS-C30 was designed to assess all the criterion symptom domains designated by 
DSM, fourth edition to diagnose a major depressive episode10; these criteria have not changed in 
the DSM-5.2 These assessments can be used to screen for depression, although they have been 
used predominantly as measures of symptom severity. The 7-day period prior to assessment is the 
usual time frame for assessing symptom severity. The psychometric properties of the IDS-C30 have 
been established in various study samples.14
This assessment will be audio-recorded for the purpose of quality monitoring.
SAFER Interview
Remote, independent psychiatrists/psychologists will perform the SAFER Interview12 for all 
participants to assess the validity of a diagnosis of depression and eligibility for the study. SAFER 
refers to:
S = State versus trait: The identified symptoms must reflect the current state of illness and not 
longstanding traits. Traits do not generally change in 4–12 weeks.
A = Assessibility: The patient’s symptoms are measurable with standard, reliable rating 
instruments. The symptoms of valid patients can be reliably assessed with standardized 
measurement tools
F = Face validity:  The patient’s presentation is consistent with our knowledge of the illness 
(symptoms map to the nosological entity; clear change from previous level of function; similar to 
previous episodes if recurrent)
E = Ecological validity: The patient’s symptoms reflect the characteristics of the illness in a real-
world setting (frequency, intensity, duration, course, impact over at least 4 weeks)
R = Rule of the Three P’s Identified symptoms must be pervasive, persistent, and pathological and 
interfere with function and quality of life.


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The interviewer will review participant screening information and conduct a live, remote interview 
with the participant. Depression severity, MGH-ATRQ, and SAFER Criteria Inventory will be 
evaluated during the interview. After the interview, the site will receive information regarding the 
SAFER Interview (ie, pass or fail) participant eligibility directly from the interviewer/designee. 
This interview will be audio-recorded for the purpose of quality monitoring.
Further information regarding this assessment will be provided to sites in a separate document.
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information 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 representative) for the duration of the study.
For further details on adverse events and serious adverse events (Definitions and Classifications; 
Attribution Definitions; Severity Criteria; Special Reporting Situations; Procedures) as well as 
product quality complaints, refer to Section 10.4, Appendix 4, 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 adverse events and special reporting situations, whether serious or nonserious, will be reported 
from the time a signed and dated ICF is obtained until completion of the participant's last study-
related procedure, which may include contact for follow-up of safety. Serious adverse events, 
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 serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form and Safety Report Form of the CRF, which must be completed and reviewed 
by a physician from the study site, and transmitted to the sponsor within 24 hours. The initial and 


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follow-up reports of a serious adverse event should be transmitted electronically or by facsimile 
(fax).
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events or serious adverse events. 
Open-ended and nonleading verbal questioning of the participant is the preferred method to inquire 
about adverse event occurrence. 
Solicited Adverse Events
Solicited adverse events are predefined local and systemic events for which the participant is 
specifically questioned.
Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the participant is not specifically 
questioned.
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 4, 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 adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. A SUSAR will be reported to regulatory 
authorities unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR 
summary, unless otherwise specified. 
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 events 
will be considered anticipated events.5
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)


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
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 serious adverse events and must be reported using the Serious Adverse Event Form. 
Any participant who becomes pregnant during the study must be promptly withdrawn from the 
study and discontinue further study intervention. 
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.
Adverse Events of Special Interest
Clinically relevant TEAEs of special interest will be examined separately grouped in the following 
categories: 

Suggestive of abuse potential (Aggression, Confusional state, Decreased activity, 
Dependence, Disorientation, Dissociation, Dissociative disorder, Dizziness, Drug abuse, Drug 
abuser, Drug dependence, Drug use disorder, Drug detoxification, Drug diversion, Drug 
rehabilitation, Drug tolerance, Drug tolerance increased, Drug withdrawal convulsions, Drug 
withdrawal headache, Drug withdrawal syndrome, Euphoric mood, Feeling abnormal, Feeling 
drunk, Feeling of relaxation, Hallucination, Hallucination, auditory, Hallucination, gustatory, 
Hallucination, olfactory, Hallucination, synaesthetic, Hallucination, tactile, Hallucination, 
visual, Hallucinations, mixed, Inappropriate affect, Mental impairment, Product tampering, 
Psychomotor hyperactivity, Psychotic disorder, Rebound effect, Somatic hallucination, 
Somnolence, Substance abuser, Substance dependence, Substance use, Substance use 
disorder, Substance-induced mood disorder, Substance-induced psychotic disorder, Thinking 
abnormal, Withdrawal arrhythmia, Withdrawal syndrome);

Increased blood pressure (Blood pressure increased, Blood pressure diastolic increased, Blood 
pressure systolic increased, Hypertensive crisis, Hypertensive emergency, Hypertension);

Increased heart rate (Heart rate increased, Tachycardia, Extrasystoles);

Transient dizziness/vertigo (Dizziness, Dizziness exertional, Dizziness postural, Dizziness 
procedural, Procedural dizziness, Vertigo, Vertigo labyrinthine, Vertigo positional, Vertigo 
CNS origin); 

Impaired cognition (Cognitive disorder);

Cystitis (Allergic cystitis, Chemical cystitis, Cystitis, Cystitis erosive, Cystitis haemorrhagic, 
Cystitis interstitial, Cystitis noninfective, Cystitis ulcerative, Cystitis-like symptom, 
Pollakiuria, Dysuria, Micturition urgency, Nocturia);

Anxiety (Agitation, Anticipatory anxiety, Anxiety, Anxiety disorder, Fear, Feeling jittery, 
Irritability, Nervousness, Panic attack, Tension);

Anticipated Dosing-related AEs (Anxiety, Anticipatory anxiety, Dissociation, Dizziness, 
Dizziness postural, Feeling abnormal, Feeling drunk, Nausea, Somnolence, Vertigo, 
Vomiting);

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)
Treatment of Overdose
There is no specific antidote for esketamine overdose. In the case of overdose, the possibility of 
multiple drug involvement should be considered. Contact a Certified Poison Control Center for 
the most up to date information on the management of overdosage (1-800-222-1222 or 
www.poison.org).


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Pharmacokinetics 
Plasma samples will be used to evaluate the PK of esketamine. The concentrations of esketamine 
and noresketamine or other metabolites (if warranted) will be measured in plasma. 
8.5.1.
Evaluations
Venous blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of esketamine and noresketamine or other metabolites (if warranted) at the time 
points specified in the Schedule of Activities. Additional information about the collection, 
handling, and shipment of biological samples can be found in the Laboratory Manual.
8.5.2.
Analytical Procedures 
Pharmacokinetics
Plasma samples will be analyzed to determine concentrations of esketamine using a validated, 
specific, and sensitive achiral liquid chromatography/tandem mass spectrometry (LC MS/MS) 
method by or under the supervision of the sponsor. 
If required, plasma samples may be analyzed to measure noresketamine using a validated assay or 
to document the presence of other circulating metabolites using a qualified research method. In 
addition, plasma PK samples may be stored for future analysis of the metabolite profile. The 
bioanalytical report, including a description of the assay and a summary of the assay performance 
data, will be included in the final study report as an addendum.
8.5.3.
Pharmacokinetic Parameters and Evaluations
Parameters
The plasma concentration-time data of esketamine and noresketamine or other metabolites (if 
warranted) may be analyzed using population PK modeling. Data would be combined with those 
of other selected studies to support a relevant structural model. Typical population values of basic 
PK parameters would be estimated together with the inter individual variability. Effects of 
participant demographics, laboratory parameter values, and other covariates on the PK of 
esketamine would be explored. If performed, details will be provided in a population PK analysis 
plan and the results of the population PK analyses will be reported separately.
Pharmacokinetic/Pharmacodynamic Evaluations
The relationship between MADRS total score (and possibly selected adverse events as additional 
PD parameters), and PK metrics of esketamine may be evaluated. If there is any visual trend in 
graphical analysis, suitable models will be applied to describe the exposure-effect relationships. 
The results of the PK/PD analyses would be reported separately. 
Biomarkers
Blood samples will be collected as indicated in Section 1.3, Schedule of Activities for exploratory 
analysis of biomarkers (protein and metabolites) related to immune system activity, hypothalamic-


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pituitary-adrenal (HPA) axis activation, neurotrophic and metabolic factors. Exploratory analyses 
may be performed for additional biomarkers as well.  Biomarker samples will be collected to:

evaluate the mechanism of action of esketamine or 

help explain inter-individual variability in clinical outcomes or 

help identify population subgroups that respond differently to a drug
At the conclusion of the biomarker analyses, these findings will be presented in a separate study 
report.
If possible, blood samples should be collected under fasting conditions (minimum 8 hours prior to 
biomarker sample collection, water is permitted). When fasting is not feasible, participants should 
follow a low-fat diet for at least 8 hours prior to sample collection. Participants should refrain from 
exercise/strenuous physical activity and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) 
for 24 hours prior to blood collection. Not following these recommendations will not constitute a 
protocol violation. Biomarkers may be added or deleted based on scientific information or 
technical innovations under the condition that the total volume of blood collected will not be 
increased. All biomarker data obtained during this study may be included in ongoing cross-study 
analyses to investigate the relationship between depression severity and phenotypes and 
biomarkers. 
Information on menstrual cycle (date of first day of last period, average length of cycle) will be 
recorded at each visit when blood samples for biomarker analysis are collected.
8.6.1.
Pharmacodynamics
The mechanism of action and inter-individual variability in clinical outcomes of esketamine is 
evaluated in this study through biomarker and pharmacogenomic evaluations (see Section 8.6.2
and 8.7 for more details).
8.6.2.
Pharmacogenomic (DNA and RNA) Evaluations
A pharmacogenomic blood sample will be collected from participants who consent separately to 
this component of the study to allow for pharmacogenomic research, as necessary. Whole blood 
samples for DNA and RNA analyses will be collected at the time points indicated in Section 1.3,
Schedule of Activities. Participation in pharmacogenomic research is optional.
DNA and RNA samples will be analyzed for the assessment of genetic variation and transcription 
of 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. 
DNA and RNA samples will be used for research related to esketamine or MDD. They may also 
be used to develop tests/assays related to esketamine and MDD. Pharmacogenomic research may
consist of the analysis of one or more candidate genes or of the analysis of genetic markers 
throughout the genome (as appropriate) in relation to esketamine or MDD clinical endpoints.


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All genetic data obtained during this study may be included in ongoing cross-study analyses to 
investigate the relationship between depression severity and phenotypes and biomarkers.
Immunogenicity Assessments 
Not applicable
Health Economics/Medical Resource Utilization and Health Economics 
Not applicable.
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. 
Statistical Hypotheses
The hypothesis of this study is that esketamine nasal spray 56 mg or 84 mg, when used as 
monotherapy, is superior to placebo nasal spray in improving depressive symptoms in participants 
with TRD.
Sample Size Determination
The sample size is calculated for the full efficacy analysis set, which includes all randomized 
patients who meet predefined nonresponse criteria (based on MADRS assessments performed 
during the screening phase). A standardized treatment effect for the primary endpoint at Day 28 
compared to the placebo arm of 0.45 (a treatment difference of 5.4 points for the change from 
baseline [Day 1 prerandomization] in MADRS total score with a standard deviation of 12) and the 
Hochberg procedure,4 with the truncation parameter equal to 1 (which results in the conventional 
Hochberg method with respect to the primary endpoint) to control the overall familywise error rate 
of 0.05 (two-sided) were used for the calculation. A 2:1:1 randomization scheme requires 71 
participants per active treatment arm and 142 for the placebo arm to complete 4 weeks of treatment 
to achieve 85% power for each dose and 93% power to correctly reject at least one null hypothesis. 
Taking into consideration a 20% drop-out rate, 356 patients who meet the predefined nonresponse 
criteria (based on MADRS assessments performed during the screening phase) will need to be 
randomized in the study. The treatment discontinuation rate will be closely monitored in a blinded 
fashion throughout the trial.
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:

Efficacy analyses for the double-blind phase will be performed on the full efficacy analysis 
set, which is defined as all randomized participants who meet nonresponse criteria and have 
received at least one dose of double-blind study medication. Participants who do not meet 
nonresponse criteria will be summarized separately for efficacy.


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
Safety analyses for the double-blind phase will be performed on the safety analysis set, which 
is defined as all randomized participants (both participants who meet and do not meet 
nonresponse criteria) who receive at least one dose of double-blind study medication.

The safety and efficacy analyses for the open-label phase will be based on all participants who 
receive at least one dose of open-label esketamine study medication.

The safety and efficacy analyses for the observational phase will be based on all participants 
who enter the observational phase but do not receive open-label esketamine study medication.
Statistical Analyses
The statistical analysis plan (SAP) will be finalized prior to database lock (DBL) 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.
9.4.1.
General Considerations 
Analyses of primary, key secondary, and other endpoints, and the safety parameters are described 
below.
Efficacy Analyses
The multiplicity, with regard to testing multiple endpoints (the primary [Day 28] and the key 
secondary [Day 2]) and multiple doses (esketamine 84 mg vs placebo and esketamine 56 mg vs 
placebo), will be controlled by a sequential gatekeeping method using the Hochberg procedure, a 
familywise error rate of 0.05 and a truncation parameter of 1. For the primary hypothesis (Day 28), 
if the largest p-value of the two dose comparisons of esketamine 84 mg vs placebo and esketamine 
56 mg vs placebo is less than two-sided 0.05 level, both esketamine 56 mg and esketamine 84 mg 
will be declared statistically significantly different from placebo. If the largest p-value of primary 
endpoint tests is greater than or equal to 0.05, the comparison associated with this p-value will be 
declared not statistically significant and the smaller p-value will be compared to the 0.025 level. 
The key secondary hypothesis (Day 2) will be tested using the Hochberg procedure only after the 
null hypothesis for the primary endpoint is rejected for both doses.
9.4.2.
Primary Endpoint
Primary Estimand
The primary estimand, the main clinical quantity of interest to be estimated in this study, is defined 
by the following 5 components:

Population: participants with TRD who have met the inclusion/exclusion criteria and the 
nonresponse criteria

Endpoint: change from baseline to Day 28 in the MADRS total score

Treatment: placebo, esketamine 56 mg, esketamine 84 mg

Intercurrent Events: All intercurrent events leading to changes in randomized treatment, 
such as premature discontinuation of the randomized treatment with or without a switch to 


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alternative antidepressant therapies, will be handled by a hypothetical strategy to estimate 
what the outcome would have been if all participants adhered to their randomized treatment. 
That is, post-treatment observations will not be included in the primary analysis.

Population Level Summary: the difference in means between each dose and placebo for the 
change from baseline in MADRS total score at Day 28.
Missing data will be closely monitored and if necessary, to assess the robustness of conclusions 
from the primary analysis to missing data assumptions, additional sensitivity analyses and/or 
estimands will be specified in the SAP. The key assumption in the primary analysis is that missing 
data arise from a Missing at Random (MAR) mechanism. This assumption is aligned with the 
estimand and the hypothetical strategy.
The primary efficacy variable, change from baseline in MADRS total score at Day 28, will be 
analyzed using a Mixed-Effect Model for Repeated Measures (MMRM) model based on observed 
case data. The model will include factors for treatment (esketamine 56 mg, esketamine 84 mg, 
placebo), center, antidepressant treatment status (on- or off-treatment) at screening entry, day, day-
by-treatment interaction, and baseline MADRS total score as a covariate. The within-participant 
covariance between visits will be estimated via an unstructured variance-covariance matrix. 
Comparisons of the esketamine groups versus placebo will be performed using the appropriate 
contrast.
9.4.3.
Key Secondary Endpoint
Key Secondary Estimand
The key secondary estimand, the secondary clinical quantity of interest to be estimated in this 
study, is defined by the following 5 components:

Population: participants with treatment-resistant depression who have met the 
inclusion/exclusion criteria and the nonresponse criteria

Endpoint: change from baseline to Day 2 in the MADRS total score

Treatment: placebo, esketamine 56 mg, esketamine 84 mg

Intercurrent Events: All intercurrent events leading to changes in randomized treatment, 
such as premature discontinuation of the randomized treatment with or without a switch to 
alternative antidepressant therapies, will be handled by a hypothetical strategy to estimate 
what the outcome would have been if all participants adhered to their randomized treatment. 
That is, post-treatment observations will not be included in the key secondary analysis.

Population Level Summary: the difference in means between each dose and placebo for the 
change from baseline in MADRS total score at Day 2
The key secondary efficacy variable, change from baseline in MADRS total score at Day 2 in the 
double-blind treatment phase, will be analyzed using the same MMRM model as described for the 
primary endpoint.


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9.4.4.
Other Endpoints
Change from baseline in MADRS total score over time will be analyzed using the same MMRM 
model as described for the primary endpoint. Response and remission rates based on the MADRS 
total score will be summarized at each visit. Frequency distributions of the CGI-S scores at each 
scheduled timepoint will be provided and change from baseline over time will be summarized. 
Change from baseline in PHQ-9 total score over time in the double-blind treatment phase will be 
analyzed using the same MMRM model as described for the primary endpoint. Response rates 
based on the PHQ-9 will be summarized at each visit. Descriptive summaries of efficacy data will 
be provided for the double-blind phase for participants who do not meet nonresponse criteria and 
for the open label/observational phase.
9.4.5.
Safety Analyses
Adverse Events
Safety data will be analyzed separately for each phase. Adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events with onset 
during the treatment phase (ie, treatment-emergent adverse events, and adverse events that have 
worsened since baseline) will be included in the analysis. For each adverse event, the percentage 
of participants who experience at least 1 occurrence of the given event will be summarized by 
treatment group. 
Treatment emergent AEs of special interest will be examined separately grouped in the following 
categories: suggestive of abuse potential, increased blood pressure, increased heart rate, transient 
dizziness/vertigo, impaired cognition, cystitis, anxiety, and anticipated dosing-related AEs (See 
Section 8.3.6 for details).
Adverse events of special interest will be further listed in the SAP. Participants who discontinue 
treatment due to an adverse event and serious adverse events (SAEs) will be summarized 
separately. Narratives will be provided for deaths, SAEs, and participants who discontinue due to 
an AE. 
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, body weight measurements, and blood 
pressure (systolic and diastolic) values and changes from baseline will be summarized at each 
scheduled time point. The percentage of participants with values beyond clinically important limits 
will be summarized.
C-SSRS
A frequency distribution of C-SSRS scores at each scheduled timepoint by treatment will be 
provided. Shifts from the baseline visit to the most severe/maximum score during each study phase 
will be summarized by treatment. The maximum score assigned for each participant will also be 
summarized into one of three categories: no suicidal ideation or behavior (0), suicidal ideation (1-
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9.4.6.
Other Analyses 
Pharmacokinetic Analyses 
The plasma concentrations of esketamine and noresketamine or other metabolites (if warranted)
will be listed for all participants and summarized descriptively.
Patient’s Assessment of Treatment-arm Assignment
Descriptive statistics will be reported.
Interim Analysis
Not applicable.
Data Monitoring Committee or Other Review Board 
Not applicable.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
Appendix 1: Abbreviations
AD
antidepressant
ADHD
attention deficit hyperactivity disorder
ALT
alanine amino transferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC∞
area under the concentration-time curve at infinity
AUClast
area under the concentration-time curve at last measurable concentration
β-hCG
β human chorionic gonadotropin
BCRP
breast cancer resistance protein
BP
blood pressure
BPRS+
Brief Psychiatric Rating Scale-4-Item Positive Symptom Subscale
CADSS
Clinician-Administered Dissociative States Scale
CGI-S
Clinical Global Impression – Severity
CI
confidence interval
Cmax
maximum concentrations
CNS
central nervous system
eCRF
electronic case report form(s)
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
Cytochrome P450
DBP
diastolic blood pressure
DBS
deep brain stimulation
DNA
deoxy ribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders (5th edition)
ECG
electrocardiogram
ECT
electroconvulsive therapy
eDC
electronic data capture
FDA
Food and Drug Administration
FT4
free thyroxine
KSS
Karolinska Sleepiness Scale
GABA
γ-amino butyric acid-ergic
GCP
Good Clinical Practice
HbA1c
Haemoglobin A1c
IC50
50% inhibition concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
IDS-C30
Inventory of Depressive Symptomatology-Clinician rated, 30-item
IEC
Independent Ethics Committee
IM
intramuscular
IRB
Institutional Review Board
IV
intravenous
IWRS
interactive web response system
MADRS
Montgomery-Asberg Depression Rating Scale
MedDRA
Medical Dictionary for Regulatory Activities
MDD
major depressive disorder
MDSI
Major depressive disorder with suicidal ideation
MGH-ATRQ
Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire
MINI
Mini International Neuropsychiatric Interview
MMRM
mixed-effects model using repeated measures
MOAA/S
Modified Observer’s Assessment of Alertness/Sedation
MTD
maximum tolerated dose
NYHA
New York Heart Association
NMDA
N-methyl D-aspartate
NMDAR
N-methyl D-aspartate receptor
NOAELs
No Observed Adverse Effect Levels


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OATP
organic anion-transporting polypeptide
OCT
organic cation transporter
OP
optimization
OTF
oral thin film
PCP
phencyclidine
PD
pharmacodynamic(s)
PHQ-9
Patient Health Questionnaire 9 item
PK
pharmacokinetic(s)
P-gp
P-glycoprotein
PQC
Product Quality Complaint
PT
preferred term
QTc
corrected QT
QTcB
QT corrected according to Bazett's formula
QTcF
QT corrected according to Fridericia's formula
RNA
ribonucleic acid
SAE
Serious adverse event
SAFER
State vs. Trait, Assessibility, Face Validity, Ecological Validity, Rule of Three P’s
SBP
Systolic blood pressure
SD
Standard deviation
SDS
Sheehan Disability Scale
SOC
Standard of care
SUSAR
suspected unexpected serious adverse reaction
t1/2
terminal half-life
tmax
Time to reach maximum concentrations
TEAE
Treatment-emergent adverse events
TRD
Treatment resistant depression
TSH
thyroid-stimulating hormone
ULN
Upper limit of normal
VNS
vagal nerve stimulation






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Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1.
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human 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 CRF 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)


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
IB (or equivalent information) and amendments/addenda

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.
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 4.2.2, Study-Specific Ethical Design 
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.2.
10.3.2.
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) for details on financial disclosure.
10.3.3.
Informed Consent Process
Each participant must give written consent according to local requirements after the nature of the 
study has been fully explained. Pharmacogenomic testing is optional, each participant must 
provide additional consent to pharmacogenomic testing. 
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 


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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 
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, which includes permission to obtain 
information about his or her survival status. 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.
10.3.4.
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, PD, biomarker and PK 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.
10.3.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand esketamine, to understand TRD, 
to understand differential intervention responders, and to develop tests/assays related to 
esketamine and TRD. 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).
10.3.6.
Committees Structure
A Data Monitoring Committee is not needed for this study because this is a post marketing 
commitment for an approved drug.
10.3.7.
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 pharmacogenomic or exploratory biomarker 
research data, generated as a result of this study, are considered confidential and remain the sole 
property of the sponsor. The investigator agrees to maintain this information in confidence and use 
this information only to accomplish this study and will not use it for other purposes without the 
sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of esketamine, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 


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study will be used to determine a coordinating investigator for the study. Results of 
pharmacogenomic or exploratory biomarker analyses performed after the Clinical Study Report 
has been issued will be reported in a separate report and will not require a revision of the Clinical 
Study Report. 
Study 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.


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10.3.8.
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, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review CRF 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.
10.3.9.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. Data relating to the study must be recorded in CRF where applicable. All CRF entries, 
corrections, and alterations must be made by the investigator or authorized study-site personnel. 
The investigator must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
electronic CRF, if applicable.  Study-specific data will be transmitted in a secure manner to the 
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the participant's source documents. Data must be entered into 
CRF in English. The CRF 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, MADRS and CGI-S) will be completed by the same individual 
who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the CRF, 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.


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10.3.10.
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 adverse events and follow-up of adverse events; 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 withdrawal 
from the study, if applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).
The following data will be recorded directly into the CRF and will be considered source data:

Race

History of smoking, all nicotine use, eg, cigarettes (including e-cigarettes or the equivalent of 
e-cigarettes), cigars, chewing tobacco, patch, gum
The minimum source documentation requirements for Section 0, Inclusion Criteria and 
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by 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 CRF in the protocol include the 
eSource system but information collected through eSource may not be limited to that found in the 
CRF.
10.3.11.
Monitoring
The sponsor will use a combination of monitoring techniques central, remote and 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 CRF 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 
CRF are known to the sponsor and study-site personnel and are accessible for verification by the 
sponsor study-site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study-site personnel. 
Direct access to source documents (medical records) must be allowed for the purpose of verifying 
that the recorded data 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.
10.3.12.
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.
10.3.13.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF 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.
10.3.14.
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 study intervention development


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Appendix 4: Adverse Events, Serious Adverse Events, Product Quality 
Complaints, and Other Safety Reporting: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.4.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant administered 
a medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the intervention. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 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 adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (The 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 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should usually be considered serious.


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If a serious and unexpected adverse event 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). 
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For esketamine, the expectedness of an adverse event will 
be determined by whether or not it is listed in the IB. 
10.4.2.
Attribution Definitions
Assessment of Causality
The causal relationship to study treatment is determined by the Investigator. The following 
selection should be used to assess all adverse events (AE).
Related
There is a reasonable causal relationship between study treatment administration and the AE.
Not Related
There is not a reasonable causal relationship between study treatment administration and the AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.4.3.
Severity Criteria
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the participant (eg, laboratory abnormalities).
10.4.4.
Special Reporting Situations
Safety events of interest on 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


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
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 CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
10.4.5.
Procedures
All Adverse Events
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
intervention, must be recorded using medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
"upper respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
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 serious adverse events 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 serious 
adverse event. 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 serious adverse 
event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such 
as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.
The cause of death of a participant in a study within 30 days of the last dose of study intervention, 
whether or not the event is expected or associated with the study intervention, is considered a 
serious adverse event.
10.4.6.
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.
10.4.7.
Product Quality Complaint Handling
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of participants, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 


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appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates will 
be conducted in accordance with those procedures.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 8.3.1, Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information). A sample of the suspected product should be maintained for further 
investigation if requested by 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.


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Appendix 5: Contraceptive and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section 0, Inclusion Criteria. 
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and 
Section 10.4, Appendix 4 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
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
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal 
occlusion/ligation procedures, 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
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)


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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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Appendix 6: List of Pharmacological Treatments Commonly Used for 
Treatment of Depression (not all-inclusive)
Class
Medications
Anticonvulsants
Carbamazepine
Gabapentin
Lamotrigine
Phenytoin
Tiagabine
Topiramate
Valproate
Anxiolytics
Buspirone
Atypical Antipsychotics
Aripiprazole
Brexpiprazole
Olanzapine
Paliperidone
Quetiapine 
Risperidone
Monoamine Oxidase Inhibitors (MAOIs)
Isocarboxazid
Moclobemide 
Phenelzine
Pirlindole 
Selegiline 
Tranylcypromine
Mood-stabilizing Agents
Lithium
Norepinephrine–dopamine reuptake inhibitor (NDRI)
Bupropion
Other
Mianserin
Mirtazapine
Olanzapine/fluoxetine
Psychostimulants
Amphetamine 
Atomoxetine 
Dextroamphetamine 
Lisdexamphetamine 
Methamphetamine
Methylphenidate
Mixed amphetamine salts 
Modafinil
Pemoline 
Serotonin Modulators
Nefazodone
Trazodone 
Vilazodone
Vortioxetine
Selective Serotonin Reuptake Inhibitors (SSRIs)
Citalopram
Escitalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Desvenlafaxine
Duloxetine
Levomilnacipran
Milnacipran
Venlafaxine


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Class
Medications
Thyroid hormones
Liothyronine
Tricyclic Agents (TCAs)
Amitriptyline
Amoxapine
Clomipramine
Desipramine
Doxepin
Imipramine
Nortriptyline
Maprotiline
Protriptyline
Noxiptiline
Pipofezine
Trimipramine
1.
Herbal agents or supplements used for the treatment of depression should be discontinued as well unless agreed 
for continuation by Medical Monitor.
2.
Any other treatments currently taken by the participant for the treatment of depression and not listed here should 
be reported in eCRF and if needed discussed with sponsor Medical Monitor.
Appendix 7: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment 1 (13 March 2020)
Overall Rationale for the Amendment:  The amendment updates the protocol design to align with 
comments received from a regulatory agency on the original protocol. 
Section number
and Name
Description of Change
Brief Rationale
Synopsis Objectives and 
Endpoints; 3. Objectives and 
Endpoints 
Specified the primary objective is to 
evaluate the efficacy of esketamine 
assessed by the change from baseline in 
MADRS total score from Day 1 to Day 28 
and the key secondary objective is to 
evaluate efficacy of esketamine as the 
change from baseline in MADRS total 
score from Day 1 to Day 2. 
The primary and key secondary 
objectives were revised as 
requested by a regulatory agency.
Synopsis Objectives and 
Endpoints, Statistical Methods; 
3. Objectives and Endpoints; 
4.2. Scientific Rationale for 
Study Design; 9.4.1. General 
Considerations; 9.4.2. Primary 
Endpoint; 9.4.3. Key 
Secondary Endpoint 
Specified the primary endpoint as the 
change from baseline in MADRS total 
score from Day 1 to Day 28 and the key 
secondary endpoint as the change from 
baseline in MADRS total score from Day 
1 to Day 2. Description of the efficacy 
analyses was revised to align with the 
change to the primary and key secondary 
endpoints.
Updated text in Section 4.2. Scientific 
Rationale for Study Design for selection of 
primary and secondary endpoints.
The primary and key secondary 
endpoints were revised as 
requested by a regulatory agency.
Synopsis Overall Design, 
Number of Participants, 
Intervention Groups and 
Duration, Statistical Methods; 
The sample size determination was revised 
based on a standardized treatment effect 
for the primary endpoint at Day 28 
compared to the placebo arm of 0.45. The 
The sample size was revised to 
ensure that the study is 
adequately powered for the Day 
28 endpoint.


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Section number
and Name
Description of Change
Brief Rationale
1.2. Schema; 4.1. Overall 
Design; 9.2. Sample Size 
Determination
minimum number of patients meeting the 
predefined nonresponse criteria who need 
to be randomized was increased to 356.
Synopsis Statistical Methods; 
9.4.6. Other Analyses, 1.3.  
Schedule of Activities (SoA)
Patient’s Assessment of Treatment-arm 
Assignment scale was categorized under 
“Other Analyses/Assessments”.
The assessment was previously 
incorrectly categorized under 
Safety Analyses/Assessments.
Synopsis Pharmacogenomic 
(DNA and RNA) Evaluations; 
1.3.  Schedule of Activities 
(SoA); 4.2.2. Study-Specific 
Ethical Design Considerations; 
5.1. Inclusion Criteria; 8. 
Study Assessments and 
Procedures; 8.7. 
Pharmacogenomic (DNA and 
RNA) Evaluations; 10.3. 
Appendix 3
Specified that participation in 
pharmacogenomic research is optional and 
that participants must sign a separate 
informed consent form to participate in the 
pharmacogenomic research component.
The requirement of mandatory 
participation in 
pharmacogenomic research for 
all study participants was 
changed to optional participation 
with a separate informed consent 
form to align with regulatory 
guidelines on clinical 
pharmacogenomic testing.
Synopsis Overall Design; 4.1. 
Overall Design; 7.1. 
Discontinuation of Study 
Intervention
The text was updated to clearly state that 
participants who discontinue study 
medication but continue in the study until 
Day 28 may be eligible to participate in 
the open-label treatment/observation 
phase. Participants who discontinue 
completely from double-blind treatment 
phase (and do not complete the Day 28 
visit) are not allowed to participate in the 
open-label phase.
The wording was updated to 
clarify that participants who 
discontinue study medication 
during the double-blind treatment 
phase (for a reason other than 
withdrawal of consent) but 
continue attending scheduled 
visits (through Day 28) will be 
allowed to participate in the 
open-label treatment/observation 
phase.
Synopsis, Overall Design, 
Intervention Groups and 
Duration; 4.1. Overall Design
Redundant text was deleted, and text was 
added to state that:
For participants remaining in the double-
blind treatment phase without study 
medication dosing, standard-of-care 
treatment may be initiated. Participants 
who complete the double-blind treatment 
phase (ie, including the Day 28 visit) may 
be eligible to proceed to the open-label 
treatment/observation phase.
The decision to receive open-label 
esketamine must be made at the start of the 
open-label treatment/observation phase, 
participants who chose to not receive 
esketamine (to be observed only) will not 
be allowed to start open-label esketamine 
treatment during this phase.
Participants who choose to be observed 
only will not be allowed to switch to the 
open-label esketamine nasal spray arm 
during the open-label 
treatment/observation phase.
Statements were added to specify 
which treatments are allowed 
during the study.
1.2. Schema
Added randomization ratio to 
nonresponder group.
Update to clarify that the same 
randomization ratio is applicable 


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Section number
and Name
Description of Change
Brief Rationale
to the nonresponder and 
responder groups.
1.3. Schedule of Activities 
(SoA)
Modified visit windows for Visits 2.3 –
2.10 in the double-blind phase.
Updated for consistency with the 
study design of the Phase 3 trials.
Added visit windows for Visits 1.2 – 1.7 in 
the Screening period.
Visit windows added to allow for 
more flexibility.
Option of clinic visit added during taper of 
antidepressant medication(s).
Option of clinic visit was added 
to allow for more flexibility 
during taper of antidepressant 
medication(s) and better control 
of patient safety when considered 
necessary by the investigator.
Height measurement, temperature 
measurement, and menstrual cycle 
tracking were added to the Schedule of 
Activities.
These measurements were not 
specifically listed in the Schedule 
of Activities in original protocol.
SAFER Interview can be scheduled and 
completed anytime within Week 1 and 2 
and as soon as the site collects and enters 
all required information into EDC.
Change in timing window of the 
procedure to establish subject 
eligibility for inclusion into the 
study as soon as possible, to limit 
the duration of time until the 
study treatment is implemented.
Added MADRS assessment at Screening 
Week 2 visit.
MADRS assessment was added 
due to change in the scope of the 
SAFER interview, which now 
includes IDS-C30 scale instead of 
previously planned MADRS 
assessment. In order to have this 
important measure at the 2-week 
time point, it will be completed 
by the site-based rater.
Modified footnote “c” to clarify that 
selected procedures at Day 1 must be 
completed prior to randomization and not 
only prior to dosing. Also, predose vital 
signs must be measured on the actual 
dosing day.
Footnote was modified to clarify 
that certain procedures must be 
completed prior to randomization 
on Day 1 to confirm participant 
eligibility. Clarify that the 
predose vital signs must be 
measured on the actual dosing 
day. When the dosing is 
postponed to another day, the 
predose vital signs must be 
repeated on the new dosing day.
Updated footnote “h” to clarify visit 
schedule for participants not taking any 
AD medication at study entry.
Added “h” for Visits 1.2 and 1.6 in the 
screening phase.
Footnote was updated to specify 
mandatory visits for participants 
not taking any AD medication at 
study entry.
Revised the Schedule of Activities For 
Participants Receiving Standard of Care 
(SOC) only to indicate that the MADRS, 
CGI-S and C-SSRS will be administered 
to participants in the Standard of Care 
group on the same schedule as those in the 
esketamine group during the open-label 
treatment/observation and follow-up 
The schedule of visits and 
MADRS, CGI-S, C-SSRS and 
other applicable assessments 
during the open-label phase for 
participants in the Standard of 
Care arm was updated to match 
the schedule of these assessments 
in the esketamine arm to 


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Section number
and Name
Description of Change
Brief Rationale
phases. The applicable clinic visits (with 
visit windows) including vital signs 
measurements and collection of 
concomitant medications and AEs were 
added to match the updated schedule of 
assessments.
Updated time-points for drug screen 
(urine) and urine pregnancy test in the 
SOC group.
minimize differences in 
participant experience and to 
allow for greater attribution of 
any differences between groups 
to drug rather than procedural 
effects such as closer follow-up 
in the esketamine arm. 
Updated time-points for drug 
screen (urine) and urine 
pregnancy test to match time-
points in the esketamine arm.
2.2. Background
Updated the cutoff date for reporting of 
deaths across all completed and ongoing 
esketamine studies.
The date was revised to reflect 
the cutoff date of the most recent 
safety update.
4.2.2. Study-Specific Ethical 
Design Considerations
Text revised to add that at any point in the 
study the participant may discontinue 
study intervention and receive standard-of-
care therapy for depression.
Text revised to clarify that 
participants may discontinue 
study intervention at any time.
4.4. End of Study Definition
Text revised to state that a participant will 
be considered to have completed the study 
if he/she completed the double-blind 
treatment phase and the follow up visit (if 
the subject did not enroll in the open-label 
phase) or completed the double-blind, 
open-label phases and the follow-up visit.
Text revised to clarify the 
definition of completing the 
study.
5.1. Inclusion Criteria
Inclusion criterion #9 was modified to add 
that a negative urine pregnancy test must 
be obtained before the first dose of study 
drug on Day 1, prior to randomization.
Inclusion criterion #9 was 
modified to confirm that a female 
participant is not pregnant before 
receiving the first dose of study 
drug.
Inclusion criterion #10 was removed.
Inclusion criterion #10 was 
removed because it was not 
consistent with Appendix 5.
Inclusion criterion #11 was modified to 
provide clarification of the acceptable 
methods of contraception.
Inclusion criterion #11 was 
modified to be consistent with 
Appendix 5.
Inclusion criteria #12 was deleted and 
inclusion criterion #13 was modified to 
convey that a male participant who is 
sexually active with a woman of 
childbearing potential must be practicing a 
highly effective method of contraception 
with his female partner during the study 
and for at least 90 days after receiving the 
last dose of study drug.
Inclusion criteria #12 and #13 
modified to provide further 
clarification regarding the 
contraceptive requirements for 
male participants who are 
sexually active with a woman of 
childbearing potential.
Inclusion criterion #14 was modified to 
replace “prohibitions” with 
“requirements”.
Inclusion criterion #14 was 
modified for clarity.
5.2. Exclusion Criteria
Exclusion criterion #8 was modified to add 
to cardiovascular-related conditions.
Exclusion criterion #8 was 
modified for consistency with the 
approved US label.
Exclusion criterion #10 was modified to 
remove “once” for repeat testing of 
abnormal ALT and AST.
Exclusion criterion #10 was 
modified to allow for multiple 
testing if applicable during the 
screening period. Since the 


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Section number
and Name
Description of Change
Brief Rationale
screening period can last up to 7 
weeks, a change in the abnormal 
liver test enzyme levels is 
possible.
Exclusion criterion #11 was modified to 
add MDMA to the examples of drugs of 
abuse. 
Text was modified to specify that any 
treatments with psychostimulants must be 
discontinued at least 2 weeks prior to 
randomization and the result of the Day 1 
test for drugs of abuse must be negative 
for the participant to be randomized.
Exclusion criterion #11 was 
modified to clarify that 
participants who have positive 
test results for MDMA at 
screening or Day 1 will be 
excluded from the study.
Pyschostimulant medication 
treatments are considered to have 
antidepressant effect and the 
study is designed to assess the 
efficacy of esketamine nasal 
spray in monotherapy.
Exclusion criterion #25 added to specify 
that a participant who has not completed 
the mandatory 2-week antidepressant 
drug-free period prior to Day 1 will be 
excluded.
Exclusion criterion #25 added 
because the 2-week 
antidepressant drug-free period is 
mandatory, and participants who 
do not complete this period 
during screening will be excluded 
from the study.
Note to investigators was updated as 
follows:
Investigators should ensure that all study 
enrollment criteria have been met at 
screening and/or Day 1 prior to 
randomization (as applicable).
Added text for clarification since 
some criteria can be assessed 
only at Day 1, eg completion of 
2-week antidepressant drug-free 
period.
Updated text for antidepressant treatments: 
All antidepressant treatment(s) 
(pharmacological, including adjunctive 
treatments and/or non-pharmacological eg 
ECT, VNS, DBS, psychotherapy) taken 
during the current depressive episode (ie, 
including those taken more than 30 days 
prior to the start of the screening phase) 
will be recorded at the start of the 
screening phase.
Clarified applicable 
antidepressant treatments.
6.5. Concomitant Therapy
Added text in Section 6.5. and in list of 
prohibited concomitant medications 
“Close monitoring for sedation is 
necessary when used with esketamine.”
Text was added to be consistent 
with information included in the 
approved US label that 
concomitant use of 
benzodiazepines with esketamine 
requires monitoring for 
symptoms of sedation.
Modified the conditions of use for ADHD 
medications in the list of prohibited 
concomitant medications with the 
comment that these medications are 
allowed for patients who discontinued the 
double-blind treatment and switched to the 
standard-of-care treatment in the open 
label phase.
ADHD medications are not 
allowed as concomitant therapies 
because they are considered to 
have antidepressant effect and the 
study is designed to assess 
efficacy of esketamine in 
monotherapy. Clarification was 
added that these medications are 


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Section number
and Name
Description of Change
Brief Rationale
prohibited during the 2-week 
antidepressant-free period.
Antidepressants and medications used for 
treatment of depression were added to the 
list of prohibited concomitant medications 
with the comment that these medications 
are allowed for patients who are switched 
to standard-of care treatment during the 
double-blind or open-label phases.
Antidepressants and medications 
used for treatment of depression 
are not allowed as concomitant 
therapies because the study is 
designed to assess efficacy in 
monotherapy. Clarification was 
added that these medications are 
also prohibited during the 2-week 
antidepressant-free period.
A comment was added to the list of 
prohibited concomitant medications to 
note that antipsychotics are allowed for 
patients who switched to standard-of care 
treatment during the double-blind or open-
label phases.
Text was added to specify when 
use of antipsychotics are allowed 
during the study. Clarification 
was added that these medications 
are prohibited during the 2-week 
antidepressant-free period.
Melatonin was removed from the list of 
prohibited concomitant medications.
Melatonin was removed from the 
list of prohibited medications 
based on updated safety 
information for esketamine.
A comment was added for use of 
intranasal corticosteroids that they should 
not be used from 1 hour prior to each nasal 
spray study medication administration.
Text was added to be consistent 
with information included in the 
approved US label for 
concomitant use of nasal 
corticosteroid with esketamine. 
6.6. Dose Modification
Text revised to indicate that no dose 
modifications are allowed during the 
double-blind treatment phase.
Text was modified to clarify that 
dose modifications during the 
double-blind treatment phase are 
not allowed due to the double-
blind nature of the phase and 
potential issues with 
interpretation of the study data.
7.2. Participant 
Discontinuation/Withdrawal 
From the Study
Text added to specify that a participant 
will be withdrawn from the study if the 
participant has a positive urine drug screen 
for phencyclidine (PCP) or cocaine at any 
time point during the study
Text added to clarify that 
participants are not permitted to 
continue in the study if they test 
positive for phencyclidine or 
cocaine.
8. Study Assessments and 
Procedures
Text was modified to recommend that the 
MADRS is performed first when multiple 
assessments are performed.
The MADRS assessment should 
be performed as the first 
assessment during a visit to limit 
the influence of other 
assessments on participant 
responses to the primary 
assessment tool.
Added information that necessary 
equipment and manuals for audio 
recording will be provided to the site.
Equipment and manuals will be 
provided to ensure consistent 
quality of audio recordings across 
all sites.
8.1. Efficacy Assessments; 
8.2.6. Other Evaluations
Added information that specified 
assessments (MADRS, IDS-C30 and 
SAFER Interview)
will be audio recorded for the purpose of 
quality monitoring and necessary 
Audio recording was 
implemented to ensure high 
quality of key assessments 
performed in the study.


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Section number
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Description of Change
Brief Rationale
equipment and manuals will be provided 
to the site.
8.2.6. Other Evaluations
Revised the Patient’s Awareness of 
Treatment-Arm Assignment Scale (Table 
2) to code the response “Don’t know” as 3 
and the response “Strongly believe the 
nasal spray treatment is placebo” as 5.
This scale was revised to be 
coded on an ordinal bipolar scale 
to facilitate exploratory 
regression analyses involving 
belief in treatment assignment.
8.3. Adverse Events and 
Serious Adverse Events
Revised text for participant’s 
representative and removed “legally 
acceptable”.
Updates made to text since 
participants who require legally 
acceptable representatives cannot 
participate in the study.
8.3.6. Adverse Events of 
Special Interest
Added adverse events related to suicidality 
as a category of clinically relevant TEAEs 
of special interest that will be examined.
Added for consistency with the 
esketamine clinical program.
9.4.2. Primary Endpoint; 9.4.3. 
Key Secondary Endpoint
Statements regarding missing data were 
added to the description of the primary 
analysis and deleted from description of 
the key secondary analysis. For the 
primary and key secondary estimands, text 
describing the intercurrent events 
component was revised.
Statements revised to align with 
changes to the primary and key 
secondary endpoints.
Text describing the primary and key 
secondary endpoints was rearranged.
Text rearranged for clarity.
For the primary and key secondary 
estimands, a treatment component was 
added.
Treatment component was 
omitted in the original protocol. 
10.2. Appendix 2
Benzodiazepines were removed from the 
list of drugs included in the urine drug 
screen.
Benzodiazepines are allowed 
medications during all phases of 
the study and positive results in 
the urine drug screen could 
confound proper assessment of 
participant eligibility.
XTC was removed and MDMA was added 
to the list of drugs included in the urine 
drug screen.
This list was modified to align 
terminology between protocol 
and other study documents (eg, 
laboratory manual).
10.4. Appendix 4
The following text was removed from the 
list of exceptions to the requirement to 
report hospitalizations as SAEs:
For convenience the investigator may 
choose to hospitalize the participant for the 
duration of the intervention period.
This text was removed to avoid 
misinterpretation that such 
hospitalizations are permitted per 
protocol and the cost reimbursed 
by the sponsor.
10.6. Appendix 6 
A list of medications used for the 
treatment of depression that will be 
tapered (if applicable) and discontinued 
during the screening phase was added as 
Section 10.6. Appendix 6.
Added cross references to Section 10.6. 
Appendix 6 in Section 4.2. Scientific 
Rationale for Study Design, Section 6.3. 
Measure to Minimize Bias: Randomization 
and Section 6.5. Concomitant Therapy
The list of medications used for 
the treatment of depression was 
added to provide guidance to 
sites about which medications 
must be discontinued in the 
screening period.


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Section number
and Name
Description of Change
Brief Rationale
10.7. Appendix 7
The appendix showing the Protocol 
Amendment History was renumbered to 
Appendix 7, and the text was updated to 
note that the Protocol Amendment 
Summary of Changes Table for the current 
amendment is located directly before the 
Table of Contents (TOC).
The text in the appendices was 
revised to note where the 
summary of changes table for the 
current amendment is located in 
the document.
11. References
Updated citations for references 12, 13 and 
14.
Citations were corrected from 
original protocol.
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted


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11.
REFERENCES
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American Psychiatric Association. Highlights of Changes from DSM-IV-TR to DSM-5. 
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11 September 2019.
3.
Desseilles M, Witte J, Chang TE, et al. Assessing the adequacy of past antidepressant trials: a clinician's guide 
to the antidepressant treatment response questionnaire. J Clin Psychiatry. 2011;72(8):1152-4.
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Dmitrienko A, Kordzakhia G, Tamhane AC. Multistage and mixture parallel gatekeeping procedures in clinical 
trials. Journal of Biopharmaceutical Statistics, 2011; 21(4):726-47.
5.
Investigator’s Brochure, JNJ-54135419-AAC (esketamine hydrochloride). Document ID: 
EDMS-ERI-49489196.
6.
Jha MK, Rush AJ, Trivedi MH.  When Discontinuing SSRI Antidepressants Is a Challenge: Management Tips. 
Am J Psychiatry. 2018;175(12):1176-84.
7.
Khan A, Warner HA, Brown WA, Symptom reduction and suicide risk in patients treated with placebo in 
antidepressant clinical trials: an analysis of the Food and Drug Administration database. Arch Gen Psychiatry. 
2000;57(4):311-7.
8.
Laughren TP. The scientific and ethical basis for placebo-controlled trials in depression and schizophrenia: an 
FDA perspective. Eur Psychiatry. 2001;16:418-423.
9.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide 
Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal risk analysis of 
antidepressants. Am J Psychiatry. 2007;164:1035-43.
10.
Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of Depressive Symptomatology 
(IDS): Psychometric properties. Psychol Med. 1996;26(3):477-86.
11.
SPRAVATO™ US Prescribing Information. Janssen Pharmaceuticals, Inc., Titusville, NJ. 
https://www.accessdata fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf. Accessed September 26, 2019.
12.
Targum SD, Pollack MH, Fava M. Redefining affective disorders: relevance for drug development. CNS 
Neurosci Ther. 2008;14(1):2-9.
13.
Temple R and Ellenberg SS. Placebo-controlled trials and active-controlled trials in the evaluation of new 
treatments. Part 1: ethical and scientific issues. Ann Intern Med. 2000;133(6):455-63.
14.
Trivedi MH, Rush AJ, Ibrahim MH, 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(1):73-82.


JNJ-54135419   (esketamine)
Clinical Protocol 54135419TRD4005 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
124
Status: Approved,  Date:  14 Jul 2020
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed 
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Institution:
 
Signature:
Date:
(Day Month Year)
Note:
If the address or telephone number of the investigator changes during the course of the study, 
written notification will be provided by the investigator to the sponsor, and a protocol amendment will not 
be required.
PPD
PPD


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 14 Jul 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
Protocol Title
A Randomized, Double-blind, Multicenter, Placebo-controlled Study to Evaluate the 
Efficacy, Safety, and Tolerability of Esketamine Nasal Spray, Administered as 
Monotherapy, in Adult Participants with Treatment-resistant Depression
Protocol 54135419TRD4005; Phase 4
JNJ-54135419  (esketamine)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics,
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact
Information page that accompanies the protocol.
United States (US) sites of  this study will be conducted under US Food & Drug Administration 
Investigational New Drug (IND) regulations (21 CFR Part 312).
Status:
Approved
Date:
14 Jul 2020
Prepared by:
Janssen Research & Development, LLC  
EDMS number:
EDMS-RIM-77286
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04599855


COVID-19 Appendix 
JNJ-54135419  (esketamine)
Clinical Protocol 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 14 Jul 2020
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by 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 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 COVID-19 Appendix after consultation with the participant, investigator, and with 
agreement of the sponsor. Missed assessments/visits will be captured in the clinical trial 
management system for protocol deviations. 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance.  
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report.


COVID-19 Appendix 
JNJ-54135419  (esketamine)
Clinical Protocol 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 14 Jul 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL
These provisions are meant to minimize the risk of exposure to COVID-19 and to safely maintain 
participants on study intervention while site capabilities are compromised by COVID-19-related 
restrictions. As restrictions are lifted and the acute phase of the COVID-19 pandemic resolves, 
sites should revert to original protocol conduct as soon as feasible.
At each contact, participants will be interviewed to collect safety data. Participants will also be 
questioned regarding general health status to fulfill any physical examination requirement.
Evaluate the participant’s situation on a case by case basis and contact the study responsible 
physician for discussion and decision if necessary. Certain measures, such as those listed below, may 
be necessary and should be instituted in accordance with applicable (including local) laws, regulations, 
guidelines, and procedures.

The safety of study participants is priority; investigators may make the decision to provide 
other available therapy to participants in the study. Please discuss any decision to provide 
other therapy outside of the protocol with the study responsible physician and ensure that this 
is recorded in the source document and the CRF along with the reason for administration.
Reminder: missed esketamine dosing of itself does not result in withdrawal from the study, and 
treatment can resume if considered beneficial per clinical judgement.
Discontinuations of study intervention and withdrawal from the study due to COVID-19 adverse 
events (AEs)/ serious adverse events (SAEs) should be documented as discontinuation due to AE. 
If a participant dies due to COVID-19, “death” should be selected as the reason for treatment 
discontinuation. Discontinuations for other COVID-19 reasons should be documented with the 
prefix “COVID-19-related” in the CRF.
Screening / Prospective Observational Phase
The following recommendations apply to those sites within regions where there is a high localized 
rate of COVID-19 infection:
Screening of new subjects should be postponed until the rate of COVID-19 infection is reduced 
and under control.
Due to uncertainty around the ability to conduct on-site clinical visits, subjects that are currently 
in screening should be screen failed and clinical standard of care for the treatment of depression 
should be arranged by the study investigator and/or the subject's treating physician. The decision 
to continue with the subject's current oral antidepressant treatment regimen should be at the 
discretion of the investigator.
The sponsor will evaluate and approve / reject requests to rescreen an individual subject on a case 
by case basis after the COVID-19 infection is under control.


COVID-19 Appendix 
JNJ-54135419  (esketamine)
Clinical Protocol 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 14 Jul 2020
Dosing/Administration
In the event that it is not feasible for the participant to be assessed and dosed at the study site (eg, 
due to temporary site closure), the following options may be used on a temporary basis after 
consultation with the sponsor and with the agreement of the participant and investigator:
Double-blind phase

Continue administering study intervention within the study site, with adjustments for 
temporary changes in dates/hours site is open for study participants;

Administer at an alternative location (to include the equipment/supplies needed for the 
care/treatment of a participant post dose) in the vicinity of the site, with the participant 
remaining there during the post dose observation period, under the supervision of site staff.
This condition will be evaluated on a case by case basis with the study responsible physician
or delegate.
Open Label phase

Administer at an alternative 54135419TRD4005 study site (data to stay with primary study 
site) after consultation with the sponsor (at which time specific guidance on the process will 
be provided) and if permitted by local regulations.

The post dose observation period can be reduced (minimum 1 hour of monitoring) per 
investigator discretion on a case by case basis; this condition is valid only under public health 
emergency declaration by the US Department of Health and Human Services and following 
consultation with the study responsible physician (only allowed after at least 8 administrations 
of esketamine in the open label phase).

Administer the study intervention at the patient's home in the presence of a designated site 
staff member during dosing and post dose observation period (home visit); this condition is 
valid only under public health emergency declaration by the US Department of Health and 
Human Services and following consultation with the study responsible physician (only 
allowed after at least 8 administrations of esketamine in the open label phase).

If neither proposed dosing option is feasible, the sponsor medical monitor or delegate should 
be contacted for directions.
Other Study-related procedures

Rating scales/ safety assessments can continue to be administered via video teleconferencing 
(MADRS) or phone (other assessments). Every effort should be made to complete the 
MADRS assessment via video teleconferencing and within the scheduled timeframe; if this 
cannot occur, the sponsor medical monitor or delegate should be contacted for direction.

Missed/ out of window visits or individual assessments should be documented with “COVID-
19-related” in the comment section of the CRF.

It is recommended that close contact be maintained with study participants and remote contact 
arranged consistent with the participant’s regularly scheduled visit interval.

If the participant is on a biweekly schedule, attempt to contact the participant biweekly.
If the participant is on weekly schedule, attempt to contact the participant weekly.


COVID-19 Appendix 
JNJ-54135419  (esketamine)
Clinical Protocol 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved,  Date: 14 Jul 2020

If the participant is on every other week schedule, attempt to contact the participant every 
other week.
Study participants who show worsening or who are at high risk for relapse may require more 
frequent monitoring as per investigator discretion.
Laboratory Assessments
If laboratory samples cannot be collected by Covance, sample collection and analysis can be 
performed using the site’s local laboratory at the discretion of the investigator.

If the investigator does not feel laboratory assessments are required at this time, and 
participant(s) want to avoid any risk to COVID-19 exposure, this rationale should be 
documented in the source documents.
Exposure to COVID-19

If a participant develops COVID-19 infection (or suspected) during the screening, double-
blind, or open label phases, the investigator should contact the sponsor’s medical monitor to 
discuss the best course of action based on individual symptoms/ participant setting and risk 
benefit relationship.

If a participant develops COVID-19 infection (or suspected) during the follow-up period, the 
investigator should contact the sponsor’s medical monitor and assessments should be 
completed remotely.

Resumption of treatment: When a participant recovers from suspected or confirmed 
COVID-19 infection, study intervention may be resumed when safe to do so as determined by 
the treating study physician in consultation with the sponsor.
Data Collection

For clinician-completed (C-SSRS, CGI-S) and participant-completed (PHQ-9)a scale 
assessments conducted by a telephone or video contact, the data should be entered directly 
onto the paper assessment. Ensure that the correct date is present on the assessment form in 
the CRF.

Missed doses should be documented in the CRF in accordance with the CRF completion 
guidelines.

For missed doses, the dosing form should be inactivated and a “COVID-19 related” comment 
entered on the Comments form.

All COVID-19-related deviations from the main study protocol will be documented according 
to the CRF completion guidelines.

A mitigation plan has been created to address the impact of the COVID-19 global pandemic 
on the completion of in-person COA assessments. 
                                                
a
C-SSRS=Columbia Suicide Severity Rating Scale; CGI-S=Clinical Global Impression – Severity; PHQ-9=Patient Health 
Questionnaire, 9-Item; SDS=Sheehan Disability Scale.


COVID-19 Appendix 
JNJ-54135419  (esketamine)
Clinical Protocol 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved,  Date: 14 Jul 2020
Statistical Analysis
The sponsor will evaluate the totality of the impact of COVID-19 on collection of key study data, 
and additional data analyses will be outlined in the statistical analysis plan.


COVID-19 Appendix 
JNJ-54135419  (esketamine)
Clinical Protocol 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
7
Status: Approved,  Date: 14 Jul 2020
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. 
I will conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that they 
are fully informed regarding the study intervention, the conduct of the study, and the obligations 
of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Institution:
Janssen Research & Development 
Signature:
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD


Signature
User
Date
Reason
15-Jul-2020
11:47:14
(GMT)
Document Approval
PPD

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 16 February 2024
Janssen Research & Development
Statistical Analysis Plan
Amendment 3
A Randomized, Double-blind, Multicenter, Placebo-controlled Study to Evaluate the 
Efficacy, Safety, and Tolerability of Esketamine Nasal Spray, Administered as 
Monotherapy, in Adult Participants with Treatment-resistant Depression
Protocol 54135419TRD4005; Phase 4
JNJ54135419  (esketamine)
Status:
Approved
Date:
16 February 2024
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-RIM-224547
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.
NCT04599855


JNJ54135419  (esketamine)
Statistical Analysis Plan 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 16 February 2024
TABLE OF CONTENTS
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Objectives and Endpoints ................................................................................................................ 7
1.2.
Study Design.................................................................................................................................... 8
2.
STATISTICAL HYPOTHESES.......................................................................................................... 11
3.
SAMPLE SIZE DETERMINATION.................................................................................................... 11
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS..................................................................... 12
5.
STATISTICAL ANALYSES............................................................................................................... 12
5.1.
General Considerations ................................................................................................................. 12
5.1.1.
Pooling Algorithm for Analysis Centers ...................................................................................... 12
5.1.2.
Visit Windows ............................................................................................................................. 12
5.1.3.
Analysis Phases ......................................................................................................................... 17
5.1.4.
Imputation of Efficacy ................................................................................................................. 18
5.2.
Participant Disposition.................................................................................................................... 19
5.3.
Primary Endpoint Analysis ............................................................................................................. 19
5.3.1.
Definition..................................................................................................................................... 19
5.3.2.
Primary Estimand ....................................................................................................................... 20
5.3.2.1.
Analysis Methods .................................................................................................................... 21
5.3.2.1.1.
Primary Analysis .................................................................................................................. 21
5.3.2.1.2.
Sensitivity Analysis............................................................................................................... 21
5.3.3.
Supplementary Estimand............................................................................................................ 23
5.3.3.1.
Analysis Methods .................................................................................................................... 23
5.4.
Secondary Endpoint(s) Analysis .................................................................................................... 24
5.4.1.
Key Secondary Endpoint ............................................................................................................ 24
5.4.1.1.
Definition.................................................................................................................................. 24
5.4.1.2.
Key Secondary Estimand ........................................................................................................ 24
5.4.1.3.
Analysis Methods .................................................................................................................... 25
5.5.
Other Endpoint(s)........................................................................................................................... 25
5.5.1.
Response (≥50% Improvement) Based on MADRS Total Score ............................................. 25
5.5.1.1.
Definition.................................................................................................................................. 25
5.5.1.2.
Analysis ................................................................................................................................... 25
5.5.2.
Remission (MADRS ≤10) Based on MADRS Total Score........................................................ 25
5.5.2.1.
Definition.................................................................................................................................. 25
5.5.2.2.
Analysis ................................................................................................................................... 25
5.5.3.
Remission (MADRS ≤12) Based on MADRS Total Score........................................................ 25
5.5.3.1.
Definition.................................................................................................................................. 25
5.5.3.2.
Analysis ................................................................................................................................... 25
5.5.4.
Clinical Global Impression – Severity (CGI-S) ........................................................................... 26
5.5.4.1.
Definition.................................................................................................................................. 26
5.5.4.2.
Analysis ................................................................................................................................... 26
5.5.5.
Patient Health Questionnaire - 9 Item (PHQ-9).......................................................................... 26
5.5.5.1.
Definition.................................................................................................................................. 26
5.5.5.2.
Analysis ................................................................................................................................... 26
5.5.6.
Response (≥6 Points Improvement) Based on PHQ-9 Total Score ........................................ 27
5.5.6.1.
Definition.................................................................................................................................. 27
5.5.6.2.
Analysis ................................................................................................................................... 27
5.5.7.
Response (≥50% Improvement) Based on PHQ-9 Total Score .............................................. 27
5.5.7.1.
Definition.................................................................................................................................. 27
5.5.7.2.
Analysis ................................................................................................................................... 27
5.5.8.
Remission (PHQ-9 <5) Based on PHQ-9 Total Score................................................................ 27
5.5.8.1.
Definition.................................................................................................................................. 27


JNJ54135419  (esketamine)
Statistical Analysis Plan 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved, Date: 16 February 2024
5.5.8.2.
Analysis ................................................................................................................................... 27
5.5.9.
Efficacy Data in the Double-blind Phase for Participants Who Do Not Meet 
Nonresponse Criteria (Randomization List 2 Analysis Set)........................................................ 27
5.5.10.
Efficacy Data in the Open-Label Treatment or Observation Phase ........................................... 28
5.5.11.
Subgroup Analyses..................................................................................................................... 28
5.6.
Safety Analyses ............................................................................................................................. 28
5.6.1.
Extent of Exposure ..................................................................................................................... 29
5.6.2.
Adverse Events........................................................................................................................... 29
5.6.3.
Additional Safety Assessments .................................................................................................. 31
5.6.3.1.
Vital Signs and Physical Examination Findings....................................................................... 31
5.6.3.2.
Other Safety Parameters......................................................................................................... 32
5.6.3.2.1.
Columbia Suicide Severity Rating Scale (C-SSRS)............................................................. 32
5.7.
Other Analyses............................................................................................................................... 33
5.7.1.
Definition of Subgroups .............................................................................................................. 33
5.7.2.
Pharmacokinetics ....................................................................................................................... 34
5.7.3.
Quality Tolerance Limit............................................................................................................... 34
5.8.
Interim Analyses............................................................................................................................. 34
6.
SUPPORTING DOCUMENTATION .................................................................................................. 35
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 35
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 36
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 37
6.4.
Appendix 4 Protocol Deviations and Quality Tolerance Limits (QTL)............................................ 38
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 39
6.6.
Appendix 6 Medical History ........................................................................................................... 40
6.7.
Appendix 7 Adverse Events of Special Interest............................................................................. 41
6.8.
Appendix 8 Medications of Special Interest................................................................................... 43
7.
REFERENCES................................................................................................................................... 49


JNJ54135419  (esketamine)
Statistical Analysis Plan 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved, Date: 16 February 2024
VERSION HISTORY
Table 1:
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
26 Jan 2021
Not Applicable
Initial release
2.0
6 Feb 2023
Removed all 1H time interval for 
vital signs, updated analysis 
phases and time intervals in Table 
2-4 of Section 5.1.2
Corrected time interval to be
consistent with protocol
Added a footnote in Table 2 for 
deriving Baseline (DB) of 
efficacy assessments. 
To be consistent with protocol, 
where baseline assessments were 
allowed to be performed before 
randomization
Updated the definition of double-
blind and Open-label end date in 
Section 5.1.3.
To be consistent with eCRF
Added additional analyses for 
exploratory endpoints analysis in 
Section 5.5.1 and 5.5.2
Added combined active 
intervention group when 
summarizing baseline disease 
characteristics in Appendix 6.3
Finetuned the analyses for the 
responder, open-label and 
observation analysis sets and 
made the analysis plan consistent 
with the protocol with minor 
changes. 
Updated the analysis set for 
safety analyses for follow-up 
phase
Given there is only one 
assessment (7 days), safety 
analyses for follow-up phase will 
be presently only for safety 
analysis set regardless of which 
phase a participant 
completed/discontinued from. 
Updated summary analyses over 
time for vital signs to include 
assessments on dosing days for 
over DB and OL phases [with the 
exception of Day 2 (DB) and Day 
28(DB)] in Section 5.6.3.1.
Updated the definition of 
clinically important abnormalities 
in vital signs and analysis for 
abnormalities in Section 5.6.3.1.
Finetuned the summary analyses 
for vital sign during DB and OL
Updated the categorization of C-
SSRS score of 11 and analyses 
performed for C-SSRS in Section 
5.6.3.2 
Finetuned the definition and 
analyses of C-SSRS. 
Added pharmacokinetics analyses 
in Section 5.7.2
Added analyses for 
pharmacokinetics
Added QTL analyses in Section 
6.4
To comply with new standard that 
a reference to the QTL must be 
included in the SAP.
3.0
26 Jun 2023
Added a robust sandwich 
variance estimator for variance-
covariance estimation in case 
unstructured variance-covariance
does not converge in Section
5.3.2.1.1
To address the potential adverse 
impact of covariance matrix mis-
specification on the estimation 
and testing of treatment effect


JNJ54135419  (esketamine)
Statistical Analysis Plan 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved, Date: 16 February 2024
SAP Version
Approval Date
Change
Rationale
Added details of multiple 
imputation model with SAS 
procedure and SAS code in 
Section 5.3.2.1.2
Provided SAS code for 
imputation model including the 
random seed to enhance the 
clarity
Expanded the last paragraph of 
5.3.2.1.2 (Sensitivity Analysis) to 
Section 5.3.3 Supplementary 
Estimand
Added more details about 
treatment policy estimand as 
supplementary analysis for the 
primary endpoint
Updated Table 9 Baseline 
Disease Characteristics to include 
screening C-SSRS for both 
lifetime and past 6/12 months and 
remove baseline C-SSRS
Including Screening C-SSRS to 
summarize lifetime C-SSRS 
information 
4.0
16 Feb 2024
Added clarification for endpoints 
in Randomization List 2, 
OL/OBS phase
Additional summaries requested
Updated “Responder Analysis 
Set’ to “Randomization List 2 
Analysis Set” in Section 4.
Added “List 1” and List 2” to the 
definition of full efficacy analysis 
set
Updated to a more 
straightforward analysis set name 
to eliminate any confusion and 
clarified the definiton of full 
efficacy analysis set
Updated “therapies” to 
“treatment” for intercurrent 
events in Section 5.3.2
To clarify intercurrent events
Added “(in case of non-
convergence, analysis center will 
be removed from the following 
model)” to multiple imputation 
for non-monotone and monotone 
missing data in Section 5.3.2.1.2.
Make sure that program can run 
in case of any non-convergence 
issues when analysis center is 
included given the large number 
of categories with analysis center. 
Added “by Imputation_” in the 
SAS code for monotone 
imputation in Section 5.3.2.1.2.
Updated the delta adjustment part 
by adding “for subjects who 
discontinued DB treatment” to 
indicate only imputed values for 
subjects who discontinued DB 
treatment will be adjusted
Updates made to keep the 
imputation procedure consistent 
with TRD3001 study 
Combined “Other Secondary 
Endpoint(s)” and “Exploratory 
Endpoints” to “Other Endpoints” 
in Section 5.4
Updates made to be consistent 
with the protocol
Added a new remission criterion 
in Section 1.1 and Section 5.4.3
based on MADRS ≤12
A new criterion and analyses was 
added to be consistent with the 
definition in phase 3 program
Added stacked bar charts for 
CGI-S in Section 5.5.4.2
To provide graphical presentation 
of the CGI-S data  for better 
visualization
Added a new remission (PHQ-9 
<5) and response (≥50% 
improvement) criteria based on 
New criteria and analyses were 
added to be consistent with the 
definition in phase 3 program


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SAP Version
Approval Date
Change
Rationale
PHQ-9 in Section 1.1 and Section 
5.5.6 and 5.5.8
Added remission and response 
rates plot for the double-blind 
phase and open-label treatment or 
observation phase in Section 
5.5.10
Provided figures for the existing 
tables for better visualization
Added Antidepressant status at 
screening / entry (On-treatment, 
Off-treatment) to Table 8
Provided summary statistics for 
stratification factor
Added two preferred terms "Self-
injurious behaviour" and 
"Suicidal behaviour" to the AE of 
special interest category of 
“Events potentially related to 
suicidality” in Section 6.7
Provided a more comprehensive 
list of preferred terms for AEs of 
special interest categories.
Remove “Clotiapine” from CM 
of special interest category of 
Typical Antipsychotics in Section 
6.8
Provided a unique CM of special 
interest category to eliminate 
confusion


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analyses for Study 54135419TRD4005. 
1.1.
Objectives and Endpoints  
Primary Objective
The primary objective of this study is to evaluate the efficacy of each individual dose of esketamine 
nasal spray, 56 mg and 84 mg, compared with placebo nasal spray in improving depressive 
symptoms in participants with Treatment Resistant Depression (TRD), as assessed by the change 
in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from Day 1 
(prerandomization) to end of the 4-week double-blind treatment phase (Day 28).
Key Secondary Objective
The key secondary objective of this study is to evaluate the efficacy of esketamine nasal spray, 
56 mg and 84 mg, compared with placebo nasal spray in improving depressive symptoms in 
participants with TRD, as assessed by the change in the MADRS total score from Day 1 
(prerandomization) to Day 2 (24 hours post first dose).
Other Objectives

To evaluate the efficacy of esketamine nasal spray, 56 mg and 84 mg, compared with placebo 
nasal spray in participants with TRD on:

Depression response and remission rates

Overall severity of depressive illness

Change in MADRS total score over time

Change in Patient Health Questionnaire 9-item (PHQ-9) total score over time

To investigate the safety and tolerability of esketamine nasal spray, 56 mg and 84 mg, 
compared with placebo nasal spray in participants with TRD, including the following:

Treatment-emergent adverse events (TEAEs), including adverse events (AEs) of special 
interest

Effects on heart rate and blood pressure

Potential effects on suicidal ideation/behavior

To assess the pharmacokinetic/pharmacodynamic (PK/PD) relationship of esketamine nasal 
spray and MADRS total score in participants with TRD 

To assess the relationship of biomarkers with response/nonresponse to esketamine nasal spray 
in participants with TRD
Primary Endpoint
The primary efficacy endpoint is the change in MADRS total score from (Day 1 
(prerandomization) to end of the 4-week double-blind treatment phase (Day 28).


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Key Secondary Endpoint
The key secondary efficacy endpoint is the change in MADRS total score from Day 1
(prerandomization) to Day 2 (24 hours post first dose).
Other Endpoints
The other efficacy endpoints are as follows:

MADRS total score 

Proportion of responders (≥50% reduction from baseline in MADRS total score) over 
time to the end of the 4- week double-blind treatment phase (Day 28)

Proportion of participants in remission (MADRS ≤10 or MADRS ≤12) over time to the 
end of the 4-week double-blind treatment phase (Day 28)

Change from baseline in MADRS total score over time to the end of the 4-week double-
blind treatment phase

Change from baseline in Clinical Global Impression – Severity (CGI-S) over time to the end 
of the 4-week, double-blind treatment phase (Day 28)

PHQ-9 total score

Proportion of responders (reduction in PHQ-9 score of ≥6 points or ≥50% reduction from 
baseline in PHQ-9 total score) over time to the end of the double-blind treatment phase 
(Day 28)

Proportion of participants in remission (PHQ-9 total score <5) over time to the end of the 
double-blind treatment phase (Day 28)

Change from baseline in PHQ-9 total score over time to the end of the 4-week double-
blind treatment phase (Day 28)
Additional efficacy endpoints will be described for participants who do not meet nonresponse 
criteria, and participants in open-label treatment or observation phase (Section 5.5.9 and 5.5.10).
1.2.
Study Design
This is a randomized, double-blind, placebo-controlled, multicenter study in male and female 
participants with TRD to evaluate the efficacy, safety, and tolerability of esketamine nasal spray, 
56 mg and 84 mg, administered as monotherapy. 
This study has 4 phases: screening, double-blind treatment, open-label treatment/observation, and 
follow-up.
A target of approximately 446 participants will be randomized in a 2:1:1 ratio to placebo, 
esketamine 56 mg, or esketamine 84 mg. A minimum of 356 participants meeting predefined 
nonresponse criteria will be randomized for the primary efficacy analysis set. Two separate 
randomization lists will be generated, a list for those participants who meet the predefined 
nonresponse criteria and a list for those participants do not meet the nonresponse criteria. The 
randomization will be stratified by study site and antidepressant treatment status (on- or off-
treatment) at screening entry.
The maximum duration of study participation is 24 weeks.


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Screening Phase (up to 7 weeks)
All participants will have a minimum of 2 weeks in the Screening Phase without any antidepressant 
(AD) medication(s) just prior to randomization. 
For participants not taking any AD medication at study entry (screening), the mandatory 2-week 
antidepressant-free period may start at entry. However, the screening phase will be at least 3 weeks 
to ensure required procedures are completed.
Participants meeting the inclusion/exclusion criteria are eligible to proceed to the double-blind 
treatment phase.
Double-blind Treatment Phase (4 weeks)
Eligible participants will be randomly assigned at a 2:1:1 ratio to receive double-blind nasal spray 
treatment with either placebo, esketamine 56 mg, or esketamine 84 mg, twice a week for 4 weeks.
The participant will self-administer nasal spray treatment (esketamine or placebo) under the direct 
supervision of a healthcare provider during a treatment session at all treatment visits. A treatment 
session consists of nasal administration of the study medication and post-administration 
observation. 
Missing data in clinical trials can lead to problems that undermine the scientific credibility of 
causal conclusions. The most common reason for missing data is participants who discontinue the 
assigned treatment because of AEs, lack of tolerability, lack of efficacy, or inconvenience. In order 
to reduce missing data in this study, if a participant discontinues double-blind study medication 
for reasons other than withdrawal of consent, the participant should complete the remaining 
scheduled visits (without study medication dosing) through the end of the phase (Day 28). For 
participants remaining in the double-blind treatment phase without study medication dosing, 
standard-of-care treatment may be initiated. Participants who complete the double-blind treatment 
phase (ie, including the Day 28 visit) may be eligible to proceed to the open-label 
treatment/observation phase.
If a participant discontinues from the study in the double-blind treatment phase (ie, prior to 
completion of the Day 28 visit), an Early Withdrawal visit should be conducted within 1 week of 
the date of discontinuation. Participants that discontinue early from the double-blind treatment 
phase (ie, prior to completion of the Day 28 visit) are not eligible to participate in the open-label 
treatment/observation phase and will proceed to the follow-up phase. 
Open-label Treatment or Observation Phase (up to 3 months)
On Day 28, following completion of the double-blind treatment phase assessments (which includes 
the 
Day 28 
MADRS 
assessment), 
participants 
may 
participate 
in 
an 
open-label 
treatment/observation phase. 
During the open-label treatment/observation phase, for a duration of up to 3 months, participants 
can: 

receive open-label esketamine nasal spray 

If clinically indicated based on the investigator’s judgment, participants receiving open-
label esketamine nasal spray treatment can also receive standard-of-care treatment for 
depression. 


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The decision to receive open-label esketamine must be made at the start of the open-label 
treatment/observation phase, participants who chose to not receive esketamine (to be 
observed only) will not be allowed to start open-label esketamine treatment during this 
phase.

choose to be observed only (ie, no nasal spray treatment sessions) and receive standard-of-
care treatment for depression. Participants who choose to be observed only will not be allowed 
to switch to the open-label esketamine nasal spray arm during the open-label 
treatment/observation phase.
Participants in this phase who have opted to receive open-label esketamine will receive 56 mg on 
Day 28 regardless of the participant's study drug/dose assignment in the double-blind phase. 
Subsequent doses can remain the same or be adjusted (56 mg or 84 mg) based on efficacy and 
tolerability. The recommended dosing frequency is as follows:

Weeks 5 to 8: twice weekly (maximum)

Weeks 9 to 12: once weekly 

Weeks 13 to 16: weekly or every other week. Dosing frequency will be based on clinical 
judgment and should be individualized to the least frequent dosing to maintain 
remission/response. 
The participant will self-administer esketamine nasal spray under the direct supervision of a 
healthcare provider during a treatment session at all treatment visits. A treatment session consists 
of nasal administration of the study medication and post-administration observation. 
If a participant discontinues the open-label treatment/observation phase for reasons other than 
withdrawal of consent, the participant will proceed to the follow-up phase. 
Follow-up Phase
All participants who have received at least 1 dose of nasal spray medication in the study will 
complete a follow-up visit in the follow-up phase. 
A diagram of the study design is provided in Figure 1.


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Figure 1:
Schematic Overview of the Study
2.
STATISTICAL HYPOTHESES
The primary efficacy endpoint is the change from baseline in MADRS total score to end of Day 28.
The hypothesis of this study is that esketamine nasal spray, 56 mg or 84 mg, when used as 
monotherapy, is superior to placebo nasal spray in improving depressive symptoms in participants 
with TRD.
3.
SAMPLE SIZE DETERMINATION
The sample size is calculated for the full efficacy analysis set, which includes all randomized 
patients who meet predefined nonresponse criteria (based on MADRS assessments performed 
during the screening phase). A standardized treatment effect for the primary endpoint at Day 28 
compared to the placebo arm of 0.45 (a treatment difference of 5.4 points for the change from 
baseline [Day 1 prerandomization] in MADRS total score with a standard deviation of 12) and the 
Hochberg procedure, with the truncation parameter equal to 1 (which results in the conventional 
Hochberg method with respect to the primary endpoint) to control the overall familywise error rate 
of 0.05 (two-sided) were used for the calculation. A 2:1:1 randomization scheme requires 
71 participants per active treatment arm and 142 for the placebo arm to complete 4 weeks of 
treatment to achieve 85% power for each dose and 93% power to correctly reject at least one null 
hypothesis. Taking into consideration a 20% drop-out rate, 356 patients who meet the predefined 
nonresponse criteria (based on MADRS assessments performed during the screening phase) will 
need to be randomized in the study. The treatment discontinuation rate will be closely monitored 
in a blinded fashion throughout the trial.


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4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Analysis Sets
Description
Randomized Analysis Set
The randomized analysis set includes all participants who were 
randomized in the study.
Full Efficacy Analysis Set
The full efficacy analysis set includes all randomized participants 
who meet nonresponse criteria (List 1) and received at least 1 dose 
of double-blind study intervention. Four participants meeting 
nonresponse criteria that were incorrectly randomized to the 
randomization list for those participants who do not meet the 
predefined nonresponse criteria (List 2) due to data migration error 
will be included in the full efficacy analysis set.
Randomization List 2 Analysis Set
The randomization list 2 analysis set includes all randomized 
participants who do not meet nonresponse criteria during screening 
and received at least 1 dose of double-blind study intervention. Four 
participants meeting nonresponse criteria that were incorrectly 
randomized to the randomization list for those participants who do 
not meet the predefined nonresponse criteria due to data migration 
error will be excluded in the randomization list 2 analysis set.
Safety Analysis Set
The safety analysis set includes all randomized participants (both 
participants who meet and do not meet nonresponse criteria) who 
received at least 1 dose of double-blind study intervention.
Open-label Analysis Set
The open-label analysis set includes all participants who received at 
least 1 dose of open-label esketamine study intervention.
Observation Analysis Set
The observation analysis set includes all participants who entered 
the observation phase but did not receive any open-label esketamine 
study intervention.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
5.1.1.
Pooling Algorithm for Analysis Centers
Pooling may be conducted for randomized participants who met nonresponse criteria only if a 
sufficient number of participants are not randomized to a site. If necessary, small study centers 
with fewer than 4 randomized participants will be combined for the purpose of analysis. These 
small centers will be ordered according to the total number of participants and then sequentially 
using the center number. The pooling will be carried out sequentially beginning with the smallest 
center. The size of any pooled analysis center should be as large as possible and not be larger than 
the size of the largest center. If the number of small centers is large, and one pooled analysis center 
cannot include all small centers, then a second (or more) pooled analysis center(s) will be formed 
after the first one is filled with as many small centers as possible. Pooled sites as described are 
called analysis centers and will be used in the analyses as center effect.
5.1.2.
Visit Windows
As participants do not always adhere to the protocol visit schedule, the following rules are applied 
to assign actual visits to analysis visits. Listed below are the visit windows and the target days for 
each visit. The reference day is double-blind start day for the screening and double-blind phases, 
and the start dates of the respective phases for open-label treatment/observation and follow-up 


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phases. 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 protocol visit for that visit window. If 2 actual visits are equidistant from 
the target day within a visit window, the later visit is used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point except for the endpoint. Listed below 
(Table 2-4) are the analysis visit windows and the target days for each visit defined in the protocol.
Table 2:
Visit Windows (Screening, Double-blind and Follow-up Phases)
Parameter
Analysis Phase
Scheduled Visit 
Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)*
MADRS
Screening
1.1
Week 1 (SC)
1.2
Week 2 (SC)
1.6
Week 1 (AD free)
1.7
Week 2 (AD free)
DB
2.1
Baseline (DB)**
≤1
1
2.2
Day 2 (DB)
2-4
2
2.4
Day 8 (DB)
5-11
8
2.6
Day 15 (DB)
12-18
15
2.8
Day 22 (DB)
19-24
22
2.10
Day 28 (DB)
25 to end of DB
28
DB final visit
Endpoint (DB)
2 to End of DB
F/U
4.1
Week 1 (F/U)
1 to end of F/U
7
DB (W/D 
subjects only)a
2.2
Day 2 (DB)
2-4
2
2.4
Day 8 (DB)
5-11
8
2.6
Day 15 (DB)
12-18
15
2.8
Day 22 (DB)
19-24
22
2.10
Day 28 (DB)
25 to end of DB
28
CGI-S
Screening
1.1
Week 1 (SC)
DB
2.1
Baseline (DB)**
≤1
1
2.2
Day 2 (DB)
2-4
2
2.4
Day 8 (DB)
5-11
8
2.6
Day 15 (DB)
12-18
15
2.8
Day 22 (DB)
19-24
22
2.10
Day 28 (DB)
25 to end of DB
28
DB final visit
Endpoint (DB)
2 to end of DB
F/U
4.1
Week 1 (F/U)
1 to end of F/U
7
DB (W/D 
subjects only)a
2.2
Day 2 (DB)
2-4
2
2.4
Day 8 (DB)
5-11
8
2.6
Day 15 (DB)
12-18
15
2.8
Day 22 (DB)
19-24
22
2.10
Day 28 (DB)
25 to end of DB
28
PHQ-9
Screening
1.6
Week 1 (AD free)
DB
2.1
Baseline (DB)**
≤1
1
2.6
Day 15 (DB)
2-21
15
2.10
Day 28 (DB)
22 to end of DB
28
DB final visit
Endpoint (DB)
2 to end of DB
DB (W/D 
subjects only)a
2.6
Day 15 (DB)
2-21
15
2.10
Day 28 (DB
22 to end of DB
28
Vital Signs 
Screening
1.1
Week 1 (SC)
1.6
Week 1 (AD free)
1.7
Week 2 (AD free)
DB
2.1
Day 1 (DB): 
Predose
Day 1 (DB): 40M
Day 1 (DB): 1.5H
1
1
2.2
Day 2 (DB) 
2
2


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Table 2:
Visit Windows (Screening, Double-blind and Follow-up Phases)
Parameter
Analysis Phase
Scheduled Visit 
Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)*
2.3
Day 4 (DB): 
Predose
Day 4 (DB): 40M
Day 4 (DB): 1.5H
3-6
4
2.4
Day 8 (DB): 
Predose
Day 8 (DB): 40M
Day 8 (DB): 1.5H
7-9
8
2.5
Day 11 (DB): 
Predose
Day 11 (DB): 40M
Day 11 (DB): 1.5H
10-13
11
2.6
Day 15 (DB): 
Predose
Day 15 (DB): 40M
Day 15 (DB): 1.5H
14-16
15
2.7
Day 18 (DB): 
Predose
Day 18 (DB): 40M
Day 18 (DB): 1.5H
17-20
18
2.8
Day 22 (DB): 
Predose
Day 22 (DB): 40M
Day 22 (DB): 1.5H
21-23
22
2.9
Day 25 (DB): 
Predose
Day 25 (DB): 40M
Day 25 (DB): 1.5H
24-26
25
2.10
Day 28 (DB)
27 to end of DB
28
F/U 
4.1
Week 1 (F/U)
1 to end of F/U
7
DB (W/D 
subjects only)a
2.2
Day 2 (DB)
2
2
2.3
Day 4 (DB)
3-6
4
2.4
Day 8 (DB)
7-9
8
2.5
Day 11 (DB)
10-13
11
2.6
Day 15 (DB)
14-16
15
2.7
Day 18 (DB)
17-20
18
2.8
Day 22 (DB)
21-23
22
2.9
Day 25 (DB)
24-26
25
2.10
Day 28 (DB)
27 to end of DB
28
Weight and BMI
Screening
1.1
Baseline (DB)**
≤1
DB
2.10
Day 28 (DB)
2 to end of DB
28
C-SSRS
Screening
1.1
Week 1 (SC)
1.2
Week 2 (SC)
1.3
Week 3 (SC)
1.4
Week 4 (SC)
1.5
Week 5 (SC)
1.6
Week 1 (AD free)
1.7
Week 2 (AD free)
DB
2.1
Baseline (DB)**
≤1
1
2.2
Day 2 (DB)
2
2
2.3
Day 4 (DB)
3-6
4
2.4
Day 8 (DB)
7-9
8
2.5
Day 11 (DB)
10-13
11
2.6
Day 15 (DB)
14-16
15
2.7
Day 18 (DB)
17-20
18
2.8
Day 22 (DB)
21-23
22
2.9
Day 25 (DB)
24-26
25


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Table 2:
Visit Windows (Screening, Double-blind and Follow-up Phases)
Parameter
Analysis Phase
Scheduled Visit 
Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)*
2.10
Day 28 (DB)
27 to end of DB
28
F/U
4.1
Week 1 (F/U)
1 to end of F/U
7
DB (W/D 
subjects only)a
2.2
Day 2 (DB)
2
2
2.3
Day 4 (DB)
3-6
4
2.4
Day 8 (DB)
7-9
8
2.5
Day 11 (DB)
10-13
11
2.6
Day 15 (DB)
14-16
15
2.7
Day 18 (DB)
17-20
18
2.8
Day 22 (DB)
21-23
22
2.9
Day 25 (DB)
24-26
25
2.10
Day 28 (DB)
27 to end of DB
28
*Relative to start date of DB phase for screening and double-blind phases, and relative to the start date of follow-up phase for 
follow-up phase.
**If a Day 1 value is not available for Baseline (DB), the closest available value prior to randomization with a visit name of 
“DOUBLE-BLIND DAY 1" will be used for Baseline (DB).
a. DB (W/D subjects only) refers to data collected during the double-blind phase after subjects have discontinued study 
intervention.
Table 3:
Visit Windows for Participants Receiving Esketamine (Open-label Treatment and follow-up 
phases)
Parameter
Analysis 
Phase
Scheduled Visit 
Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)*
MADRS
Open-label 
3.3
Day 35 (OL)
<=11
8
3.5
Day 42 (OL)
12-18
15
3.7
Day 49 (OL)
19-25
22
3.9
Day 56 (OL)
26-32
29
3.10
Day 63 (OL)
33-39
36
3.11
Day 70 (OL)
40-46
43
3.12
Day 77 (OL)
47-53
50
3.13
Day 84 (OL)
54-60
57
3.14
Day 91 (OL)
61-67
64
3.15
Day 98 (OL)
68-74
71
3.16
Day 105 (OL)
75 to end of OL 
78
OL final visit
Endpoint (OL)
1 to end of OL
F/U
4.1
Week 1 (F/U)
1 to end of F/U
7
CGI-S
Open-label 
3.2
Day 31 (OL)
<=6
4
3.3
Day 35 (OL)
7 - 9
8
3.4
Day 38 (OL)
10 - 12
11
3.5
Day 42 (OL)
13 - 16
15
3.6
Day 45 (OL)
17 - 19
18
3.7
Day 49 (OL)
20 - 23
22
3.8
Day 52 (OL)
24-26
25
3.9
Day 56 (OL)
27-32
29
3.10
Day 63 (OL)
33-39
36
3.11
Day 70 (OL)
40-46
43
3.12
Day 77 (OL)
47-53
50
3.13
Day 84 (OL)
54-60
57
3.14
Day 91 (OL)
61-67
64
3.15
Day 98 (OL)
68-74
71
3.16
Day 105 (OL)
75 to end of OL 
78
OL final visit
Endpoint (OL)
1 to end of OL
F/U
4.1
Week 1 (F/U)
1 to end of F/U
7
Vital sign
Open-label 
3.1
Day 28 (OL): Predose
Day 28 (OL): 40M
Day 28 (OL): 1.5H
1
1


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Table 3:
Visit Windows for Participants Receiving Esketamine (Open-label Treatment and follow-up 
phases)
Parameter
Analysis 
Phase
Scheduled Visit 
Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)*
3.2
Day 31 (OL): Predose
Day 31 (OL): 40M
Day 31 (OL): 1.5H
2-6
4
3.3
Day 35 (OL): Predose
Day 35 (OL): 40M
Day 35 (OL): 1.5H
7 - 9
8
3.4
Day 38 (OL): Predose
Day 38 (OL): 40M
Day 38 (OL): 1.5H
10 - 12
11
3.5
Day 42 (OL): Predose
Day 42 (OL): 40M
Day 42 (OL): 1.5H
13 - 16
15
3.6
Day 45 (OL): Predose
Day 45 (OL): 40M
Day 45 (OL): 1.5H
17 - 19
18
3.7
Day 49 (OL): Predose
Day 49 (OL): 40M
Day 49 (OL): 1.5H
20 - 23
22
3.8
Day 52 (OL): Predose
Day 52 (OL): 40M
Day 52 (OL): 1.5H
24-26
25
3.9
Day 56 (OL): Predose
Day 56 (OL): 40M
Day 56 (OL): 1.5H
27-32
29
3.10
Day 63 (OL): Predose
Day 63 (OL): 40M
Day 63 (OL): 1.5H
33-39
36
3.11
Day 70 (OL): Predose
Day 70 (OL): 40M
Day 70 (OL): 1.5H
40-46
43
3.12
Day 77 (OL): Predose
Day 77 (OL): 40M
Day 77 (OL): 1.5H
47-53
50
3.13
Day 84 (OL): Predose
Day 84 (OL): 40M
Day 84 (OL): 1.5H
54-60
57
3.14
Day 91 (OL): Predose
Day 91 (OL): 40M
Day 91 (OL): 1.5H
61-67
64
3.15
Day 98 (OL): Predose
Day 98 (OL): 40M
Day 98 (OL): 1.5H
68-74
71
3.16
Day 105 (OL):
Predose
Day 105 (OL): 40M
Day 105 (OL): 1.5H
75 to end of OL 
78
F/U
4.1
Week 1 (F/U)
1 to end of F/U
7
C-SSRS
Open-label 
3.1
Day 28 (OL) a
1
1
3.2
Day 31 (OL)
2-6
4
3.3
Day 35 (OL)
7 - 9
8
3.4
Day 38 (OL)
10 - 12
11
3.5
Day 42 (OL)
13 - 16
15
3.6
Day 45 (OL)
17 - 19
18
3.7
Day 49 (OL)
20 - 23
22
3.8
Day 52 (OL)
24-26
25
3.9
Day 56 (OL)
27-32
29
3.10
Day 63 (OL)
33-39
36
3.11
Day 70 (OL)
40-46
43


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Table 3:
Visit Windows for Participants Receiving Esketamine (Open-label Treatment and follow-up 
phases)
Parameter
Analysis 
Phase
Scheduled Visit 
Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)*
3.12
Day 77 (OL)
47-53
50
3.13
Day 84 (OL)
54-60
57
3.14
Day 91 (OL)
61-67
64
3.15
Day 98 (OL)
68-74
71
3.16
Day 105 (OL)
75 to end of OL 
78
F/U
4.1
Week 1 (F/U)
1 to end of F/U
7
*Relative to the first day of open-label treatment phase and relative to the start date of follow-up phase for follow-up phase.
a.
If assessment was performed as part of Visit 2.10 (on the same day) in double-blind phase, duplicate predose assessment is 
not required.
Table 4:
Visit Windows for Participants Receiving SOC only: (Observation and follow-up Phases)
Parameter
Analysis 
Phase
Scheduled Visit 
Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)*
MADRS
Observation
3.3
Day 35 (OBS)
<=11
8
3.5
Day 42 (OBS)
12-18
15
3.7
Day 49 (OBS)
19-25
22
3.9
Day 56 (OBS)
26-32
29
3.10
Day 63 (OBS)
33-39
36
3.11
Day 70 (OBS)
40-46
43
3.12
Day 77 (OBS)
47-57
50
3.14
Day 91 (OBS)
58-71
64
3.16
Day 105 (OBS)
72 to end of OBS
78
OBS final visit
Endpoint (OBS)
1 to end of OBS
F/U
4.1
Week 1 (F/U)
1 to end of F/U
7
CGI-S,
Vital signs,
C-SSRS
Observation
3.1
Day 28 (OBS) a
1
1
3.2
Day 31 (OBS)
2-6
4
3.3
Day 35 (OBS)
7 - 9
8
3.4
Day 38 (OBS)
10 - 12
11
3.5
Day 42 (OBS)
13 - 16
15
3.6
Day 45 (OBS)
17 - 19
18
3.7
Day 49 (OBS)
20 - 23
22
3.8
Day 52 (OBS)
24-26
25
3.9
Day 56 (OBS)
27-32
29
3.10
Day 63 (OBS)
33-39
36
3.11
Day 70 (OBS)
40-46
43
3.12
Day 77 (OBS)
47-57
50
3.14
Day 91 (OBS)
58-71
64
3.16
Day 105 (OBS)
72 to end of OBS
78
OBS final visitb
Endpoint(OBS)
1 to end of OBS
F/U
4.1
Week 1 (F/U)
1 to end of F/U
7
*Relative to the first day of observation phase and relative to the start date of follow-up phase for follow-up phase.
a.
If assessment was performed as part of Visit 2.10 (on the same day) in double-blind phase, duplicate predose assessment is 
not required.
b. Endpoint (OBS) is only derived for CGI-S.
5.1.3.
Analysis Phases
Double-blind Phase
The analysis reference start date of the double-blind analysis phase is the date of the first dose of
double-blind study intervention. The analysis reference end date of the double-blind analysis phase 
is the maximum of the date of the last visit in the double-blind phase and date of early withdrawal 


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from the double-blind phase. For participants who entered the open-label phase and received first 
dose of open-label treatment after the date of last visit in double-blind phase, the analysis reference 
end date of the double-blind analysis phase is the date of first open-label treatment. For randomized 
participants who did not receive any study intervention in the double-blind phase, both analysis 
reference start and end dates are missing for the double-blind analysis phase.
Open-label treatment or Observation Phase
Start and end dates for the open-label treatment or observation phase are only defined for 
participants who participated in the open-label treatment or observation phase. The analysis 
reference start date of the open-label treatment or observation phase is the reference end date of 
the double-blind analysis phase. The analysis reference end date of the open-label treatment or 
observation phase is the maximum of the date of the last visit in the open-label treatment or 
observation phase and date of early withdrawal from the open-label treatment or observation
phase. For randomized participants who did not participate in the open-label treatment or 
observation phase, both analysis reference start and end dates are missing for the open-label
treatment or observation phase.
Follow-up Phase
Start and end dates for the follow-up phase are only defined for participants who continued into 
the follow-up phase. The analysis reference start date of the follow-up analysis phase is the day 
after the reference end date for the double-blind analysis phase (for participants who did not 
continue into open-label treatment or observation phase), or the open-label treatment or 
observation phase (for participants who participated in the open-label treatment or observation 
phase). The analysis reference end date of the follow-up analysis phase is the maximum of the last 
follow-up visit date or the disposition date at follow-up.
5.1.4.
Imputation of Efficacy
Imputation method for missing data will include the following methods (Table 5).
Table 5: 
Imputation of Missing Efficacy Data
Imputation
Text
Multiple Imputation (MI) method
Delta Adjustment
Imputation of total scores will be performed for the following efficacy scales as shown in Table 6
below. If the number of items with missing scores is greater than the maximum number of items 
presented in the table, the total score will be missing.
For the remaining efficacy assessments which require adding multiple item scores, the total score 
will be missing if any item score is missing.
Table 6:
Imputation of Total Score for Efficacy Scales
Efficacy Scale
Total Number 
of Items
Maximum Number of
Items That Can Be 
Missing *
Formula for Total Score 
MADRS
10
1
Sum of non-missing item scores *


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(10 / number of non-missing items)
5.2.
Participant Disposition
The number of participants in the following disposition categories will be summarized throughout 
the study by intervention group and overall for the all randomized full efficacy, responder, safety, 
observation and open-label analysis sets as appropriate for the relevant phases:

Participants randomized

Participants who received study intervention during each phase

Participants who completed and discontinued and reasons for discontinuation of study 
intervention during each phase

Participants who completed, terminated and reasons for termination from each phase of the 
study 
Listings of participants will be provided for the following categories:

Participants who discontinued double-blind study intervention

Participants who discontinued double-blind phase

Participants who discontinued open-label study intervention

Participants who discontinued open-label phase

Participants who terminated study prematurely (trial disposition page)

Participants who were unblinded during the study period

Participants who were randomized yet did not receive study intervention.
5.3.
Primary Endpoint Analysis
The multiplicity, with regard to testing multiple endpoints (the primary [Day 28] and the key 
secondary [Day 2]) and multiple doses (esketamine 84 mg vs placebo and esketamine 56 mg vs 
placebo), will be controlled by a sequential gatekeeping method using the Hochberg procedure, a 
familywise error rate of 0.05 and a truncation parameter of 1. For the primary hypothesis (Day 28), 
if the largest p-value of the two dose comparisons of esketamine 84 mg vs placebo and esketamine 
56 mg vs placebo is less than two-sided 0.05 level, both esketamine 56 mg and esketamine 84 mg 
will be declared statistically significantly different from placebo. If the largest p-value of primary 
endpoint tests is greater than or equal to 0.05, the comparison associated with this p-value will be 
declared not statistically significant and the smaller p-value will be compared to the 0.025 level. 
The key secondary hypothesis (Day 2) will be tested using the Hochberg procedure only if the null 
hypothesis for the primary endpoint is rejected for both doses.
5.3.1.
Definition
The primary efficacy endpoint is the change in MADRS total score from Day 1 (prerandomization) 
to end of the 4-week double-blind treatment phase (Day 28).


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The MADRS is a clinician-administered scale designed to measure depression severity and detects
changes due to antidepressant intervention. (Montgomery 1979) 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).Higherscores represent a moreseverecondition.TheMADRSevaluates reported
sadness, apparent sadness, inner tension, reduced sleep, reduced appetite, concentration
difficulties, lassitude, inabilityto feel, pessimistic thoughts, and suicidal thoughts. The test exhibits
high inter-rater reliability. The typical recall period for the MADRS is 7 days.
The MADRS total score is the sum of scores from individual question items at a given time point, 
and ranges from 0 to 60. Higher scores represent a more severe condition. Imputation of total score 
is presented in section 5.1.4.
Negative changes in MADRS total score indicate improvement.
One estimand is defined for the primary endpoint: Primary Estimand.
5.3.2.
Primary Estimand 
Primary Trial Objective: To evaluate the efficacy of each individual dose of esketamine nasal 
spray, 56 mg and 84 mg, compared with placebo nasal spray in improving depressive symptoms 
in participants with TRD who have met nonresponse criteria, as assessed by the change from 
baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from Day 1 
(prerandomization) to end of the 4-week double-blind treatment phase (Day 28).
Estimand Scientific Question of Interest: What is the antidepressant benefit from each individual 
dose (56 mg and 84 mg) of esketamine nasal spray compared with placebo nasal spray in 
improving depressive symptoms in participants with TRD who have met nonresponse criteria 
based on the change in the Montgomery-Asberg Depression Rating Scale (MADRS) total score 
from Day 1 (prerandomization) to end of the 4-week double-blind treatment phase (Day 28) if the 
participants take study intervention as directed?
The primary estimand is defined by the following 5 components: 
Study Intervention:

Experimental: esketamine 56 mg, esketamine 84 mg

Control: Placebo 
Population: Participants with TRD who have met the inclusion/exclusion criteria and the 
nonresponse criteria
Variable: Change from baseline to Day 28 in the MADRS total score
Summary Measure: Difference in means between each dose and placebo for the change from 
baseline in MADRS total score at Day 28.




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MADRS total score at Day 28 in each dose of esketamine nasal spray compared to placebo. 
(National Research Council 2010; Permutt 2015)
This method will employ the following 3 steps:
Step 1 – Multiple Imputation (MI)
Missing at random (MAR) is assumed for intermediate missing data (ie, missing data between 
non-missing observations). If there are participants with a non-monotone missing data pattern, 
datasets with only monotone missing data patterns will be created first by imputing the 
intermediate missing values using methods such as the MCMC (Markov Chain Monte Carlo) 
method. Five hundred (500) imputations will be performed to create 500 unique datasets which 
now have monotone missing (ie., missing data after the participant experienced an intercurrent 
event) data pattern. This will be done using SAS PROC MI and the MCMC statement with the 
following specifications (in case of non-convergence, analysis center will be removed from the 
following model):
    PROC MI DATA=INPUT NIMPUTE=500 SEED=234 OUT=IN MCMC;
    VAR …; (intervention group, analysis center, antidepressant treatment status, and the
    preceding non-missing values in the order of clinical visits: baseline, Day 2, Day 8, Day 15,
    Day 22 and Day 28)
    MCMC CHAIN=SINGLE NBITER=200 NITER=100 IMPUTE=MONOTONE;
RUN;
Monotone missing data will first be imputed by MAR-based MI regression, and the imputed scores 
in the experimental intervention groups will be adjusted to be worse than the other participants in 
same group with non-missing data as discussed below. The multiple imputation will be performed 
using SAS PROC MI with the MONOTONE statement and the REGRESSION option with the 
following specifications (in case of non-convergence, analysis center will be removed from the 
following model):
PROC MI DATA=IN_MCMC NIMPUTE=1 (see note) SEED=234 OUT=OUTPUT;
BY IMPUTATION ;
    VAR …; (intervention group, analysis center, antidepressant treatment status, and the
    preceding non-missing values in the order of clinical visits: baseline, Day 2, Day 8, Day 15,
    Day 22 and Day 28)
CLASS …; (intervention group, analysis center, antidepressant treatment status)
MONOTONE REGRESSION;
RUN;
   *Note: NIMPUTE=500 if MCMC was NOT applied at the previous step.
The imputed values for subjects who discontinued DB treatment [QX[1]will be adjusted by adding 
 to the imputed values for participants randomized to the control group and adding  to the 
imputed values for participants randomized to the experimental intervention groups. Delta-
adjusted fully imputed datasets will be generated for different combinations of  and  values as 
defined below:




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Once monotone missing datasets are created after imputing intermediate missing data using the 
MCMC method as described in Section 5.3.2.1.2, the monotone missing data will be imputed using 
the Copy Reference (CR) MI method for the primary analysis as a supplementary analysis.
Missing not at random (MNAR) is assumed for monotone missing (i.e., missing data after the 
occurrence of an intercurrent event under treatment policy) in the experimental intervention group, 
where efficacy scores are assumed as if participant had always been in the control group. MAR is 
assumed for missing data in the control group.
The efficacy data that is either missing or not used after the intercurrent event at a given timepoint 
will be imputed using the imputation model of the control group, i.e., conditional on the data 
observed or imputed at previous timepoints relative to the mean of the model for the control group.
This approach does not assume a sustained benefit of experimental intervention for the efficacy 
data that is either missing or not used after the intercurrent event, and uses an imputation method 
that is based on the control group distribution and the estimated correlations between time points 
in the control group.
Step 2 – Analysis
Same MMRM analysis as described for the primary efficacy analysis (Section 5.3.2.1.1) will be 
performed for each set of the adjusted fully imputed datasets. 
Step 3 – Pooling
Rubin’s methodology will be applied to the MMRM results from the 500 imputed datasets to 
produce final inferences. (Rubin 1987) 
5.4.
Secondary Endpoint(s) Analysis
5.4.1.
Key Secondary Endpoint
Similar to the primary analysis, analysis of the key secondary endpoint will be based on the full
efficacy analysis set using the MADRS total scores collected during the double-blind phase.
5.4.1.1.
Definition
The key secondary efficacy endpoint is the change from baseline in MADRS total score from Day 
1 (prerandomization) to Day 2.
5.4.1.2.
Key Secondary Estimand
All components as described under Primary Estimand (Section 5.3.2) apply to the Key Secondary 
Estimand except for the variable and summary measure:
Variable: Change from baseline to Day 2 in the MADRS total score
Summary Measure: Difference in means between each dose and placebo for the change from 
baseline in MADRS total score at Day 2.


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5.4.1.3.
Analysis Methods
The key secondary efficacy variable, change from baseline in MADRS total score at Day 2 in the 
double-blind treatment phase, will be analyzed using the same MMRM model as described for the 
primary endpoint.
5.5.
Other Endpoint(s)
Analyses of other endpoints will be based on the full efficacy analysis set unless otherwise 
specified. 
5.5.1.
Response (≥50% Improvement) Based on MADRS Total Score
5.5.1.1.
Definition
A participant is defined as a responder at a given time point if the percent improvement from 
baseline in MADRS is ≥50% at that time point (ie, percent change ≤-50%). 
5.5.1.2.
Analysis 
The number and percentage of participants who achieve a response will be summarized at each 
time point during the double-blind phase by intervention group. 
Response rates over time will be plotted for double-blind phase.
5.5.2.
Remission (MADRS ≤10) Based on MADRS Total Score
5.5.2.1.
Definition
A participant is defined as a remitter at a given time point if the MADRS total score is ≤10 at that 
time point. 
5.5.2.2.
Analysis
The number and percentage of participants who achieve remission (MADRS ≤10) will be 
summarized at each time point during the double-blind phase by intervention group. 
Remission rates will be plotted for double-blind phase.
5.5.3.
Remission (MADRS ≤12) Based on MADRS Total Score
5.5.3.1.
Definition
A participant is defined as a remitter at a given time point if the MADRS total score is ≤12 at that 
time point. 
5.5.3.2.
Analysis
The number and percentage of participants who achieve remission (MADRS ≤12) will be 
summarized at each time point during the double-blind phase by intervention group. 
Remission rates will be plotted for double-blind phase.


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5.5.4.
Clinical Global Impression – Severity (CGI-S)
5.5.4.1.
Definition
The CGI-S provides an overall clinician-determined summary measure of the severity of the
participant's illness that takes into account all available information, including knowledge of the
participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the
symptoms on the participant’s ability to function. (Guy 1991) The CGI-S evaluates the severity
of psychopathology on a scale of 1 to 7. Considering total clinical experience with the depression
population, a participant is assessed on severity of illness at the time of rating according to:
0=not assessed; 1=normal (not at all ill); 2=borderline ill; 3=mildly ill; 4=moderately ill; 
5=markedly ill; 6=severely ill; 7=among the most extremely ill patients.
A score of 0 indicates that the participant was not assessed, and will be treated as missing. The 
score from 1 to 7 will be summarized as recorded.
Negative changes in CGI-S score indicate improvement.
5.5.4.2.
Analysis 
Descriptive statistics of the actual values and the change from baseline will be presented by 
intervention group for observed case data.
A frequency distribution over time of the CGI-S scores will be provided by intervention group. 
The frequency distributions will be presented graphically using stacked bar charts for the baseline, 
Day 2 and Day 28.
5.5.5.
Patient Health Questionnaire - 9 Item (PHQ-9)
5.5.5.1.
Definition
The 9-item Patient Health Questionnaire - 9 Item (PHQ-9) 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 intervention 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 recall period is 2 weeks.
Negative changes in PHQ-9 total score indicate improvement.
5.5.5.2.
Analysis 
Descriptive statistics of the actual values and the change from baseline to each postbaseline time 
point will be presented for PHQ-9 total score by intervention group.
Changes from baseline over time in PHQ-9 total score will be analyzed based on the same MMRM 
model as described for the primary endpoint with baseline PHQ-9 total score as the covariate. 
Least squares mean changes from baseline (+/- SE) over time will be presented graphically.


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5.5.6.
Response (≥6 Points Improvement) Based on PHQ-9 Total Score 
5.5.6.1.
Definition
A participant is defined as a responder at a given time point if improvement in PHQ-9 total score 
is ≥6 points at that time point.
5.5.6.2.
Analysis 
The number and percentage of participants who achieve response (≥6 points improvement) will 
be summarized at each time point during the double-blind phase by intervention group. 
Response rates over time will be plotted for the double-blind phase.
5.5.7.
Response (≥50% Improvement) Based on PHQ-9 Total Score 
5.5.7.1.
Definition
A participant is defined as a responder at a given time point if the percent improvement from 
baseline in PHQ-9 total score is ≥50% at that time point (ie, percent change ≤-50%). 
5.5.7.2.
Analysis 
The number and percentage of participants who achieve response (≥50% Reduction) will be 
summarized at each time point during the double-blind phase by intervention group. 
Response rates over time will be plotted for the double-blind phase.
5.5.8.
Remission (PHQ-9 <5) Based on PHQ-9 Total Score 
5.5.8.1.
Definition
A participant is defined as a remitter at a given time point if the PHQ-9 total score is <5 at that 
time point. 
5.5.8.2.
Analysis 
The number and percentage of participants who achieve remission (PHQ-9 <5) will be summarized 
at each time point during the double-blind phase by intervention group. 
Remission rates over time will be plotted for the double-blind phase.
5.5.9.
Efficacy Data in the Double-blind Phase for Participants Who Do Not 
Meet Nonresponse Criteria (Randomization List 2 Analysis Set)
These summaries will be provided for the randomization list 2 analysis set. Descriptive statistics 
of the actual values and the change from baseline to each post baseline time point in the double-
blind phase, will be presented for MADRS total score, CGI-S score and PHQ-9 score by 
intervention group.
Means and mean changes from baseline (+/- SE) over time will be presented graphically for 
MADRS total score during double-blind phase. 


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The number and percentage of participants who achieve remission based on MADRS total score, 
achieve response based on MARDS total score or achieve response based on PHQ-9 will be 
summarized at each time point during the double-blind phase by intervention group. 
A frequency distribution over time of the CGI-S scores will be provided for the double-blind phase 
by intervention group. 
5.5.10.
Efficacy Data in the Open-Label Treatment or Observation Phase
The summaries will be provided for the open-label analysis set and observation analysis set, 
separately. Descriptive statistics of the actual values and the change from baseline to each post 
baseline time point in the double-blind and open-label treatment or observation phase, will be 
presented for MADRS total score and CGI-S score.
Means and mean changes from baseline (+/- SE) over time will be presented graphically for 
MADRS total score during double-blind phase and open-label treatment or observation phase.
The number and percentage of participants who achieve remission based on MADRS total score, 
achieve response based on MARDS total score will be summarized at each time point during the 
double-blind phase and open-label treatment or observation phase by intervention group. 
Remission and response rates based on MARDS total score will be plotted for the double-blind 
phase and open-label treatment or observation phase.
A frequency distribution over time of the CGI-S scores will be provided for the double-blind phase 
and open-label treatment or observation phase by intervention group. 
5.5.11.
Subgroup Analyses
Forest plots will be provided displaying analysis results for each subgroup listed in Section 5.7.1. 
The point estimate of the treatment difference and its 95% confidence interval for each subgroup 
will be based on an MMRM analysis for the primary endpoint using the appropriate contrast. The 
model will include factors for treatment, analysis center, antidepressant treatment status at 
screening entry, day, subgroup, day-by-treatment interaction, treatment-by-subgroup interaction, 
day-by-treatment-by-subgroup, and baseline MADRS total score as a covariate. The terms in the 
models will be adjusted for the subgroup of baseline MADRS total score (≤/> median). Baseline 
MADRS total score (as a continuous covariate) will not be included in the model when the 
dichotomized baseline MADRS total score is included in the model.
The analyses will be performed for the full efficacy analysis set.
5.6.
Safety Analyses
All safety analyses for double-blind phase will be based on the safety analysis set based on actual 
intervention received, unless otherwise specified. All safety analyses for the open-label treatment/ 
observation phase will be based on open-label analysis set and observation analysis set based on 
participants receiving esketamine or SOC only, respectively, in this phase. Safety analyses for the 
follow-up analysis phase will be based on the safety analysis set. 


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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.
5.6.1.
Extent of Exposure
The number and percentage of participants who receive each study agent within a study 
intervention will be summarized by phase. 
Descriptive statistics for duration of each study agent within a study intervention (N, mean, SD, 
median, and range [minimum, maximum]) will be summarized by phase. 
Duration of intervention will be summarized for the double-blind phase in the following duration 
categories: ≤7 days, 8-14 days, 15-21 days, 22-25 days, >25 days for each study agent within a 
study intervention.
Duration of intervention will be summarized for the open-label treatment phase in the following 
duration categories: ≤28 days, 29-56 days, 57-84, >84 days for participants receiving open-label 
esketamine study intervention. 
Study intervention duration is defined as (date of last dose of study intervention – date of first dose 
of study intervention) +1.
Total dose days of intervention is defined as the total number of days that study intervention was 
administered to the participant (excluding days off study intervention). Descriptive statistics for 
total dose days within a study intervention (N, mean, SD, median, and range [minimum, 
maximum]) will be summarized. A frequency distribution will also be provided. 
The analysis will be performed on safety analysis set and open-label analysis set. 
Patients’ awareness of study intervention assignment will be summarized for the double-blind 
phase on the full efficacy analysis set and safety analysis set.
5.6.2.
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). Any AE occurring at or after the 
initial administration of study intervention through the day of last dose is considered to be 
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.


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Assignment of adverse events to double-blind, open-label treatment/observation or follow-up
phase will be made based on the following rules:
Double-blind phase:
AEs will be assigned to the double-blind analysis phase as detailed below.

For participants who did not continue to open-label treatment/observation phase or 
participants who chose to be observed only (receive SOC only) in the observation phase: 
double-blind phase start date/time ≤AE onset date/time ≤double-blind phase end date.

For participants who received open-label esketamine nasal spray: double-blind phase start 
date /time ≤AE onset date/time <double-blind phase end date/time (ie, open-label phase 
start date/time)
o
AEs that occur on the last day of double-blind phase but AE onset time is missing 
will be assigned to the double-blind phase. 
AEs that are assigned to the double-blind analysis phase as detailed below will be considered as 
treatment-emergent.

For participants completed double-blind treatment: all the AEs in the double-blind 
treatment phase will be considered as treatment-emergent for the double-blind phase.

For participants who discontinued double-blind treatment and double-blind phase at the 
same time, all the AEs in the double-blind treatment phase will be considered as treatment-
emergent for the double-blind phase.

For participants who discontinued double-blind treatment but continued to be assessed until 
the end of double-blind phase (Day 28), AEs will be considered as treatment-emergent for 
the double-blind phase only if they satisfy the condition: double-blind phase start date /time 
≤AE onset date/time ≤ last day of double-blind treatment.
Open-label treatment phase: 

For participants who received open-label esketamine nasal spray, all AEs that are assigned 
to the open-label treatment phase will be considered as treatment-emergent if they satisfy
the condition: open label treatment phase start date/time≤ AE onset date/time ≤ open label 
treatment phase end date.
o
AEs that occur on the last day of double-blind phase but AE onset time is after 
open-label dosing will be considered as treatment-emergent for the open-label 
treatment phase. 
Observation phase: 

For participants who received SOC only in the observation phase, all AEs that are assigned 
to the observation phase will not be considered as treatment-emergent if they satisfy the 
condition: double-blind phase end date+1≤ AE onset date ≤ observation phase end date.


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Follow-up phase:

Any AEs that are assigned to the follow-up phase will not be considered as treatment-
emergent. AEs during the follow-up phase should satisfy the condition: follow-up phase 
start date ≤AE onset date ≤follow-up phase end date.
Summary tables will be provided for adverse events by phase:

AEs

Serious AEs (SAEs)

AEs leading to discontinuation of each study agent within a study intervention

AEs by severity

AEs by relationship to each study agent within a study intervention

AEs of special interest
In addition to the summary tables, listings will be provided for participants who had:

SAEs

AEs leading to discontinuation of study intervention

AEs of special interest
Incidence of other treatment-emergent adverse events of special interest will be summarized. See 
Appendix 7 for list of adverse events in each category.
The proportion of TEAEs occurring on dosing days and the proportion of TEAEs that occur on 
dosing days with same day resolution will be summarized. Duration and resolution time of severe 
TEAEs will also be summarized.
A listing of participants who died will be provided.
5.6.3.
Additional Safety Assessments 
5.6.3.1.
Vital Signs and Physical Examination Findings
Descriptive statistics for values and changes from baseline at each scheduled time-point will be 
presented for temperature, systolic blood pressure, diastolic blood pressure, pulse rate, weight, and 
BMI by phase. In addition, descriptive statistics of pulse rate and blood pressure (systolic and 
diastolic) values, changes and percent changes from predose will be provided for each dosing day
by phase. These summaries will also be provided by hypertension status (history of hypertension 
recorded in medical history: Yes/No). For DB and OL phases, summary statistics over time will 
only be provided on dosing days with the exception of Day 2 (DB) and Day 28(DB). Frequency
distributions of maximum percent change increase from predose and time of maximum percent
change increase will also be presented by phase. Note that if the maximum value within a phase 
occurs at multiple time points, the earliest time point is selected.


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The proportion of participants who have a treatment-emergent abnormality, as defined in Table 7
below, will be presented over time and by phase. Both the double-blind baseline and the predose 
assessment will be used to determine abnormal values. A listing of participants meeting any of the 
criteria will also be provided.
Table 7: 
Clinically Important Abnormalities in Vital Signs
Vital Sign
Abnormal Category
Criteria
Pulse
Abnormally high
≥100 bpm and with ≥15 bpm increase from baseline/predose
Abnormally low
≤50 bpm and with ≥15 bpm decrease from baseline/predose
Systolic blood 
pressure
Abnormally high
≥180 mm Hg and with ≥20 mm Hg increase from baseline/predose
Abnormally low
≤90 mm Hg and with ≥20 mm Hg decrease from baseline/predose
Diastolic blood 
pressure
Abnormally high
≥105 mm Hg and with ≥15 mm Hg increase from baseline/predose
Abnormally low
≤50 mm Hg and with ≥15 mm Hg decrease from baseline/predose
The proportion of participants who experienced acute hypertension (systolic BP≥180 or diastolic
BP≥110) at any time during the double-blind phase will be summarized by treatment group and 
hypertension status.
Mean (+/-SE) values for systolic BP, diastolic BP and heart rate will be presented graphically over 
the double-blind phase by intervention group and hypertension status. In addition, for participants 
with hypertension who receive antihypertensive medication, the same graphs will be summarized 
by medication type (beta-blockers, all other agents).
5.6.3.2.
Other Safety Parameters
5.6.3.2.1.
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed to assess severity and track suicidal events through any intervention (Posner 2007). It 
is a clinical interview providing a summary of both suicidal ideation and behavior that can be 
administered during any evaluation or risk assessment to identify the level and type of suicidality 
present. The C-SSRS has been used frequently in clinical studies, and is a validated, standard 
measure for suicidal ideation assessment. Using the C-SSRS, the outcomes will be categorized 
using the scoring for the 11 categories:
Suicidal Ideation (1-5)
1
Wish to be dead
2
Non-specific active suicidal thoughts
3
Active suicidal ideation with any methods (not plan) without intent to act
4
Active suicidal ideation with some intent to act, without specific plan
5
Active suicidal ideation with specific plan and intent
Suicidal Behavior (6-10)
6
Preparatory acts or behavior
7
Aborted attempt
8
Interrupted attempt


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9
Actual attempt
10
Suicide
Non-suicidal self-injurious behavior (11)
11
Non-suicidal self-injurious behavior
At each time point, an event of suicidal ideation or behavior will be assigned a score of 1 to 10 
based on the maximum response for the C-SSRS at that visit. If there is no event of suicidal 
ideation or behavior, a score of 0 will be assigned (0=“no suicidal ideation or behavior that can be 
assessed on the basis of C-SSRS”). A participant with an event of non-suicidal self-injurious 
behavior only will not be considered as having suicidal ideation or behavior, therefore a score of 
0 will be assigned. However, an additional score of 11 will be assigned to summarize any 
participants with an event of non-suicidal self-injurious behavior.
Shifts from the baseline to the maximum postbaseline score pertaining to suicidal ideation or 
suicidal behavior (i.e., scores 1 to 10) will be summarized by study intervention for each phase.  
The maximum score (of scores 0 to 10) assigned to each participant will be grouped into one of 
three broad categories: No suicidal ideation or behavior (0), Suicidal ideation (1-5), Suicidal 
behavior (6-10). Shifts from baseline to the maximum postbaseline category will be summarized 
by study intervention for each phase. 
A frequency distribution of the scores for the 11 categories (0 to 10) will be provided by study 
intervention at each time point for each phase. In addition, the number and proportion of 
participants with non-suicidal self-injurious behavior (a score of 11) will be provided by study 
intervention at each time point for each phase. 
5.7.
Other Analyses
5.7.1.
Definition of Subgroups
Subgroup
Definition
Sex
Male
Female
Undifferentiated
Race
White
Black
Other
Age Group
18-34 years
35-54 years
55-64 years
≥ 65 years
Failed antidepressant 
intervention history
2
3 or more
Number of major 
depressive episodes to date, 
including current episode
1
2
≥3
Baseline MADRS total 
score (<=/>median)
Yes
No


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Subgroup
Definition
Antidepressant status at 
screening / entry
On-treatment
Off-treatment
5.7.2.
Pharmacokinetics
PK analyses will be performed on the safety analysis set.
Descriptive statistics (N, mean, SD, median, range, CV (%) and IQ range) will be used to 
summarize plasma concentrations at each sampling time point for esketamine (and noresketamine 
if measured)  
5.7.3.
Quality Tolerance Limit 
Quality Tolerance Limit (QTL) parameters and thresholds are defined and will be monitored in 
this study. QTL parameters will be summarized. More details are described in the Integrated 
Analytical Risk-Based Monitoring (iARBM) Plan.
5.8.
Interim Analyses
Not applicable.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AD
antidepressant
AE
adverse event
ANCOVA
analysis of covariance
BMI
body mass index
BP
Blood pressure
CGI-S
Clinical Global Impression – Severity
CI
confidence interval
CR
Copy reference
CRF
case report form
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
DB
Double-blind
DSM-5
Diagnostic and Statistical Manual of Mental Disorders (5th edition)
eCRF
electronic case report form
FDA
Food and Drug Administration
F/U
Follow-up
ICH
International Conference on Harmonisation
MADRS
Montgomery-Asberg Depression Rating Scale
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MDD
Major Depressive Disorder
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
MMRM
Mixed-Effect Model for Repeated Measures
MNAR
Missing not at random
OBS
Observation
OL
Open-label
PD
pharmacodynamic(s)
PHQ-9
Patient Health Questionnaire - 9 Item
PK
pharmacokinetic(s)
SAE
serious adverse event
QTL
Quality Tolerance Limits
SAP
Statistical Analysis Plan
SD
standard deviation
SE
Standard error
SOC
Standard of care
TEAE
TRD
treatment-emergent adverse event
Treatment Resistant Depression
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
Not applicable


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6.3.
Appendix 3 Demographics and Baseline Characteristics
The number of participants in each analysis set will be summarized and listed by intervention
group, combined active intervention group, and overall. In addition, the distribution of participants
by site ID will be presented.
Table 8 presents a list of the demographic variables that will be summarized by intervention group, 
combined active intervention group, and overall for the full efficacy analysis set, safety analysis 
set and randomization list 2 analysis set.  
Table 8: 
Demographic Variables
Continuous Variables
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median and 
range [minimum and maximum]).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables
Frequency distribution with the number 
and percentage of participants in each 
category.
Age (18-34 years, 35-54 years, 55-64 years, and ≥65 years)
Sex (male, female, undifferentiated)
Racea (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or other Pacific Islander, White, Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
BMI (underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, overweight 
25-<30 kg/m2, obese >=30 kg/m2)
Antidepressant status at screening / entry (On-treatment, Off-treatment)
a
If multiple race categories are indicated, the Race is recorded as 'Multiple'
A summary of the stratification factors will be provided by intervention arm.
Table 9 presents a list of the baseline disease characteristics variables that will be summarized by 
intervention group, combined active intervention group, and overall for the full efficacy analysis 
set, safety analysis set and randomization List 2 analysis set.  
Table 9: 
Baseline Disease Characteristics
Continuous Variables
Summary Type
Age (years) when diagnosed with MDD
Descriptive statistics (N, mean, 
standard deviation [SD], median and 
range [minimum and maximum]).
Duration (weeks) of current depressive episode
Baseline MADRS total score
Baseline CGI-S score
Baseline PHQ-9 total score
Screening IDS-C30 total score
Categorical Variables
Frequency distribution with the number 
and percentage of participants in each 
category.
Baseline CGI-S score (Normal (not at all ill), Borderline mentally ill, Mildly ill, 
Moderately ill, Markedly ill, Severely ill, Among the most extremely ill patients)
Screening C-SSRS lifetime (no event, suicidal ideation, suicidal behavior)
Screening C-SSRS past 6 or 12-month (no event, suicidal ideation, suicidal 
behavior)
Antidepressant treatment history (number of medications taken for at least 6 weeks 
during the current episode as obtained in the MGH-ATRQ)
Failed antidepressant intervention history (2, 3 or more)
Number of major depressive episodes to date, including current episode (1, 2, ≥3)
Family history of alcohol abuse (Yes, No)
Family history of anxiety disorder (Yes, No)
Family history of bipolar disorder (Yes, No)
Family history of depression (Yes, No)


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Family history of schizophrenia (Yes, No)
Family history of substance abuse (Yes, No)
6.4.
Appendix 4 Protocol Deviations and Quality Tolerance Limits (QTL)
In general, the following list of 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 and the 
participants with major protocol deviations will be summarized by category for the all randomized
analysis set.

Developed withdrawal criteria but not withdrawn

Entered but did not satisfy criteria

Received a disallowed concomitant treatment

Received wrong treatment or incorrect dose

Other
Number of participants not meeting inclusion criteria, or meeting exclusion criteria will be 
summarized by study intervention group for the all randomized analysis set.
Quality Tolerance Limit parameters and thresholds are defined and will be monitored in this study. 
QTL parameters will be summarized. More details are described in the Integrated Analytical Risk-
Based Monitoring (iARBM) Plan.


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6.5.
Appendix 5 Prior and Concomitant Medications
Prior medications 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 on after the first dose of study intervention.
Summaries of concomitant medications will be presented by base preferred term for the double-
blind, open-label treatment/observation and follow-up phases for safety, open-label/observation
and safety analysis sets, respectively. 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 
summarized. These include antidepressant medications received prior to the first dose of study 
intervention. See Appendix 8 for list of medications in each category.
Prior medications and prior medications of special interest will be summarized by base preferred 
term.


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6.6.
Appendix 6 Medical History
Not applicable


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6.7.
Appendix 7 Adverse Events of Special Interest
Adverse events of special interest are defined as follows:
AE Special Interest Category
Preferred Term
Drug abuse, dependence and 
withdrawal
Aggression, Confusional state, Decreased activity, Dependence, 
Disorientation, Dissociation, Dissociative disorder, Dizziness, Drug use 
disorder, Drug abuse, Drug abuser, Drug dependence, Drug detoxification, 
Drug diversion, Drug rehabilitation, Drug tolerance, Drug tolerance 
increased, Drug withdrawal convulsions, Drug withdrawal headache, Drug 
withdrawal syndrome, Euphoric mood, Feeling abnormal, Feeling drunk, 
Feeling of relaxation, Hallucination, Hallucination auditory, Hallucination 
gustatory, Hallucination olfactory, Hallucination 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
Increased blood pressure
Blood pressure increased, Blood pressure diastolic increased, Blood 
pressure systolic increased, Hypertensive crisis, Hypertensive emergency, 
Hypertension
Increased heart rate
Heart rate increased, Tachycardia, Extrasystoles
Transient dizziness/vertigo
Dizziness, Dizziness exertional, Dizziness postural, Dizziness procedural, 
Procedural dizziness, Vertigo, Vertigo labyrinthine, Vertigo positional, 
Vertigo CNS origin
Impaired cognition
Cognitive disorder
Cystitis
Allergic cystitis, Chemical cystitis, Cystitis, Cystitis erosive, Cystitis 
haemorrhagic, Cystitis interstitial, Cystitis noninfective, Cystitis 
ulcerative, Cystitis-like symptom, Pollakiuria, Dysuria, Micturition 
urgency, Nocturia
Anxiety
Anticipatory anxiety, Anxiety, Anxiety disorder, Agitation, Fear, Feeling 
jittery, Irritability, Nervousness, Panic attack, Tension
Anticipated Dosing-related AEs
Anxiety, Anticipatory anxiety, Dissociation, Dizziness, Dizziness postural, 
Feeling abnormal, Feeling drunk, Nausea, Somnolence, Vertigo, Vomiting
Events potentially related to 
suicidality
Completed suicide, Depression suicidal, Intentional overdose, Intentional 
self-injury, Multiple drug overdose intentional, Poisoning deliberate, Self-
injurious behavior, Self-injurious behaviour Self-injurious ideation, 
Suicidal behavior, Suicidal behaviour, Suicidal ideation, Suicide attempt
Hepatic adverse events
Cholecystitis, Cholelithiasis, Hepatic steatosis, Hepatitis, Non-alcoholic 
steatohepatitis, Primary biliary cholangitis, Alanine aminotransferase 
increased, Aspartate aminotransferase increased, Blood bilirubin increased, 
Gamma-glutamyl transferase increased, Hepatic enzyme increased, Liver 
function test abnormal, Liver function test increased, Transaminases 
increased, Urine bilirubin increased, Urobilinogen urine increased
Events related to renal disorders
Cystitis, Pyelonephritis, Urethritis, Urinary tract infection, Blood 
creatinine increased, Blood urea increased, Blood urine present, Creatinine 
renal clearance increased, Protein urine present, Urine analysis abnormal, 
Urine leukocyte esterase positive, Bladder discomfort, Bladder irritation, 
Bladder outlet obstruction, Cystitis noninfective, Dysuria, Haematuria, 
Hypertonic bladder, Lower urinary tract symptoms, Micturition urgency, 
Nephrolithiasis, Nocturia, Pollakiuria, Polyuria, Proteinuria, Renal colic, 
Renal failure, Semenuria, Stress urinary incontinence, Ureterolithiasis, 
Urge incontinence, Urinary bladder polyp, Urinary hesitation, Urinary 
incontinence, Urinary retention


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AE Special Interest Category
Preferred Term
Symptoms of dissociation 
persisting beyond the typical ≤2 
hour post esketamine 
administration 
Dissociation[QX[2]
Delirium
Post-injection delirium sedation syndrome, Postoperative delirium, 
Delirium, Intensive care unit delirium
Psychosis
Acute psychosis, Affective disorder, Alcoholic psychosis, Bipolar I 
disorder, Epileptic psychosis, Hysterical psychosis, Mania, Parkinson's 
disease psychosis, Postictal psychosis, Psychosis postoperative, Psychotic 
disorder, Psychotic disorder due to a general medical condition, Reactive 
psychosis, Rebound psychosis, Schizoaffective disorder, Substance-
induced psychotic disorder, Transient psychosis
Mania
Hypomania, Mania


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6.8.
Appendix 8 Medications of Special Interest
Concomitant medications of special interest are defined as follows:
Concomitant Medication Special Interest Category
Standard Medication Name
Antidepressants
Agomelatine
Antidepressants
Amfebutamone
Antidepressants
Amfebutamone Hydrochloride
Antidepressants
Amitriptyline
Antidepressants
Amitriptyline Hydrochloride
Antidepressants
Amixid
Antidepressants
Amoxapine
Antidepressants
Bupropion
Antidepressants
Bupropion Hydrochloride
Antidepressants
Citalopram
Antidepressants
Citalopram Hydrobromide
Antidepressants
Clomipramine
Antidepressants
Clomipramine Hydrochloride
Antidepressants
Desipramine
Antidepressants
Desipramine Hydrochloride      
Antidepressants
Desvenlafaxine
Antidepressants
Desvenlafaxine Succinate
Antidepressants
Dibenzepin Hydrochloride
Antidepressants
Dosulepin
Antidepressants
Dosulepine
Antidepressants
Doxepin
Antidepressants
Doxepin Hydrochloride
Antidepressants
Duloxetine
Antidepressants
Duloxetine Hydrochloride
Antidepressants
Escitalopram
Antidepressants
Escitalopram Oxalate 
Antidepressants
Fluoxetine
Antidepressants
Fluoxetine Hydrochloride
Antidepressants
Fluvoxamine
Antidepressants
Fluvoxamine Maleate
Antidepressants
Imipramine
Antidepressants
Imipramine Hydrochloride
Antidepressants
Levomilnacipran
Antidepressants
Levomilnacipran Hydrochloride
Antidepressants
Maprotiline
Antidepressants
Maprotiline Hydrochloride
Antidepressants
Mianserin
Antidepressants
Mianserin Hydrochloride        


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Concomitant Medication Special Interest Category
Standard Medication Name
Antidepressants
Milnacipran
Antidepressants
Milnacipran Hydrochloride
Antidepressants
Mirtazapine
Antidepressants
Moclobemide
Antidepressants
Nefazodone Hydrochloride
Antidepressants
Nortriptyline  
Antidepressants
Nortriptyline Hydrochloride    
Antidepressants
Paroxetine
Antidepressants
Paroxetine Hydrochloride
Antidepressants
Paroxetine Mesilate 
Antidepressants
Phenelzine
Antidepressants
Pipofezine
Antidepressants
Pirlindole
Antidepressants
Reboxetine
Antidepressants
Sertraline
Antidepressants
Sertraline Hydrochloride
Antidepressants
Stangyl     
Antidepressants
Symbiax
Antidepressants
Tianeptine
Antidepressants
Tranylcypromine
Antidepressants
Trazodone
Antidepressants
Trazodone Hydrochloride
Antidepressants
Trimipramine Maleate                                                  
Antidepressants
Venlafaxine
Antidepressants
Venlafaxine Hydrochloride
Antidepressants
Vilazodone
Antidepressants
Vortioxetine
Antidepressants
Vortioxetine Hydrobromide
Antidepressants
Deanxit  
Atypical Antipsychotics
Amisulpride
Atypical Antipsychotics
Aripiprazole
Atypical Antipsychotics
Asenapine
Atypical Antipsychotics
Asenapine Maleate
Atypical Antipsychotics
Brexpiprazole
Atypical Antipsychotics
Cariprazine Hydrochloride
Atypical Antipsychotics
Clotiapine
Atypical Antipsychotics
Clozapine
Atypical Antipsychotics
Lurasidone
Atypical Antipsychotics
Olanzapine
Atypical Antipsychotics
Paliperidone
Atypical Antipsychotics
Prothipendyl                                                                 


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Status: Approved, Date: 16 February 2024
Concomitant Medication Special Interest Category
Standard Medication Name
Atypical Antipsychotics
Quetiapine
Atypical Antipsychotics
Quetiapine Fumarate
Atypical Antipsychotics
Risperidone
Atypical Antipsychotics
Seroquel  
Atypical Antipsychotics
Ziprasidone
Atypical Antipsychotics
Ziprasidone Hydrochloride
Atypical Antipsychotics
Melperone
Atypical Antipsychotics
Melperone Hydrochloride
Atypical Antipsychotics
Nemonapride              
Atypical Antipsychotics
Rapitry-3
Atypical Antipsychotics
Sertindole
Atypical Antipsychotics
Sulpiride
Typical Antipsychotics
Benperidol
Typical Antipsychotics
Chlorpromazine
Typical Antipsychotics
Chlorpromazine Hydrochloride
Typical Antipsychotics
Chlorpromazine Maleate                                              
Typical Antipsychotics
Chlorprothixene
Typical Antipsychotics
Chlorprothixene Hydrochloride
Typical Antipsychotics
Clopenthixol
Typical Antipsychotics
Clopenthixol Hydrochloride
Typical Antipsychotics
Cyamemazine
Typical Antipsychotics
Droperidol
Typical Antipsychotics
Etrafon-D
Typical Antipsychotics
Flupentixol
Typical Antipsychotics
Flupentixol Dihydrochloride
Typical Antipsychotics
Fluphenazine
Typical Antipsychotics
Fluphenazine Hydrochloride
Typical Antipsychotics
Haloperidol
Typical Antipsychotics
Haloperidol Lactate
Typical Antipsychotics
Levomepromazine
Typical Antipsychotics
Levomepromazine Hydrochloride
Typical Antipsychotics
Levomepromazine Maleate
Typical Antipsychotics
Loxapine
Typical Antipsychotics
Loxapine Succinate
Typical Antipsychotics
Mesoridazine
Typical Antipsychotics
Molindone
Typical Antipsychotics
Penfluridol
Typical Antipsychotics
Perazine
Typical Antipsychotics
Perazine Dimaleate
Typical Antipsychotics
Periciazine
Typical Antipsychotics
Perphenazine


JNJ54135419  (esketamine)
Statistical Analysis Plan 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
46
Status: Approved, Date: 16 February 2024
Concomitant Medication Special Interest Category
Standard Medication Name
Typical Antipsychotics
Perphenazine Enantate
Typical Antipsychotics
Pimozide
Typical Antipsychotics
Pipamperone
Typical Antipsychotics
Pipotiazine
Typical Antipsychotics
Prochlorperazine                 
Typical Antipsychotics
Promazine
Typical Antipsychotics
Promazine Hydrochloride
Typical Antipsychotics
Promethazine
Typical Antipsychotics
Promethazine Hydrochloride
Typical Antipsychotics
Thioproperazine
Typical Antipsychotics
Thioproperazine Dimesilate
Typical Antipsychotics
Thioridazine
Typical Antipsychotics
Thioridazine Hydrochloride
Typical Antipsychotics
Tiapride
Typical Antipsychotics
Tiotixene
Typical Antipsychotics
Trifluoperazine
Typical Antipsychotics
Trifluoperazine Hydrochloride
Typical Antipsychotics
Trinicalm Forte
Typical Antipsychotics
Trinicalm Plus
Typical Antipsychotics
Zotepine
Typical Antipsychotics
Zuclopenthixol
Typical Antipsychotics
Zuclopenthixol Acetate
Typical Antipsychotics
Zuclopenthixol Hydrochloride
Mood Stabilizers And Antiepileptics
Carbamazepine
Mood Stabilizers And Antiepileptics
Ergenyl Chrono
Mood Stabilizers And Antiepileptics
Gabapentin
Mood Stabilizers And Antiepileptics
Lamotrigine
Mood Stabilizers And Antiepileptics
Levetiracetam
Mood Stabilizers And Antiepileptics
Lithium
Mood Stabilizers And Antiepileptics
Lithium Carbonate
Mood Stabilizers And Antiepileptics
Lithium Citrate            
Mood Stabilizers And Antiepileptics
Primidone
Mood Stabilizers And Antiepileptics
Topiramate
Mood Stabilizers And Antiepileptics
Valproate Semisodium
Mood Stabilizers And Antiepileptics
Valproate Sodium
Mood Stabilizers And Antiepileptics
Valproic Acid
Mood Stabilizers And Antiepileptics
Zonisamide
Benzodiazepines
Alprazolam
Benzodiazepines
Bromazepam
Benzodiazepines
Brotizolam
Benzodiazepines
Chlordiazepoxide


JNJ54135419  (esketamine)
Statistical Analysis Plan 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
47
Status: Approved, Date: 16 February 2024
Concomitant Medication Special Interest Category
Standard Medication Name
Benzodiazepines
Chlordiazepoxide Hydrochloride
Benzodiazepines
Cinolazepam
Benzodiazepines
Clobazam
Benzodiazepines
Clonazepam
Benzodiazepines
Clorazepate
Benzodiazepines
Clorazepate Dipotassium
Benzodiazepines
Clorazepic Acid
Benzodiazepines
Clotiazepam                           
Benzodiazepines
Cloxazolam                       
Benzodiazepines
Diazepam
Benzodiazepines
Estazolam
Benzodiazepines
Ethyl Loflazepate
Benzodiazepines
Fludiazepam
Benzodiazepines
Flunitrazepam
Benzodiazepines
Flurazepam
Benzodiazepines
Flurazepam Hydrochloride
Benzodiazepines
Gidazepam
Benzodiazepines
Loprazolam
Benzodiazepines
Loprazolam Mesilate
Benzodiazepines
Lorazepam
Benzodiazepines
Lormetazepam
Benzodiazepines
Medazepam
Benzodiazepines
Midazolam
Benzodiazepines
Midazolam Hydrochloride        
Benzodiazepines
Midazolam Maleate
Benzodiazepines
Nimetazepam                           
Benzodiazepines
Nitrazepam
Benzodiazepines
Noctran
Benzodiazepines
Nordazepam
Benzodiazepines
Oxazepam
Benzodiazepines
Phenazepam
Benzodiazepines
Prazepam
Benzodiazepines
Staurodorm
Benzodiazepines
Temazepam
Benzodiazepines
Tofisopam
Benzodiazepines
Triazolam                      
Benzodiazepines
Valium For Injection
Benzodiazepines
Benzodiazepine Derivatives
Non-Benzodiazepines Hypnotics And Anxiolytics
Buspirone
Non-Benzodiazepines Hypnotics And Anxiolytics
Buspirone Hydrochloride
Non-Benzodiazepines Hypnotics And Anxiolytics
Clonidine


JNJ54135419  (esketamine)
Statistical Analysis Plan 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
48
Status: Approved, Date: 16 February 2024
Concomitant Medication Special Interest Category
Standard Medication Name
Non-Benzodiazepines Hypnotics And Anxiolytics
Diphenhydramine
Non-Benzodiazepines Hypnotics And Anxiolytics
Diphenhydramine Hydrochloride
Non-Benzodiazepines Hypnotics And Anxiolytics
Doxylamine Succinate
Non-Benzodiazepines Hypnotics And Anxiolytics
Eszopiclone
Non-Benzodiazepines Hypnotics And Anxiolytics
Etifoxine
Non-Benzodiazepines Hypnotics And Anxiolytics
Etifoxine Hydrochloride
Non-Benzodiazepines Hypnotics And Anxiolytics
Hydroxyzine
Non-Benzodiazepines Hypnotics And Anxiolytics
Hydroxyzine Embonate
Non-Benzodiazepines Hypnotics And Anxiolytics
Hydroxyzine Hydrochloride
Non-Benzodiazepines Hypnotics And Anxiolytics
Melatonin
Non-Benzodiazepines Hypnotics And Anxiolytics
Pregabalin
Non-Benzodiazepines Hypnotics And Anxiolytics
Ramelteon
Non-Benzodiazepines Hypnotics And Anxiolytics
Tasimelteon
Non-Benzodiazepines Hypnotics And Anxiolytics
Zolpidem
Non-Benzodiazepines Hypnotics And Anxiolytics
Zolpidem Tartrate
Non-Benzodiazepines Hypnotics And Anxiolytics
Zopiclone
Non-Benzodiazepines Hypnotics And Anxiolytics
Prothipendyl Hydrochloride                                         
Non-Benzodiazepines Hypnotics And Anxiolytics
Dexmedetomidine


JNJ54135419  (esketamine)
Statistical Analysis Plan 54135419TRD4005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
49
Status: Approved, Date: 16 February 2024
7.
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