Conditions: Depressive Disorder, Treatment-Resistant
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 252
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of switching adult participants with treatment-resistant depression (TRD) from a prior antidepressant treatment (to which they have not responded) to flexibly dosed intranasal esketamine (56 milligram \[mg\] or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in improving depressive symptoms. Efficacy will be assessed by the change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) total score from Day 1 (before randomization) to the end of the 4-week double-blind treatment phase.

Detailed description:

Arms:
arm 1: Eligible participants will self-administer esketamine (56 mg or 84 mg) intranasally twice per week for 4 weeks as a flexible dose regimen in the Double-Blind Treatment Phase. All participants will start at a dose of 56 milligram (mg) on Day 1. The dose may be increased to 84 mg or maintained at 56 mg per investigator's discretion. In addition, participants will simultaneously initiate a new, open-label 1 of 4 oral antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine extended release \[XR\]) on Day 1 that will be continued for the duration of the 4-week Double-Blind Treatment Phase. arm 2: Eligible Participants will self-administer matching placebo intranasally twice per week for 4 weeks in Double-Blind Treatment Phase. In addition, participants will simultaneously initiate a new, open-label oral antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Treatment Phase.

Interventions: intervention 1: Esketamine 56 mg intervention 2: Esketamine 84 mg intervention 3: Placebo intervention 4: Duloxetine (Oral Antidepressant) intervention 5: Escitalopram (Oral Antidepressant) intervention 6: Sertraline (Oral Antidepressant) intervention 7: Venlafaxine Extended Release (XR) (Oral Antidepressant)
Intervention descriptions: intervention 1: Participants will self-administer 56 mg of esketamine as intranasal spray. intervention 2: Participants will self-administer 84 mg of esketamine as intranasal spray. intervention 3: Participants will self-administer matching placebo as intranasal spray. intervention 4: Duloxetine can be selected as the oral antidepressant medication based on investigator's discretion. The minimum therapeutic dose is 60 milligram per day (mg/day). intervention 5: Escitalopram can be selected as the oral antidepressant medication based on investigator's discretion. Escitalopram will be started at a dose of 10 mg/day and up-titrated to a maximum dose of 20 mg/day. intervention 6: Sertraline can be selected as the oral antidepressant medication based on investigator's discretion. Sertraline will be started at a dose of 50 mg/day and up-titrated to a maximum dose of 200 mg/day. intervention 7: Venlafaxine XR can be selected as the oral antidepressant medication based on investigator's discretion. Venlafaxine XR will be started at a dose of 75 mg/day and up-titrated to a maximum dose of 225 mg/day.

Protocol document:
Prot_000.pdf: 
Confidential – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 21 January 2021
Janssen Research & Development *
Clinical Protocol
A Randomized, Double-blind, Multicenter Active-controlled Study to Evaluate the Efficacy, 
Pharmacokinetics, Safety and Tolerability of Flexible Doses of Intranasal Esketamine Plus 
an Oral Antidepressant in Adult Subjects with Treatment-resistant Depression
Protocol ESKETINTRD3006; Phase 3
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 Pharmaceutica NV; Janssen, Inc; Janssen
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information
page that accompanies the protocol.
This compound is being investigated in Phase 3 clinical studies.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
Status:
Approved
Date:
21 January 2021
Prepared by:
Janssen Research & Development, LLC  
EDMS number:
EDMS-ERI-120309540, 3.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03434041


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Status: Approved, Date: 21 January 2021
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 18
TIME AND EVENTS SCHEDULE (SCREENING/PROSPECTIVE OBSERVATIONAL PHASE 
AND DOUBLE-BLIND TREATMENT PHASE)................................................................................. 30
TIME AND EVENTS SCHEDULE (FOLLOW-UP PHASE)........................................................................ 34
ABBREVIATIONS ...................................................................................................................................... 35
1.
INTRODUCTION................................................................................................................................ 37
1.1.
Background .................................................................................................................................... 37
1.1.1.
Nonclinical Studies ..................................................................................................................... 37
1.1.2.
Clinical Studies ........................................................................................................................... 40
1.1.2.1.
Pharmacokinetics .................................................................................................................... 41
1.1.2.2.
Efficacy and Safety Studies..................................................................................................... 43
1.2.
Active Comparator ......................................................................................................................... 50
1.2.1.
Selective Serotonin Reuptake Inhibitors..................................................................................... 50
1.2.1.1.
Escitalopram............................................................................................................................ 50
1.2.1.2.
Sertraline ................................................................................................................................. 51
1.2.2.
Serotonin and Norepinephrine Reuptake Inhibitors ................................................................... 52
1.2.2.1.
Duloxetine................................................................................................................................ 52
1.2.2.2.
Venlafaxine Extended-release................................................................................................. 52
1.3.
Overall Rationale for the Study...................................................................................................... 53
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 53
2.1.
Objectives and Endpoints .............................................................................................................. 53
2.1.1.
Objectives ................................................................................................................................... 53
2.1.2.
Endpoints.................................................................................................................................... 55
2.2.
Hypothesis ..................................................................................................................................... 56
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 56
3.1.
Overview of Study Design.............................................................................................................. 56
3.1.1.
Overview of Study Phases.......................................................................................................... 57
3.2.
Study Design Rationale.................................................................................................................. 60
3.2.1.
Study Population......................................................................................................................... 60
3.2.2.
Study Phases.............................................................................................................................. 62
3.2.3.
Blinding and Randomization....................................................................................................... 63
3.2.4.
Treatment Groups and Dose Selection ...................................................................................... 63
3.2.5.
Efficacy Measures ...................................................................................................................... 65
3.2.6.
Safety Evaluations...................................................................................................................... 66
3.2.7.
Other Assessments .................................................................................................................... 67
3.2.8.
Pharmacokinetic Assessments................................................................................................... 68

Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations .............................. 68
4.
SUBJECT POPULATION.................................................................................................................. 69
4.1.
Inclusion Criteria ............................................................................................................................ 69
4.2.
Exclusion Criteria ........................................................................................................................... 73
4.3.
Prohibitions and Restrictions ......................................................................................................... 78


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5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 78
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 80
6.1.
Screening/Prospective Observational Phase (4-week duration + optional 3-week taper 
period) ............................................................................................................................................ 80
6.2.
Double-blind Treatment Phase (4-week duration) ......................................................................... 81
6.3.
Follow-up Phase (8-weeks or until relapse)................................................................................... 83
6.4.
Guidance on Blood Pressure Monitoring on Intranasal Treatment Session Days......................... 84
7.
TREATMENT COMPLIANCE............................................................................................................ 84
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 85
9.
STUDY EVALUATIONS .................................................................................................................... 86
9.1.
Study Procedures........................................................................................................................... 86
9.1.1.
Overview..................................................................................................................................... 86
9.1.2.
Screening/Prospective Observational Phase ............................................................................. 88
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 90
9.1.4.
Follow-up Phase......................................................................................................................... 91
9.2.
Efficacy Evaluations....................................................................................................................... 92
9.2.1.
Evaluations ................................................................................................................................. 92
9.2.1.1.
Primary Efficacy Evaluation..................................................................................................... 92
9.2.1.2.
Key Secondary Efficacy Evaluation......................................................................................... 93
9.2.1.3.
Other Secondary Efficacy Evaluations .................................................................................... 93
9.2.1.3.1.
Other Secondary Efficacy Evaluations (Clinician-completed).............................................. 93
9.2.1.3.2.
Other Secondary Efficacy Evaluations (Patient-reported Outcomes).................................. 93
9.3.
Pharmacokinetics (Chinese subjects only) .................................................................................... 94
9.3.1.
Evaluations ................................................................................................................................. 94
9.3.2.
Analytical Procedures................................................................................................................. 94
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 95
9.4.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations.................................. 95
9.5.
Safety Evaluations ......................................................................................................................... 96
9.6.
Other Evaluations......................................................................................................................... 100
9.7.
Sample Collection and Handling.................................................................................................. 101
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ......................................................................................................................... 101
10.1.
Completion ................................................................................................................................... 101
10.2.
Discontinuation of Study Treatment or Withdrawal from the Study............................................. 101
10.3.
Withdrawal from the Use of Samples in Future Research........................................................... 103
11.
STATISTICAL METHODS............................................................................................................... 103
11.1.
Subject Information ...................................................................................................................... 103
11.2.
Sample Size Determination ......................................................................................................... 104
11.3.
Efficacy Analyses ......................................................................................................................... 104
11.4.
Pharmacokinetic Analyses........................................................................................................... 106
11.5.
Biomarker and Pharmacogenomic Analyses.............................................................................. 106
11.6.
Safety Analyses ........................................................................................................................... 107
12.
ADVERSE EVENT REPORTING .................................................................................................... 108
12.1.
Definitions .................................................................................................................................... 109
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 109
12.1.2.
Attribution Definitions................................................................................................................ 110
12.1.3.
Severity Criteria ........................................................................................................................ 111
12.2.
Special Reporting Situations........................................................................................................ 111
12.3.
Procedures................................................................................................................................... 111
12.3.1.
All Adverse Events.................................................................................................................... 111
12.3.2.
Serious Adverse Events ........................................................................................................... 112
12.3.3.
Pregnancy................................................................................................................................. 113


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12.4.
Contacting Sponsor Regarding Safety......................................................................................... 114
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 114
13.1.
Procedures................................................................................................................................... 114
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 114
14.
STUDY DRUG INFORMATION....................................................................................................... 114
14.1.
Physical Description of Study Drug(s) ......................................................................................... 114
14.2.
Packaging .................................................................................................................................... 115
14.3.
Labeling........................................................................................................................................ 116
14.4.
Preparation, Handling, and Storage............................................................................................. 116
14.5.
Drug Accountability ...................................................................................................................... 116
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 117
16.
ETHICAL ASPECTS ....................................................................................................................... 118
16.1.
Study-Specific Design Considerations......................................................................................... 118
16.2.
Regulatory Ethics Compliance..................................................................................................... 120
16.2.1.
Investigator Responsibilities ..................................................................................................... 120
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 120
16.2.3.
Informed Consent ..................................................................................................................... 122
16.2.4.
Privacy of Personal Data .......................................................................................................... 122
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 123
16.2.6.
Country Selection ..................................................................................................................... 123
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 123
17.1.
Protocol Amendments.................................................................................................................. 123
17.2.
Regulatory Documentation .......................................................................................................... 124
17.2.1.
Regulatory Approval/Notification .............................................................................................. 124
17.2.2.
Required Prestudy Documentation........................................................................................... 124
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 125
17.4.
Source Documentation................................................................................................................. 125
17.5.
Case Report Form Completion .................................................................................................... 126
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 127
17.7.
Record Retention ......................................................................................................................... 127
17.8.
Monitoring .................................................................................................................................... 128
17.9.
Study Completion/Termination..................................................................................................... 128
17.9.1.
Study Completion/End of Study................................................................................................ 128
17.9.2.
Study Termination..................................................................................................................... 129
17.10.
On-Site Audits .............................................................................................................................. 129
17.11.
Use of Information and Publication.............................................................................................. 129
REFERENCES.......................................................................................................................................... 131
INVESTIGATOR AGREEMENT ............................................................................................................... 142
LIST OF ATTACHMENTS
Attachment 1:
Prohibited Concomitant Medications with Intranasal Study Medication 
(Esketamine or Placebo) .......................................................................................... 135
Attachment 2:
New York Heart Association Classification of Cardiac Disease............................... 138
Attachment 3:
Oral Antidepressant Titration Schedule for Double-Blind Treatment Phase............ 139
Attachment 4:
Anticipated Events.................................................................................................... 140


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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Intranasal Treatment Sessions in the Double-Blind Treatment Phase..................................... 81
Table 2:
Volume of Blood to Be Collected from Each Subject ............................................................... 88
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 60


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Status: Approved, Date: 21 January 2021
PROTOCOL AMENDMENTS
Protocol Version
Date
Original Protocol
22 May 2017
Amendment 1
23 Aug 2019
Amendment 2
21 Jan 2021
Amendments below are listed beginning with the most recent amendment.
Amendment 2 (21 January 2021)
The overall rationale of the protocol amendment: The overall rationale of the protocol amendment is to 
change the first key secondary endpoint to a clinically meaningful endpoint for evaluating the rapid reduction of 
depressive symptoms by intranasal esketamine.
Applicable Section(s)
Description of Change(s)
Rationale: The first key secondary endpoint is being changed to a clinically meaningful endpoint for evaluating
the rapid reduction of depressive symptoms by intranasal esketamine. The current key secondary endpoint is 
being changed to an “Other Secondary Endpoint”. Corresponding updates are being made to key secondary and 
other secondary objectives.
Synopsis Objectives and Endpoints;
2.1. Objectives and Endpoints
Key Secondary Objectives
The key secondary objectives are to assess the effect of
intranasal esketamine plus a newly initiated oral 
antidepressant compared with a newly initiated oral 
antidepressant (active comparator) plus intranasal placebo 
on the following parameters in adult subjects with TRD:

Change from baseline in the MADRS total score at 24 
hours post first dose
Other Secondary Objectives
To assess the effect of intranasal esketamine plus a newly 
initiated oral antidepressant compared with a newly 
initiated oral antidepressant (active comparator) plus 
intranasal placebo on the following parameters in adult 
subjects with TRD:

Onset of clinical response by Day 2 
Secondary Endpoints

MADRS: The first key secondary endpoint is the 
change from baseline (Day 1, predose) to 24 hours 
post first dose in depressive symptoms, as measured 
by the MADRS total score.
Other Secondary Endpoints

Proportion of subjects showing onset of clinical 
response (≥50% reduction from baseline in MADRS 
total score) by Day 2 that is maintained through the end 
of the 4-week double-blind treatment phase with one 
excursion allowed.


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Applicable Section(s)
Description of Change(s)
Synopsis Efficacy Evaluations;
3.2.5. Efficacy Measures
MADRS
In addition to the primary efficacy measure, the change in 
MADRS total score from baseline (Day 1, prior to 
randomization) to 24 hours post dose (Day 2) will be 
included as a key secondary efficacy endpoint to evaluate 
rapid reduction of depressive symptoms.
MADRS will also be used to evaluate a secondary objective 
assessing the onset of clinical response (ie, antidepressant 
effect) by Day 2 that is maintained for the duration of the 
double-blind treatment phase. Onset of clinical response is 
defined as ≥50% improvement in MADRS total score by 
Day 2 (ie, the day after taking the first dose of double-blind 
intranasal medication) that is maintained through the end of 
the 4-week double-blind treatment phase with one 
excursion allowed. Additionally, MADRS will be used to 
evaluate a secondary objective assessing the proportion of 
subjects in remission (MADRS total score ≤12) at the end 
of the 4-week double-blind treatment phase; and the 
proportion who remain in remission (MADRS total score 
≤12) through to the end of the follow-up phase. 
9.2.1.2. Key Secondary Efficacy Evaluation
Montgomery-Asberg Depression Rating Scale (MADRS) 
Total Score
The MADRS will also be administered using a modified 
recall period of 24 hours for the key secondary efficacy 
evaluation related to change from baseline to 24 hours.
Synopsis Statistical Methods: Efficacy Analyses; 
11.3. Efficacy Analyses
Secondary Endpoints
For the analysis of the first of the two key secondary 
efficacy endpoints, change from baseline in MADRS total 
score at 24 hours post first dose (Day 2), will be analyzed 
using the same model described above for the MADRS 
total score at Week 4 in the double-blind treatment phase.
To strongly control Type I error across the primary and the 
two key secondary efficacy endpoints, a fixed sequence 
approach15,16 will be applied to adjust for multiplicity. The 
hypotheses will be tested sequentially in the following 
order:

Change in MADRS total score at the end of the 4-week 
double-blind treatment phase

Change in MADRS total score at 24 hours post first 
dose
The proportion of subjects showing onset of clinical 
response by Day 2 (in the event that no MADRS was 
collected on Day 2, a MADRS collected on Day 3 could be 
used) that is maintained for the duration of the double-blind 
treatment phase (≥50% reduction in MADRS total score by 
the second day after taking the first dose of double-blind 
medication that continued through the end of the double-
blind phase) in esketamine arm will be compared with the 
active comparator using a Cochran-Mantel-Haenszel chi-
square test adjusting for country and class of antidepressant 
(SNRI or SSRI). Subjects who discontinued the study prior 


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Status: Approved, Date: 21 January 2021
Applicable Section(s)
Description of Change(s)
to the end of the double-blind treatment phase will not be 
considered to have maintained clinical response.
Rationale: Update to footnote “d” of the Time and Events Schedule (screening/prospective observational phase 
and double-blind treatment phase) to clarify the MADRS assessment at Visit 2.1.
Time and Events Schedule (screening/prospective 
observational phase and double-blind treatment 
phase)
Footnote “d” will be updated as follows:
Performed for subjects who require a taper period or who 
do not require a taper period but their Visit 1.3 and Visit 2.1 
occur more than 1 week apart; the result will be considered 
as the subject’s baseline MADRS for the double-blind 
treatment phase. For all other subjects, the baseline 
MADRS for the double-blind treatment phase will be the 
MADRS performed at the end of Week-4 of the 
screening/prospective observational phase.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 1 (23 August 2019)
The overall rationale of the protocol amendment: The overall rationale of the protocol amendment is to 
provide updates in line with feedback from investigators and the Human Genetic Resource Administration Office 
of China (HGRAO), and to provide overall clarification on procedures, wherever applicable.
Applicable Section(s)
Description of Change(s)
Rationale: Correction to criteria for recruiting subjects with major depressive disorder (MDD)
Synopsis Study Population;
3.2.1. Study Population;
4.1. Inclusion Criteria;
9.1.2. Screening/Prospective Observational Phase
Inclusion criterion No.2 and associated text revised as 
follows (strikethrough text deleted):
At the start of the screening/prospective observational 
phase, subject must meet the Diagnostic and Statistical 
Manual of Mental Disorders–Fifth Edition (DSM-5) 
diagnostic criteria for recurrent MDD or single-episode 
MDD (if single episode MDD, the duration must be ≥2 
years), without psychotic features, based upon clinical 
assessment and confirmed by the MINI.
Rationale: Clarification that the testing of oral antidepressant levels in blood during the Screening/Prospective 
Observation Phase is optional.
4.1. Inclusion Criteria
Inclusion criterion No. 3 revised as follows (bold text 
added):
Clarification that the testing of oral antidepressant levels in 
blood during the screening/prospective observational phase
is optional:

For specific tricyclic antidepressants which are 
ongoing and being taken at a dose below the 
MGH-ATRQ minimum therapeutic dose, a blood 
level that is within the therapeutic (antidepressant) 
range, is acceptable to establish the adequacy of 


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Applicable Section(s)
Description of Change(s)
the antidepressant treatment. Note: performing 
the test depends on availability of kit.
Rationale: Clarification of the criteria for defining clinically significant ECG abnormalities.
4.2. Exclusion Criteria
Exclusion Criterion No. 10 revised as follows 
(strikethrough text deleted):
Subject has clinically significant ECG abnormalities at the 
start of the screening/prospective observational phase or on 
Day 1 of the double-blind treatment phase prior to 
randomization, defined as:

During screening, a QT interval corrected 
according to Fridericia's formula (QTcF): 
≥470 msec in males and ≥480 msec in females; if 
the QTcF is prolonged on the initial ECG, the 
average QTcF of three ECGs, recorded 4 minutes 
apart, must not be ≥450 msec.

On Day 1 (predose), a QT interval corrected 
according to Fridericia’s formula (QTcF): 
≥470 msec in males and ≥480 msec in females 
based on the site-evaluated ECG; if the QTcF is 
prolonged on the initial ECG, the average QTcF 
of three ECGs, recorded 4 minutes apart, must not 
be ≥450 msec.
Rationale: Revised to reflect that there is no evidence to date to support the potential for esketamine to induce 
liver toxicity, with the cut-off level for alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in 
serum, as evidence of underlying hepatoxicity in subjects at screening, raised from ≥2 times to ≥3 times the upper 
limit of normal, and deletion of reference to elevations in bilirubin levels at screening, which are indicative of 
Gilbert’s disease
4.2. Exclusion Criteria
Exclusion Criterion No. 12 revised as follows (bold text 
added, strikethrough text deleted):
Subject has a history of, or symptoms and signs suggestive 
of, liver cirrhosis (eg, esophageal varices, ascites, and 
increased prothrombin time) OR alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) values ≥2x 3x
the upper limit of normal or total bilirubin > 1.5 times the 
ULN in the screening/prospective observational phase.
Repeat of screening test for abnormal ALT and AST is 
permitted once during the screening period provided per 
investigator discretion and provided there is an alternative 
explanation for the out of range value.
For elevations in bilirubin, if in the opinion of the 
investigator and agreed upon by the sponsor’s medical 
officer, the elevation in bilirubin is consistent with 
Gilbert’s disease, the subject may participate in the study.


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Applicable Section(s)
Description of Change(s)
Rationale: Clarification of the criteria for optional testing of subjects for use of drugs of abuse, at screening or 
prior to randomization on Day 1 of the Double-blind Treatment Phase.
4.2. Exclusion Criteria
Exclusion Criterion No. 13 revised as follows (bold text 
added, strikethrough text deleted): 
Subject has positive test result(s) for drugs of abuse 
(including barbiturates, methadone, opiates, cocaine, 
phencylicdinee, and amphetamine/methamphetamine) at 
the start of the screening/prospective observational phase 
(including barbiturates, methadone, opiates, cocaine
phencyclidine, and amphetamine) or Day 1 of the 
double-blind treatment phase prior to randomization 
(including cannabinoids, methadone, opiates, cocaine, 
and amphetamine). Note: performing the test depends
on availability of the kit.

Subjects who have a positive test result at 
screening due to prescribed psychostimulants 
(eg, amphetamine, etc.) taken for an indication 
other than MDD, are permitted to continue to 
take this medication during the study.
Rationale: Clarification that urine samples will be tested during the Double-blind Treatment Phase for the 
presence of cocaine only, and that the test is optional.
4.3. Prohibitions and Restrictions No. 4
The following changes were made (bold text added, 
strikethrough text deleted):
A positive urine drug screen for use of phencyclidine 
(PCP), 3, 4-methylenedioxy-methamphetamine (MDMA), 
lysergic acid diethylamide (LSD), or cocaine from Day 1 of 
the double-blind treatment phase through the final visit in 
the double-blind treatment phase will lead to 
discontinuation. Note: performing the test depends on 
availability of the kit.
Rationale: Clarification of the criteria for urinalysis during the Screening/Prospective Observational and 
Double-blind Treatment Phase
9.5. Safety Evaluations
Clinical Laboratory Tests 
Revised as follows (bold text added, strikethrough text 
deleted):
Urinalysis
Urine Drug Screen: Barbiturates, methadone, opiates, 
cocaine, cannabinoids (cannabinoids are only tested at Day 
1, predose) phencyclidine, and amphetamine /
methamphetamine
at the start of the Screening/Prospective 
Observational Phase: barbiturates, methadone, 
opiates, cocaine, phencyclidine, and 
amphetamine
on Day 1 of the Double-blind Treatment Phase 
prior to randomization: cannabinoids, 
methadone, opiates, cocaine, and amphetamine


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Status: Approved, Date: 21 January 2021
Applicable Section(s)
Description of Change(s)
on Day 15 and 25 of the Double-blind Treatment
Phase: cocaine
Rationale: Clarify that the Site-Independent Qualification Assessment to be used in this study is the Clinical 
Validation Inventory for Study Admission (C-VISA), to ensure enrollment of subjects who have symptoms that 
reflect the current state of illness.
Synopsis Study Population;
Time and Events Schedule 
Screening/Prospective Observational Phase and 
Double-blind Treatment Phase;
3.2.1. Study Population;
4.1. Inclusion Criteria (Criterion No.4);
9.6. Other Evaluations;
15. Study-Specific Materials
Time and Events Schedule
Screening/Prospective Observational Phase
Clarify that the Site-Independent Qualification Assessment 
tool used in this study is the Clinical Validation Inventory for 
Study Admission (C-VISA). 
Footnote (r):C-VISA can be completed prior to 
randomization.
Rationale: Correction to blood volumes to be collected from subjects in China, to clarify that Biomarkers and 
Pharmacogenomic evaluations will not be performed.
9.1.1. Overview
Revised as follows (bold text added):
The approximate total blood volume to be collected from 
subjects in China has been changed to 50 mL (34 mL for 
eligibility and safety and 16 mL for PK). 
No blood will be collected for Biomarkers and 
Pharmacogenomic evaluations. The “74.5 ml for 
biomarkers” was deleted.
Table 2: Volume of Blood to be Collected from Each Subject
The following text was added to footnote (e): “This applies 
to US sites only, as not applicable for China”
Footnote (e) added to the following:
Screening/Prospective Observational Phase:
Biomarker: DNA
Biomarker: RNA 
The following text (in bold) was added to footnote (g): 50 
mL for Chinese subjects and 108.5 mL for non-Chinese 
subjects.
Rationale: Correction to footnotes as measurement of HbA1c levels in blood is mandatory.
9.1.1. Overview
Table 2. Volume of Blood to be Collected from Each Subject
Deletion of footnote (c) “as needed, HbA1c will be measured 
from the sample collected for hematology”
Footnotes within the Table renumbered accordingly


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Status: Approved, Date: 21 January 2021
Applicable Section(s)
Description of Change(s)
Rationale: Clarification that sections relation to Biomarkers Pharmacogenomic (DNA), and Expression (RNA) 
Evaluations are not applicable to China
Synopsis Biomarker, Pharmacogenomic (DNA) 
and Expression (RNA) Evaluations;
Synopsis Statistical Methods: Biomarker and
Pharmacogenomic Analyses;
Synopsis Exploratory Objectives and Exploratory 
Endpoints;
Time and Events Schedule: Screening/prospective 
observational phase and double-blind treatment 
phase;
2.1.1. Objectives;
2.1.2. Endpoints;
3.2.3. Blinding and Randomization;
3.2.9. Biomarker, Pharmacogenomic (DNA) 
and Expression (RNA) Evaluations;
9.1.1. Overview;
9.4. Biomarker, Pharmacogenomic (DNA) and 
Expression (RNA) Evaluations;
11.5. Biomarker and Pharmacogenomic Analyses.
Synopsis Statistical Methods: Biomarker and 
Pharmacogenomic Analyses;
11.5 Biomarker and Pharmacogenomic Analysis
Footnote (a) stating that “Not applicable to China” added
to text, to clarify that sections relating to Biomarkers, 
Pharmacogenomic (DNA) and Expression (RNA) 
evaluations will not be performed in China.
Addition of following text (bold) to clarify that statistical 
analysis will not be performed due to insufficient number:
Baseline biomarker values and changes from baseline 
biomarker values to the time points specified in the Time 
and Events Schedule will be summarized if available 
number is sufficient for analyses.
Rationale: Correction to doses of oral antidepressant available and clarification of responsibility for sourcing 
study drug.
14.1. Physical Description of Study Drug(s)
9.1.4. Follow-up Phase
Correction to study drug doses:

Sertraline 25 mg: not available

Venlafaxine XR: 37.5 mg not available
The following text was revised (bold text added):
At the start of the follow-up phase, further clinical/standard 
of care for the treatment of depression will be arranged by 
the study investigator and/or the subject’s treating 
physician and medication changes are permitted. The 
decision to continue the antidepressant will be at the 
discretion of the investigator. If the subject continues to 
receive the same antidepressant medication for the 
duration of the follow-up phase, then the 
antidepressant will be sourced by the sponsor.


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Status: Approved, Date: 21 January 2021
Applicable Section(s)
Description of Change(s)
Rationale: Addition of a time point during the Double-blind Treatment Phase and Follow-up Phase for 
dispensing of new oral antidepressant for those subjects who will continue with the same oral antidepressant on 
entering the Follow-up Phase. 
Time and Events Schedule 
Screening/Prospective Observational Phase and 
Double-Blind Treatment Phase;
Time and Events Schedule, Follow-up Phase
Study Drug: Dispensing of new oral antidepressant 
(duloxetine, escitalopram, sertraline, or venlafaxine XR): 
Addition of a footnote: (q) “For subjects entering the 
Follow-up phase and continuing with the same oral AD”. 
And an “X” to Visit number 2.10 of the double-blind 
treatment phase
Addition of a row for “Dispensing of oral antidepressant 
(duloxetine, escitalopram, sertraline, or venlafaxine XR)” 
and an “X” to Visit number 3.5. of the follow-up phase, 
Addition of footnote (h) “For subjects continuing with the 
same oral antidepressant”.
Rationale: Clarification that in the event the last visit of the Screening/Prospective Observational Phase and the 
first visit of the Double-blind Treatment Phase do not occur on the same day, then the baseline MADRS 
assessment will be performed at the first visit of the Double-blind Treatment Phase
Time and Events Schedule Screening/Prospective 
Observational Phase and Double-blind Treatment 
Phase
Footnote (d) revised as follows (bold text added, 
strikethrough text deleted): 
Performed if Visit 1.3 and Visit 2.1 do not occur on the 
same day for subjects requiring a taper period during the 
screening/prospective observational phase; the result will 
be considered as the subject’s baseline MADRS for the 
double-blind treatment phase. For all other subjects, the 
baseline MADRS for the double-blind treatment phase will 
be the MADRS performed at the end of Week 4 of the 
screening/prospective observational phase.
Rationale: Clarification on performing MADRS assessments during the Screening/Prospective Observational 
Phase and the Double-blind Treatment Phase
Time and Events Schedule, Screening/Prospective 
Observational Phase and Double-blind Treatment 
Phase;
6.1 Screening/Prospective Observational Phase
Footnote (e) revised as follows: 
The following text was deleted: “At each “Remote 
MADRS” visit, site staff will perform the MADRS 
assessment either at the clinic or remotely by 
contacting the subject by telephone.”
The following text was added: “The MADRS 
interview should be performed in Week 1 (Visit 1.1 or 
as soon as possible) of the screening/prospective 
observational phase.”
Footnote (e ) deleted from text “Remote MADRS 
interview only (RM) at Study Visit 2.2. of the double-blind 
treatment phase:”
Footnote (e ) added to text “MADRS (7-day recall) 
interview performed in Week 1 (Visit 1.1. or as soon as 
possible) of the screening/prospective observational 
phase).


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Status: Approved, Date: 21 January 2021
Applicable Section(s)
Description of Change(s)
Rationale: Clarification that the C-SSRS assessment will be performed at each Remote Assessment visit.
Time and Events Schedule, 
Follow-up Phase
Footnote (b) revised as follows (bold text added): 
At each “Remote Assessment” visit, site staff will contact 
the subject by telephone to perform the C-SSRS and to
obtain information regarding adverse events and 
concomitant therapies.
Rationale: Clarification of the criteria for treatment blinding
5. Treatment Allocation and Blinding;
11. Statistical Methods
The following text was deleted:
Blinding
At the end of the double-blind treatment phase the database 
will be locked for the analysis and reporting of this phase. 
The subject treatment assignment will be revealed only to 
sponsor’s study staff. The investigators and the site 
personnel will be blinded to the treatment assignment until 
all subjects have completed study participation through the 
follow-up phase.
Rationale: Clarification that Pharmacokinetic analysis will only be performed in Chinese subjects
9.3. Pharmacokinetics;
11.4 Pharmacokinetic Analysis
Section header edited to clarify that Pharmacokinetic 
Analysis only applicable to Chinese subjects
Section 9.3. Pharmacokinetics (Chinese subjects only)
Section 11.4. Plasma esketamine concentrations will be 
tested for all Chinese subjects
Rationale: Clarification that only Pharmacokinetic analysis for esketamine levels in serum is mandatory; 
Pharmacokinetic analysis on all metabolites including noresketamine is optional, and this will not impact on the 
interpretation of the data.
Synopsis Pharmacokinetic Evaluations;
Statistical Methods;
3.2.8. Pharmacokinetic Assessments;
9.3.1 Evaluations;
9.3.2. Analytical Procedures;
9.3.3. Pharmacokinetic Parameters;
11.4 Pharmacokinetic Analyses
Reference to noresketamine deleted.


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Status: Approved, Date: 21 January 2021
Applicable Section(s)
Description of Change(s)
Rationale: Clinically relevant treatment-emergent adverse events of special interest have been updated to reflect 
changes to the FDA’s guidance for industry in assessing abuse potential of drugs.
3.2.6. Safety Evaluations
References
Treatment-emergent adverse events (TEAEs) of special 
interest have been revised as follows (bold text added, 
strikethrough text deleted):
Clinically relevant TEAEs of special interest will be 
examined separately grouped in the following categories as 
defined by the Standardized Medical Dictionary for 
Regulatory Activities (MedDRA) (version 20.0, or above if 
applicable) queries (SMQ): Drug abuse dependence and 
withdrawal AEs potentially suggestive of abuse, increased 
blood pressure, increased heart rate, transient 
dizziness/vertigo, impaired cognition, anxiety, and cystitis.
The following text was added:

The preferred terms used to determine TEAEs 
potentially suggestive of abuse, as defined by the 
Food and Drug Administration’s Assessment of 
Abuse Potential of Drugs Guidance for Industry 
(January 2017), include: Aggression, Confusional 
state, Decreased activity, Disorientation, Dissociation, 
Dissociative disorder, Dizziness, Drug tolerance, 
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, Somatic hallucination, Somnolence, 
Substance use disorder, Substance-induced psychotic 
disorder, and Thinking abnormal. 
Narrative descriptions will be provided for deaths, subjects 
with serious adverse events, and subjects who discontinued 
study medication due to an adverse event. If applicable, 
narratives will be prepared for subjects with a TEAE of 
cystitis, with postdose oxygen saturation <93% for 2 or 
more consecutive assessments within the same visit, with 
post-baseline cases of QTcF >500 msec, with clinically 
significant suicidal ideation (score of 4 or 5 on the C-
SSRS) or suicidal behavior (scores 6-10 on the C-SSRS), 
and for subjects who experienced a motor vehicle accident 
and/or who had TEAEs potentially suggestive of abuse.
The following reference for the Food and Drug 
Administration’s Assessment of Abuse Potential of Drugs 
Guidance for Industry (January 2017) was added:


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Status: Approved, Date: 21 January 2021
Applicable Section(s)
Description of Change(s)
Rationale: Update section on Clinical Studies to include Phase 1 studies performed by the sponsor in healthy 
volunteers and special populations; recently completed Phase 3 efficacy and safety studies conducted in subjects 
with treatment resistant depression (TRD); and a Phase 2 proof-of-concept study in subjects with major 
depressive disorder with suicidal ideation (MDSI).
1.1.2. Clinical Studies.
The section on Clinical Studies was updated to reflect recently completed 
studies conducted by the sponsor.
Subsections 1.1.2.1. and 1.1.2.2. added to differentiate between studies 
conducted to investigate the Pharmacokinetics of esketamine and 
Pharmacodynamic Efficacy and Safety studies conducted in patient 
populations.
The following text was added: 
The clinical program for esketamine includes: a comprehensive clinical 
pharmacology program in healthy volunteers and special populations to fully 
characterize the product’s pharmacokinetic (PK) and pharmacodynamic (PD) 
activity, including Phase 2 studies with IV esketamine and ketamine; a Phase 
2 dose response study in adults with TRD; a Phase 2 proof-of-concept study in 
the related condition of MDD with imminent risk for suicide; and data from 
5 completed Phase 3 studies establishing efficacy and safety in adults with 
TRD, including those 65 years and older. Results from 1 ongoing Phase 2 
study and 2 additional ongoing Phase 3 studies in adults with TRD are not 
available at the time of finalization.
Section 1.1.2.1. Pharmacokinetics
The following Human Pharmacokinetic (PK) and initial tolerability Phase 1 
studies were conducted by the sponsor in healthy adult subjects. Further 
details are available in the Investigator Brochure34: 

Intravenous and oral dose of radiolabeled esketamine: 
54135419TRD1016.

Intravenous, intranasal and oral esketamine: ESKETINTRD1009 

Intranasal esketamine:

Healthy adult non-Asian and Asian subjects: ESKETINTRD1001, 
ESKETINTRD1002, ESKETINTRD1004, ESKETINTRD1005, 
ESKETINTRD1006, ESKETINTRD1009, ESKETINTRD1010, 
ESKETINTRD1013, 54135419TRD1020 (Japanese subjects only).

Healthy elderly and younger adult non-Asian and Asian subjects: 
ESKETINTRD1003, ESKETINTRD1012, and 54135419TRD1018 
(Japanese subjects only). 

Subjects with a history of allergic rhinitis: ESKETINTRD1007.

Recreational users of perception-altering drugs: 
54135419TRD1015

Subjects with hepatic impairment: ESKETINTRD1011

Subjects with renal impairment: 54135419TRD1014
Subjects with MDD; On-Road Driving effects: 54135419TRD1019.


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Status: Approved, Date: 21 January 2021
Applicable Section(s)
Description of Change(s)
Section 1.1.2.2. Efficacy and Safety Studies
The following Efficacy and Safety Phase 2a and Phase 3 studies were 
conducted by the sponsor in subjects with TRD or MDD who are at imminent 
risk for suicidal ideation. 

Phase 2a: Intravenous ketamine or esketamine administered to subjects 
with TRD: KETIVTRD2002, KETIVTRD2004 and ESKETIVTRD2001, 
respectively.

Phase 2a: Intranasal esketamine administered to subjects with TRD: 
ESKETINTRD2003; Intranasal esketamine administered to subjects with 
MDD who are at imminent risk for suicidal ideation: ESKETINSUI2001.

Phase 3: Intranasal esketamine administered to subjects with TRD: 

Short-term studies: ESKETINTRD3001, ESKETINTRD3002, and 
ESKETINTRD3005

Long-term studies: ESKETINTRD3003 and ESKETINTRD3004
For the most comprehensive information regarding these clinical studies, refer 
to the latest version of the Investigator Brochure.34
Human Pharmacokinetics Metabolism: Include reference to esketamine and 
update to include a paragraph outlining data obtained on esketamine 
metabolism and excretion. 
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.


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Status: Approved, Date: 21 January 2021
SYNOPSIS
A Randomized, Double-blind, Multicenter Active-controlled Study to Evaluate the Efficacy, 
Pharmacokinetics, Safety and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral 
Antidepressant in Adult Subjects with Treatment-resistant Depression
Major depressive disorder (MDD), a serious, recurrent, and disabling psychiatric illness, is the second 
leading cause of years lost to disability worldwide. MDD is associated with excess mortality, and with years 
of potential life lost. About 30% of patients fail to achieve remission despite treatment with multiple 
antidepressant medications, and are considered to have treatment-resistant depression (TRD). There is a 
significant need to develop novel treatments based upon relevant pathophysiologic pathways underlying 
MDD for the rapid relief of symptoms of depression, especially in patients with TRD.
Esketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist. It is the S-enantiomer of racemic 
ketamine, and has been shown to have approximately 3- to 4 fold stronger binding affinity for the 
phencyclidine (PCP) site of the N-methyl-D-aspartate (NMDA) receptor than the R-enantiomer. The 
mechanism of action of ketamine and esketamine is distinct from conventional monoaminergic 
antidepressant treatments and ketamine profoundly affects fast excitatory glutamate transmission, increases 
brain-derived neurotrophic factor (BDNF) release, and stimulates synaptogenesis.
Janssen Research & Development (JRD) is developing intranasal esketamine as an antidepressant therapy. 
A higher NMDA receptor affinity of esketamine allows a lower volume of medication to be administered 
via the non-invasive, rapidly absorbed intranasal route.
The current study is being conducted to evaluate the efficacy, safety, and tolerability of flexibly dosed 
intranasal esketamine plus a newly initiated oral antidepressant in adult subjects with TRD. The study will 
serve as a Phase 3 short-term efficacy and safety study in support of Chinese regulatory agency 
requirements for registration of intranasal esketamine for the treatment of TRD.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of switching adult subjects with TRD from a 
prior antidepressant treatment (to which they have not responded) to flexibly dosed intranasal esketamine 
(56 mg or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated 
oral antidepressant (active comparator) plus intranasal placebo, in improving depressive symptoms, as 
assessed by the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total 
score from Day 1 (pre-randomization) to the end of the 4-week double-blind treatment phase. 
Secondary Objectives
Key Secondary Objectives
The key secondary objectives are to assess the effect of intranasal esketamine plus a newly initiated oral 
antidepressant compared with a newly initiated oral antidepressant (active comparator) plus intranasal 
placebo on the following parameters in adult subjects with TRD:

Change from baseline in the MADRS total score at 24 hours post first dose

Functioning and associated disability


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Status: Approved, Date: 21 January 2021
Other Secondary Objectives
To assess the effect of intranasal esketamine plus a newly initiated oral antidepressant compared with a 
newly initiated oral antidepressant (active comparator) plus intranasal placebo on the following parameters 
in adult subjects with TRD:

Onset of clinical response by Day 2 

Depression response rates

Depression remission rates

Overall severity of depressive illness

Anxiety symptoms

Health-related quality of life and health status
To investigate the safety and tolerability of intranasal esketamine plus a newly initiated oral antidepressant 
compared with a newly initiated oral antidepressant (active comparator) plus intranasal placebo in adult 
subjects with TRD, including the following parameters:

Treatment-emergent adverse events (TEAEs), including AEs of special interest

Local nasal tolerability

Effects on heart rate, blood pressure, respiratory rate, and blood oxygen saturation

Dissociative symptoms

Potential effects on suicidal ideation/behavior

Potential withdrawal and/or rebound symptoms following cessation of intranasal esketamine 
treatment.
To assess the pharmacokinetics (PK) of intranasal esketamine in Chinese adult subjects with TRD receiving 
intranasal esketamine plus a newly-initiated oral antidepressant.
Exploratory Objectives
For subjects who receive esketamine during the double-blind treatment phase, the proportion of subjects 
who relapse during the follow-up phase will be evaluated separately for subjects who are remitters 
(MADRS ≤12) at the end of the 4 week double-blind treatment phase and for subjects who are responders 
but not remitters (≥50% reduction in MADRS total score, but MADRS ˃12) at the end of the 4 week 
double-blind treatment phase.

Time to relapse during the follow-up phase will be evaluated in esketamine subjects who remitted 

Time to relapse during the follow-up phase will be evaluated in esketamine subjects who are 
responders but not remitters
To assess the potential relationship of biomarkers with response/non-response to intranasal esketamine or 
oral antidepressants in adult subjects with TRD.
                                                
Not applicable to China


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Status: Approved, Date: 21 January 2021
Endpoints
Primary Endpoint

The primary endpoint is the change in the MADRS total score as measured by the change from baseline 
(Day 1 prior to randomization) to the end of the 4-week double-blind treatment phase.
Secondary Endpoints

MADRS: The first key secondary endpoint is the change from baseline (Day 1, predose) to 24 hours 
post first dose in depressive symptoms, as measured by the MADRS total score.

Sheehan Disability Scale (SDS): The second key secondary endpoint is the change in SDS total score 
as measured by the change from baseline (Day 1, prior to randomization) to the end of the 4-week 
double-blind treatment phase
Other Secondary Endpoints

Proportion of subjects showing onset of clinical response (≥50% reduction from baseline in MADRS 
total score) by Day 2 that is maintained through the end of the 4-week double-blind treatment phase 
with one excursion allowed.

Proportion of responders (≥50% reduction from baseline in MADRS total score) at the end of the 
4-week double-blind treatment phase.

Proportion of subjects in remission (MADRS ≤12) at the end of the 4-week double-blind treatment 
phase.

Proportion of subjects who remain in remission (MADRS ≤12) through to the end of the follow-up
phase.

Change from baseline (Day 1, prior to randomization) to the end of the 4-week double-blind treatment 
phase in:

Severity of depressive illness, using the Clinical Global Impression–Severity (CGI-S);

Anxiety symptoms, using the Generalized Anxiety Disorder (GAD-7);

Health-related quality of life and health status, as assessed by the EuroQol-5 dimension-5 level 
(EQ-5D-5L).
Refer to Section 9, Study Evaluations for related evaluations.
Exploratory Endpoints
For subjects who receive esketamine during the double-blind treatment phase, the proportion of subjects 
who relapse during the follow-up phase will be evaluated separately for subjects who are remitters 
(MADRS ≤12) at the end of the 4 week double-blind treatment phase and for subjects who are responders 
but not remitters (≥50% reduction in MADRS total score, but MADRS ˃12) at the end of the 4 week 
double-blind treatment phase.

Time to relapse during the follow-up phase in esketamine subjects who remitted. 

Time to relapse during the follow-up phase in esketamine subjects who are responders but not 
remitters.


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To assess the potential relationship of biomarkers with response/non-response to intranasal esketamine and
oral antidepressant.
Hypothesis
The hypothesis for this study is that, in adult subjects with TRD, switching from a failed antidepressant 
treatment to intranasal esketamine plus a newly initiated oral antidepressant is superior to switching to a 
newly initiated oral antidepressant treatment (active comparator) plus intranasal placebo in improving 
depressive symptoms.
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, active-controlled, multicenter study in male and female adult subjects 
with TRD to assess the efficacy, safety, tolerability, and pharmacokinetics of flexibly dosed intranasal 
esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant compared with a newly initiated 
oral antidepressant (active comparator) plus intranasal placebo. 
The study has 3 phases;

Screening/Prospective Observational Phase 

Double-blind Treatment Phase

Follow-up Phase
Overview of Study Phases
Screening/Prospective Observational phase (4-week duration + optional 3-week taper period) 
This phase will prospectively assess treatment response to the subject’s current oral antidepressant 
treatment regimen. 
At the start of the screening/prospective observational phase, the subject must have had documented 
non-response to at least 1 antidepressant treatment (based on Massachusetts General Hospital 
[MGH]-Antidepressant Treatment Response Questionnaire [ATRQ] [MGH-ATRQ]) in the current episode 
of depression, and subject is taking a different oral antidepressant treatment (on the MGH-ATRQ) for at 
least the previous 2 weeks at or above the minimum therapeutic dose. This antidepressant treatment, as well 
as 
any 
other 
ongoing 
medications 
being 
taken 
for 
depression at 
screening 
(including 
adjunctive/augmentation therapies), will continue from the start of Week 1 through the end of Week 4 of 
the screening/prospective observational phase. Dose adjustment is permitted per clinical judgment, but the 
oral antidepressant treatment is to remain at or above the minimum therapeutic dose (per the MGH-ATRQ) 
through the end of Week 4.
After 4 weeks, subjects who are non-responders to their current oral antidepressant treatment (as assessed 
by independent, remote raters) may be eligible to proceed to the double-blind treatment phase. 
Non-response at the end of the screening/prospective observational phase is defined as ≤25% improvement 
in the MADRS total score from Week 1 to Week 4 and a MADRS total score of ≥28 on Week 2 and Week 4.
Eligible subjects who are entering the double-blind treatment phase will discontinue all their current 
medication(s) being used for depression treatment, including adjunctive/augmentation therapies. Of note, 
subjects taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of lorazepam) 
and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, zaleplon, eszopiclone and 
ramelteon) during the screening/prospective observational phase, can continue these medications, but no 
                                                
Not applicable to China


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Status: Approved, Date: 21 January 2021
dose increases beyond the equivalent of 6 mg/day of lorazepam or new benzodiazepine medications are 
permitted during the screening/prospective observational phase. If clinically indicated, a subject’s current 
antidepressant treatment(s) may be tapered and discontinued over an additional, optional period of up to 
3 weeks per the local prescribing information or clinical judgment, or discontinued and switched directly 
to one of the four new oral antidepressant medications on Day 1 of the double-blind treatment phase, per 
clinical judgment.
Double-blind Treatment Phase (4-week duration)
Approximately 234 eligible subjects (210 Chinese subjects, 24 non-Chinese subjects) with TRD, will be 
randomly assigned at a 1:1 ratio (n=117 subjects per treatment arm, with approximately 105 Chinese 
subjects per arm) to receive double-blind treatment with either intranasal esketamine or intranasal placebo. 
The intranasal treatment sessions (esketamine 56 mg, 84 mg or placebo) will occur twice per week for 
4 weeks as a flexible dose regimen at the study site. In addition, all subjects will initiate a new open-label 
oral antidepressant on Day 1, that will be taken daily for the duration of the double-blind treatment phase. 
The assigned oral antidepressant will be 1 of 4 oral antidepressant medications (duloxetine, escitalopram, 
sertraline, or venlafaxine extended release [XR]), that the subject has not previously had a non-response to 
in the current depressive episode, has not been previously intolerant to (lifetime), and is available in the 
participating country.
Subjects who were taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of 
lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, zaleplon, eszopiclone 
and ramelteon) during the screening/prospective observational phase can continue these medications 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 (eg, alprazolam, clorazepate, triazolam, 
lorazepam and temazepam).
Refer to the Time and Events Schedule for a list of study evaluations that will be performed during the 
double-blind treatment phase.
If a subject withdraws from the study before the end of the double-blind treatment phase for reasons other 
than withdrawal of consent, an Early Withdrawal visit should be conducted within 1 week of the date of 
discontinuation, followed by the follow-up phase.
Follow-up Phase (8-weeks or until relapse)
The follow-up phase will include all subjects who received at least 1 dose of intranasal study medication in 
the double-blind treatment phase. No intranasal study medication will be administered during this phase.
At the start of the follow-up phase, further clinical/standard of care for the treatment of depression will be 
arranged by the study investigator and/or the subject’s treating physician and medication changes are 
permitted. The decision to continue the oral antidepressant in this phase will be at the discretion of the 
investigator.
This follow-up phase will provide additional information required to assess the course of the subject’s major 
depressive episode over an 8-week period. Safety and tolerability, including potential withdrawal 
symptoms, following discontinuation of intranasal esketamine will also be assessed.
The follow-up phase is completed at the end of the 8-week period or when a subject meets the criteria below
for relapse (in remitters and responders), whichever occurs earlier.
Relapse is defined as any of the following:

MADRS total score ≥22 for 2 consecutive assessments separated by 5 to 15 days. The date of the 
second MADRS assessment will be used for the date of relapse.


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3006 Amendment 2
Confidential – FOIA Exemptions Apply in U.S.
23
Status: Approved, Date: 21 January 2021

Hospitalization for worsening depression or any other clinically relevant event determined per clinical 
judgment to be suggestive of a relapse of depressive illness such as suicide attempt, completed suicide, 
or hospitalization for suicide prevention. If hospitalized for any of these events, the start date of 
hospitalization will be used for the date of relapse. Otherwise the date of the event will be used if the 
subject is not hospitalized.

In case more than one relapse criteria are met, the earlier date will be defined as the date of relapse for 
this subject. 
The total duration of a subject’s study participation will be up to 19 weeks (including an optional 3-week 
taper period) for subjects completing the 8-week follow-up phase.
STUDY POPULATION
The study population will consist of approximately 234 subjects (210 Chinese subjects and 24 non-Chinese 
subjects) with TRD. After giving informed consent, subjects who are 18 to 64 years of age (inclusive), will 
be screened to determine eligibility for study participation. 
Subjects must meet Diagnostic and Statistical Manual of Mental Disorders–Fifth Edition (DSM-5) 
diagnostic criteria for recurrent MDD or single-episode MDD, without psychotic features, based upon 
clinical assessment and confirmed by the Mini International Neuropsychiatric Interview (MINI) [DSM-5 
diagnostic code 296.23 or 296.33]. An independent rater will conduct the MADRS at screening as well as 
confirming the diagnosis and the validity of the major depressive episode.
At the start of the screening/prospective observational phase, subjects must have had non-response (ie, lack 
of clinically meaningful improvement, defined as ≤25% improvement) to ≥1 but ≤5 (if current episode is 
˃2 years or undefinable, upper limit is only applicable to the last 2 years) oral antidepressant treatments, 
taken at adequate dosage and for adequate duration, as assessed using the MGH-ATRQ and documented 
by records (eg, medical/pharmacy/prescription records or a letter from treating physician, etc.), for the 
current episode of depression. In addition, the subject must currently be taking one of a different oral 
antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or above the minimum 
therapeutic dose. This antidepressant treatment, as well as any other ongoing medications being taken for 
depression at screening (including adjunctive/augmentation therapies), will continue from the start of Week 
1 through the end of Week 4 of the screening/prospective observational phase. Dose adjustment is permitted 
per clinical judgment, but the oral antidepressant treatment is to remain at or above the minimum therapeutic 
dose (per the MGH-ATRQ) through the end of Week 4. Antidepressant treatment adherence will be 
assessed using the PAQ. Subjects who report missing ≥4 days of antidepressant medication treatment(s) in 
the prior 2-week period will be considered as screen failed due to inadequate adherence.
Non-response at the end of the screening/prospective observational phase is defined as ≤25% improvement 
from Week 1 to Week 4 in the MADRS total score and a MADRS total score of ≥28 on Week 2 and Week 4.
Treatment-resistant depression is defined as a lack of clinically meaningful improvement after treatment 
with at least 2 different antidepressant agents prescribed in adequate doses for adequate duration.
The subject’s current major depressive episode, depression symptom severity (Week 1 MADRS total score 
≥28 required), and antidepressant treatment response in their current depressive episode (retrospectively 
assessed) must be deemed valid for participation in the clinical study based on a Clinical Validation 
Inventory for Study Admission (C-VISA). The C-VISA is a tool to facilitate subject selection for MDD 
clinical studies, with a goal to ensure enrollment of subjects who have symptoms that reflect the current 
state of illness and that these symptoms can be reliably measured with appropriate measurement tools.
Potential subjects will be excluded from participating in the study if they have previously demonstrated 
non-response of depressive symptoms to esketamine or ketamine in the current major depressive episode, 
or to all 4 of the oral antidepressant treatment options available for the double-blind treatment phase 
(ie, duloxetine, escitalopram, sertraline, and venlafaxine XR) in the current major depressive episode (based 


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3006 Amendment 2
Confidential – FOIA Exemptions Apply in U.S.
24
Status: Approved, Date: 21 January 2021
on MGH-ATRQ), or an adequate course of treatment with electroconvulsive therapy (ECT) in the current 
major depressive episode, defined as at least 7 treatments with unilateral/ bilateral ECT. Subjects, who in 
the current depressive episode have received vagal nerve stimulation (VNS) or who have received deep 
brain stimulation (DBS), in the current depressive episode will be excluded. Subjects will also be excluded 
if they have a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, 
bipolar or related disorders (confirmed by the MINI), 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/prospective observational phase per the 
investigator’s clinical judgment and/or based on the Columbia Suicide Severity Rating Scale (C-SSRS); or 
if they have a history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria.
DOSAGE AND ADMINISTRATION
During the double-blind treatment phase, subjects will be randomized to receive double-blind intranasal 
treatment with esketamine (56 mg or 84 mg) or placebo. In addition, subjects will simultaneously initiate a 
new, open-label oral antidepressant on Day 1 that will be continued for the duration of the 4-week double-
blind treatment phase.
Double-Blind Treatment Phase
Intranasal Study Medication
All subjects will self-administer the intranasal study drug (esketamine or placebo) at treatment sessions 
twice a week for 4 weeks at the study site. The first treatment session will be on Day 1 of the double-blind 
treatment phase. Intranasal treatment sessions will not take place on consecutive days. 
Prior to the first intranasal dose on Day 1, subjects will practice spraying (into the air, not intranasally) a 
demonstration intranasal device that is filled with placebo solution. 
On Day 1, subjects randomized to intranasal esketamine will start with a dose of 56 mg. On any of the 
subsequent dosing days (Day 4, 8, 11, 15, 18, 22 and 25), the investigator can judge, based on efficacy and 
tolerance, whether to increase the dose of intranasal esketamine to 84 mg or to maintain the dose at 56 mg. 
In the event that an increase in dose is poorly tolerated, the investigator may decide to reduce the dose to 
56 mg. Food will be restricted for at least 2 hours before each administration of study drug. Drinking of 
fluids will be restricted for at least 30 minutes before the first nasal spray.
On all intranasal treatment session days, a site staff member with training in cardiopulmonary resuscitation 
(eg, Basic Life Support course or equivalent course) that is up to date per local regulations, must be present 
with the subject during the intranasal treatment sessions and the postdose observation period. In addition, 
equipment for supportive ventilation and resuscitation needs to be present. Subjects must remain at the site 
until study procedures have been completed and the subject is ready for discharge. At the time of discharge, 
subjects should be accompanied by a responsible adult when released from the clinical site. Subjects must 
not drive a car or work with machines for 24 hours after receiving intranasal study drug.
Oral Antidepressant Study Medication
Starting on Day 1, a new, open-label oral antidepressant treatment will be initiated in all subjects. The oral 
antidepressant will be 1 of 4 oral antidepressant medications (duloxetine, escitalopram, sertraline, or 
venlafaxine XR). The antidepressant medication will be assigned by the investigator based on review of 
MGH-ATRQ and relevant prior antidepressant medication information and will be one that the subject has 
not previously had a non-response to in the current depressive episode, has not been previously intolerant 
to (lifetime), and is available in the participating country.


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Status: Approved, Date: 21 January 2021
Dosing of the oral antidepressant will begin on Day 1 and will follow a specific titration schedule. The use 
of the titration schedule is mandatory. Doses are not to exceed the maximum dose defined in the titration 
schedule. If higher doses are not tolerated, a down-titration is permitted based on clinical judgment. 
EFFICACY EVALUATIONS
Primary Efficacy Evaluation and Endpoint
The primary efficacy evaluation will be the MADRS total score. The MADRS will be performed by 
independent remote raters during the study. The Structured Interview Guide for the Montgomery Asberg 
Depression Rating Scale (SIGMA: Williams 2008) will be used for each administration. 
The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to 
antidepressant treatment. 
The primary efficacy endpoint will be change from baseline in MADRS total score from Day 1 
pre-randomization to the end of the 4-week double-blind treatment phase.
Secondary Efficacy Evaluation and Endpoints
Key Secondary Efficacy Evaluations and Endpoints

MADRS: The first key secondary endpoint is change from baseline (Day 1, predose) to 24 hours post 
first dose in depressive symptoms, as measured by the MADRS total score.

Sheehan Disability Scale (SDS): The SDS is a subject-reported outcome measure that will be used to 
assess functional impairment and associated disability. The second key secondary endpoint is the 
change in SDS total score as measured by the change from baseline (Day 1 prior to randomization) to 
the end of the 4-week double-blind treatment phase. 
Other Secondary Efficacy Evaluations and Endpoints

Proportion of subjects showing onset of clinical response (≥50% reduction from baseline in MADRS 
total score) by Day 2 that is maintained through the end of the 4-week double-blind treatment phase 
with one excursion allowed.

Proportion of responders (50% reduction from baseline in MADRS total score) at the end of the 
4-week double-blind treatment phase.

Proportion of subjects in remission (MADRS 12) at the end of the 4-week double-blind treatment 
phase.

Proportion of subjects who remain in remission (MADRS ≤12) through to the end of the follow-up 
phase.

Change from baseline (Day 1, prior to randomization) to the end of the 4-week double-blind treatment 
phase in:
o
Severity of depressive illness, using the Clinical Global Impression–Severity (CGI-S);
o
Anxiety symptoms, using the Generalized Anxiety Disorder (GAD-7), and 
o
Health-related quality of life and health status, as assessed by the EuroQol-5 dimension-
5 level (EQ-5D-5L).


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3006 Amendment 2
Confidential – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 21 January 2021
Exploratory Efficacy Evaluation and Endpoints

For subjects who receive esketamine during the double-blind treatment phase, the proportion of 
subjects who relapse during the follow-up phase will be evaluated separately for subjects who are 
remitters (MADRS ≤12) at the end of the 4 week double-blind treatment phase and for subjects who 
are responders but not remitters (≥50% reduction in MADRS total score, but MADRS ˃12) at the end 
of the 4 week double-blind treatment phase.

Time to relapse during the follow-up phase in esketamine subjects who remitted. 

Time to relapse during the follow-up phase in esketamine subjects who are responders but not 
remitters.
See Section 9.2 for further details
PHARMACOKINETIC EVALUATIONS
Pharmacokinetic Venous blood samples of approximately 4 mL will be collected from Chinese subjects at 
all clinical sites, for measurement of plasma concentrations of esketamine (JNJ-54135419), and other 
metabolites (if warranted), at the time points specified in the Time and Events Schedule. The exact dates 
and times of PK blood sampling must be recorded.
BIOMARKER, PHARMACOGENOMIC (DNA) AND EXPRESSION (RNA) EVALUATIONS
Assessment of biomarkers and their potential relationship to intranasal esketamine plus a newly initiated 
oral antidepressant and to maintenance/stabilization of response, non-response, and relapse will be 
explored. Blood samples will be collected to measure genetic and epigenetic markers (including but not 
limited to BDNF allelic variants) and protein markers (including but not limited to growth factors, 
inflammation, endocrine, or metabolic markers). Samples of deoxyribonucleic acid (DNA) and biomarkers 
(protein and RNA) may be used to help address emerging issues and to enable the development of safer, 
more effective, and ultimately individualized therapies. Subjects who agree to participate in the biomarker, 
pharmacogenomic (DNA) and expression (RNA) component will need to sign a separate written informed 
consent form.
SAFETY EVALUATIONS
Safety evaluations will include:
Monitoring of Treatment Emergent Adverse Events (TEAEs), clinical laboratory tests (including 
hematology, serum chemistry, and urinalysis), pregnancy testing (for women of childbearing potential), 
urine drug screen, 12-lead electrocardiogram (ECG), vital signs, pulse oximetry, physical examination, and 
body weight measurements. 

Nasal examinations 

Columbia Suicide Severity Rating Scale (C-SSRS), to assess potential suicidal ideation and behavior

Clinician Administered Dissociative States Scale (CADSS), to assess treatment-emergent dissociative 
symptoms 

Physician Withdrawal Checklist (20 items; PWC-20) to assess potential withdrawal symptoms 
following cessation of intranasal esketamine treatment
                                                

Not applicable to China


JNJ-54135419 (esketamine)
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Status: Approved, Date: 21 January 2021
STATISTICAL METHODS
Subject Information
The primary efficacy and safety analysis sets are defined below:
Full Analysis Set: All randomized subjects who receive at least 1 dose of intranasal study medication and 
1 dose of oral antidepressant medication in the double-blind treatment phase.
Safety Analysis Set: All randomized subjects who receive at least 1 dose of intranasal study medication or 
1 dose of oral antidepressant medication in the double-blind treatment phase.
Sample Size Determination
Assuming a treatment difference for the double-blind treatment phase of 6.5 points in MADRS total score 
between esketamine plus oral antidepressant compared with oral antidepressant plus intranasal placebo at 
the Week 4 endpoint, a standard deviation of 12, a one-sided significance level of 0.025, a drop-out rate of 
25%, 117 subjects will be randomized to each treatment arm to achieve greater than 90% power and a 
sample size of 105 Chinese subjects per treatment arm (total n = 210) plus 12 non-Chinese subjects per 
treatment arm (total of n = 24) will be included. The treatment difference and standard deviation used in 
this calculation were based on results from Panel A of the ESKETINTRD2003 study and based on clinical 
judgment.
Efficacy Analyses
Efficacy analyses will be performed on the full analysis set, which will include all randomized subjects 
who receive at least 1 dose of intranasal study drug and 1 dose of oral antidepressant medication, in the 
double-blind treatment phase.
Primary Endpoint
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined by the 
following 4 components:

Population: subjects with treatment-resistant depression;

Variable: change from Day 1 to end of 4-week double-blind treatment phase;

Intervention Effect: the effect of the initially randomized treatment together with the oral 
antidepressant medication that would have been observed had all subjects remained on their 
treatment throughout the double-blind treatment phase;

Summary Measure: the difference in variable means.
The primary analysis will be based on the full analysis set and the MADRS total scores collected during 
the double-blind treatment phase.
For the primary efficacy analysis, change from baseline in MADRS total score at Week 4 in the double-
blind treatment phase will be analyzed using a mixed-effects model for repeated measures (MMRM). The 
model will include baseline MADRS total score as a covariate, and treatment, country, class of 
antidepressant (Serotonin and Norepinephrine Reuptake Inhibitors [SNRI] or Selective Serotonin Reuptake 
Inhibitor [SSRI]), day, and day-by-treatment interaction as fixed effects. Comparison of the esketamine 
plus oral antidepressant arm to the active comparator (oral antidepressant plus intranasal placebo) arm will 
be performed using the appropriate contrast. 
Sensitivity analysis for the primary efficacy endpoint to assess the robustness of the results to missing data 
might be performed. The detailed assumptions and methods will be provided in the statistical analysis plan 
(SAP).


JNJ-54135419 (esketamine)
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Status: Approved, Date: 21 January 2021
Secondary Efficacy Endpoint Analysis
For the analysis of the first of the two key secondary efficacy endpoints, change from baseline in MADRS 
total score at 24 hours post first dose (Day 2), will be analyzed using the same model described above for 
the MADRS total score at Week 4 in the double-blind treatment phase.
The second key efficacy endpoint, change from baseline in SDS total score at Week 4 in the double-blind 
treatment phase, will be analyzed using the same models described above for the MADRS total score.
To strongly control Type I error across the primary and the two key secondary efficacy endpoints, a fixed 
sequence approach will be applied to adjust for multiplicity. The hypotheses will be tested sequentially in 
the following order:

Change in MADRS total score at the end of the 4-week double-blind treatment phase

Change in MADRS total score at 24 hours post first dose

Change in SDS total score
Further details of this approach will be provided in the SAP.
The proportion of subjects showing onset of clinical response by Day 2 (in the event that no MADRS was 
collected on Day 2, a MADRS collected on Day 3 could be used) that is maintained for the duration of the 
double-blind treatment phase (≥50% reduction in MADRS total score by the second day after taking the 
first dose of double-blind medication that continued through the end of the double-blind phase) in 
esketamine arm will be compared with the active comparator using a Cochran-Mantel-Haenszel chi-square 
test adjusting for country and class of antidepressant (SNRI or SSRI). Subjects who discontinued the study 
prior to the end of the double-blind treatment phase will not be considered to have maintained clinical 
response.
Response and remission rates will be summarized at each visit.
The proportion of subjects who remain in remission through to the end of the follow-up phase will be 
presented. 
Change from baseline in GAD-7 total scores at the end of the 4-week double-blind treatment phase will be 
analyzed using an ANCOVA model, with treatment, country and class of antidepressant (SNRI or SSRI) 
as factors, and the respective baseline score as the covariate. 
Ranks of change from baseline in CGI-S scores during the 4-week double-blind treatment phase will be 
analyzed using the MMRM for repeated measures, as described above for the MADRS and SDS total 
scores.
Dimension scores of EQ-5D-5L descriptive system, health status index, and the overall health status score 
will be summarized over time.
Additionally, scores of all efficacy endpoints will be summarized for all visits in the double-blind period. 
Summaries will be provided to show consistency of effect among relevant subgroups (eg, antidepressant 
class SSRI [escitalopram, sertraline] and SNRI [duloxetine, venlafaxine]).
For subjects who receive esketamine during the double-blind treatment phase, the proportion of subjects 
who relapse during the follow-up phase will be summarized separately for subjects who are remitters 
(MADRS ≤12 at the end of the double-blind treatment phase) and for subjects who are responders but not 
remitters (≥50% reduction in MADRS total score, but MADRS ˃12 at the end of the double-blind treatment 
phase). In addition, the time to relapse during the follow-up phase will be estimated by the Kaplan-Meier 
method separately for subjects who are remitters, and for subjects who are responders but not remitters. 
Descriptive statistics (number of relapses, number of censored subjects, and median, 25th, and 75th percentile 
of time to relapse, if estimable) will be provided.


JNJ-54135419 (esketamine)
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Confidential – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 21 January 2021
Pharmacokinetics Analyses
Plasma esketamine concentrations will be listed for all subjects. The plasma concentration-time data of 
esketamine will be analyzed using population PK modeling. Data may be combined with those of other 
selected studies to support a relevant structural model. Typical population values of basic PK parameters 
will be estimated together with the inter-individual variability. Additional pharmacokinetic parameters may
be calculated if deemed appropriate. Effects of subject demographics, laboratory parameter values, and 
other covariates on the PK of esketamine will be explored. The results of the population PK analyses may 
be reported separately.
Biomarker and Pharmacogenomics Analyses

Baseline biomarker values and changes from baseline biomarker values to the time points specified in the 
Time and Events Schedule will be summarized if available number is sufficient for analyses. Exploratory 
biomarker analyses may include comparison of biomarker measures between the treatment groups, 
correlation with efficacy and other measures, and relationship with clinical response, relapse and non-
response.
The analysis plan and summarized results from both biomarker and pharmacogenomics analyses will be 
reported separately.
Safety Analyses
The primary population for safety analysis will consist of all randomized subjects who receive at least 
1 dose of intranasal medication or 1 dose of oral antidepressant in the double-blind treatment phase. The 
safety data from the follow-up phase will be analyzed separately.
Adverse events (AEs) will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). All reported AEs with onset during the 4-week double-blind treatment phase (ie, TEAEs, and 
AEs that have worsened from baseline), will be included in the analysis. For each AE, the percentage of 
subjects who experience at least 1 occurrence of the given event will be summarized by treatment group. 
Subjects who die, or who discontinue treatment due to an adverse event or serious adverse events, will be 
summarized separately. AEs occurring during the follow-up phase will be summarized separately.
Body weight, vital signs, 12-lead ECG and clinical laboratory test results, and changes from baseline will 
be tabulated over time by treatment group, using descriptive statistics. Any treatment-emergent 
abnormalities will be presented. 
Changes in findings from the baseline nasal examination will be listed by treatment group. A shift table for 
changes from double-blind baseline in ratings for each nasal examination will be presented by treatment 
group. 
Descriptive statistics of the CADSS, and changes from baseline will be summarized at each scheduled time 
point.
Descriptive statistics of the PWC-20 scores and changes and/or percent changes from baseline will be 
summarized at each scheduled time point. 
Suicide-related thoughts and behaviors based on the C-SSRS will be summarized by treatment group in 
incidence and shift tables.
                                                

Not applicable to China


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3006 Amendment 2
Confidential – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 21 January 2021
TIME AND EVENTS SCHEDULE (SCREENING/PROSPECTIVE OBSERVATIONAL PHASE AND DOUBLE-BLIND 
TREATMENT PHASE)
Screening/ Prospective 
Observational Phase
Double-blind Treatment Phase
Visit number
1.1
1.2
1.3 a
2.1 a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10
EW b
Week
Week 1
End of 
Week 2
End of 
Week 4
1
2
3
4
—
Study day
—
—
—
1
(baseline)
2
4
8
11
15
18
22
25
28
EW
Clinic visit window (in days)
—
±2
±2
—
—
±1
±1
±1
±1
±1
±1
±1
±1
—
Clinic visit (C) or remote MADRS 
interview only (RM)
C
C
C
C
RM
C
C
C
C
C
C
C
C
C
Screening/Administrative
Informed consent (ICF)
X
Medical history, psychiatric history, 
demographics, employment status 
X
MINI
X
MGH-ATRQ
X
C-VISA r
X
Height 
X
Inclusion/exclusion criteria
X
X
Prestudy therapy
X
Preplanned surgery/procedures
X
Study Drug
Randomization
X
Dispensing of new oral 
antidepressant (duloxetine, 
escitalopram, sertraline, or 
venlafaxine XR)
X
Xq
X
Practice session for use of intranasal 
device
X
Intranasal esketamine or placebo 
X
X
X
X
X
X
X
X
Drug accountability
(intranasal study medication)
X
X
X
X
X
X
X
X
X
Drug accountability (oral 
antidepressant study medication)
X
X
X
Dispense subject diary for oral 
antidepressant
X


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3006 Amendment 2
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Status: Approved, Date: 21 January 2021
Screening/ Prospective 
Observational Phase
Double-blind Treatment Phase
Visit number
1.1
1.2
1.3 a
2.1 a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10
EW b
Week
Week 1
End of 
Week 2
End of 
Week 4
1
2
3
4
—
Study day
—
—
—
1
(baseline)
2
4
8
11
15
18
22
25
28
EW
Clinic visit window (in days)
—
±2
±2
—
—
±1
±1
±1
±1
±1
±1
±1
±1
—
Clinic visit (C) or remote MADRS 
interview only (RM)
C
C
C
C
RM
C
C
C
C
C
C
C
C
C
Review subject diary and update 
(if applicable)
X
X
X
X
X
X
X
X
X
Oral antidepressant adherence check
X
X
X
X
X
Return of subject diary if not 
entering follow-up phase
X
Safety Assessments (Clinician)
Physical examination
X
X
X
X
Nasal examination c
X
X
X
X
Vital signs: blood pressure, pulse
rate, respiratory rate, temperature c ,l
X
X
X
X
X
X
X
X
X
X
Vital signs (postdose): blood 
pressure, pulse, respiratory rate f, l
X
X
X
X
X
X
X
X
Weight
X
X
X
X
12-lead ECG g ,l
X
X
X
X
X
C-SSRS: Baseline/Screening 
version
X
C-SSRS: Since last visit version l
X
X
X m
X
X
X
X
X
X
X
X
X
Pulse oximetry h, l
X
X
X
X
X
X
X
X
X
CADSS i, l
X
X
X
X
X
X
PWC-20
X
X
Efficacy Assessments (Clinician)
MADRS (7-day recall; performed 
by independent, remote raters)
X e
X k
X k
X d
X k
X k
X k
X k
X
MADRS (24-hr recall; performed 
by independent, remote raters)
X
CGI-S c
X
X
X
X
X
X
X
X
X
Subject-completed Assessments
PAQ
X
X
X
SDS c
X
X
X
X
X


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Screening/ Prospective 
Observational Phase
Double-blind Treatment Phase
Visit number
1.1
1.2
1.3 a
2.1 a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10
EW b
Week
Week 1
End of 
Week 2
End of 
Week 4
1
2
3
4
—
Study day
—
—
—
1
(baseline)
2
4
8
11
15
18
22
25
28
EW
Clinic visit window (in days)
—
±2
±2
—
—
±1
±1
±1
±1
±1
±1
±1
±1
—
Clinic visit (C) or remote MADRS 
interview only (RM)
C
C
C
C
RM
C
C
C
C
C
C
C
C
C
GAD-7 c
X
X
X
X
EQ-5D-5L c
X
X
X
X
X
Clinical Laboratory Assessments
TSH, HbA1c
X
Hematology, Chemistry c, n
X
X
X
X
Urine drug screen c
X
X
X
X
Alcohol breath test
X
X
Urinalysis c
X
X
X
X
X
Serum pregnancy test
X
Urine pregnancy test c
X
X
X
X
Pharmacokinetics
Blood collection j
X
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations o
Blood sample collection 
(protein) c, n
X
X
X
X
X p
Blood collection (DNA) c, n
X
X
X p
Blood sample collection (RNA) c, n
X
X
X
X
X p
Ongoing Subject Review
Concomitant therapy
Ongoing
Adverse events
Ongoing
Footnotes:
Abbreviations: BMI, body mass index; C, clinic visit; CGI-S, Clinical Global Impression – Severity; CADSS, Clinician Administered Dissociative States Scale; 
C-SSRS, Columbia Suicide Severity Rating Scale; C-VISA, Clinical Validation Inventory for Study Admission; ECG, electrocardiogram; EQ-5D-5L, EuroQol-5 
dimension- 5-level; EW, early withdrawal; GAD-7, Generalized Anxiety Disorder, 7-item scale; HbA1c test, glycated hemoglobin test; MADRS, Montgomery-Asberg 
Depression Rating Scale; MGH-ATRQ, Massachusetts General Hospital - Antidepressant Treatment History Questionnaire; MINI, Mini-International Neuropsychiatric 
                                                
Not applicable to China


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Interview; PAQ, Patient Adherence Questionnaire; PWC-20, Physician Withdrawal Checklist, 20-item scale; SDS, Sheehan Disability Scale; TSH, thyroid-stimulating 
hormone
Note: On intranasal dosing days, time 0 is defined as the time of the first intranasal spray. Therefore, postdose time points are referenced from this time point.
Note: On intranasal dosing days, food will be restricted for at least 2 hours before each administration of study drug. Drinking of any fluids will be restricted for at least 
30 minutes before the first nasal spray.
a) An additional, optional period of up to 3 weeks is permitted to taper and discontinue current antidepressant treatment(s) after completion of the Week 4 (Visit 1.3) 
assessments, per the local prescribing information or clinical judgment. Subjects who do not require a taper and are thus eligible to immediately proceed to the 
double-blind treatment phase can have Visit 1.3 and Visit 2.1 occur on the same day or within 1 week of each other (if not occurring the same day, the antidepressant 
treatment regimen should be continued and discontinued prior to Visit 2.1). 
b) If a subject withdraws before the end of the double-blind treatment phase (ie, before completing Visit 2.10/Day 28) for reasons other than withdrawal of consent, an 
early withdrawal visit should be conducted within 1 week of the date of discontinuation, followed by the follow-up phase. If the early withdrawal visit is conducted 
on the same day as a scheduled visit, duplicate assessments are not required.
c) Predose (if/when performed on intranasal dosing days). Predose subject-reported outcome assessments should be administered before all other study-related 
procedures during a clinic visit.
d) Performed for subjects who require a taper period, or who do not require a taper period but their Visit 1.3 and Visit 2.1 occur more than 1 week apart; the result will 
be considered as the subject’s baseline MADRS for the double-blind treatment phase. For all other subjects, the baseline MADRS for the double-blind treatment 
phase will be the MADRS performed at the end of Week-4 of the screening/prospective observational phase.
e) The MADRS interview should be performed in Week 1 (Visit 1.1 or as soon as possible) of the screening/prospective observational phase.  
f) Postdose vital signs will be performed at 40 minutes, 1 hour, and 1.5 hours postdose. Please refer to Section 6.4 for guidance for blood pressure monitoring on 
intranasal dosing days.
g) Twelve-lead ECG will be performed predose and at t=1 hour postdose at Visit 2.1. Twelve-lead ECG will be performed at t=1 hour postdose only (ie, no predose 
ECG required) at Visits 2.4 and 2.9. A time window of ±15 minutes is permitted.
h) Pulse oximetry will be performed every 15 minutes from predose to t=1.5 hours postdose (please refer to Section 9.5 for further guidance on timing of pulse 
oximetry assessments).
i)
The CADSS to be performed predose and at 40 minutes and 1.5 hours postdose. 
j)
Only for Chinese subjects. PK blood collection will be performed at predose, t=40 minutes (30min~50min), t=2 hours (1.5hr ~ 2.5hr) and t=6hr (5.5hr ~ 6.5hr)
postdose (where time=0 is defined as the time of the first intranasal spray). 
k) The MADRS should be administered no more than 2 days prior to the subject’s targeted (not actual) clinic visit date (except Visit 2.10, which is within 1 day prior). 
If performed on the day of the scheduled clinic visit for an intranasal treatment session, the MADRS must be performed prior to the intranasal treatment session.
l)
If intranasal dosing is postponed (but occurs within visit window) due to vital sign results (eg, blood pressure elevation), all assessment time points (including 
predose) must be performed on the actual intranasal dosing day.
m) The C-SSRS to be performed only if Visit 1.3 and Visit 2.1 do not occur on the same day.
n) Blood samples should be collected prior to dosing. It is preferred that subjects adhere to a low fat diet on the day of sample collection.
o) Only for subjects who give written consent to participate in the biomarker, pharmacogenomic (DNA), and expression (RNA) component of the study.
p) If a subject withdraws after Visit 2.9 of the double-blind treatment phase, the blood collection doesn’t need to be repeated at the EW Visit.
q) For subjects entering the Follow-up phase and continuing with the same oral AD.
r) C-VISA can be completed prior to randomization.


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TIME AND EVENTS SCHEDULE (Follow-up Phase)
Follow-up Phase a
Visit number
3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8 g
Weeks after last intranasal dose
1
2
3
4
5
6
7
8
Visit window for clinic visit or remote assessments only (days)
±3
±3
±3
±3
±3
±3
±3
±3
Clinic visit (C) or remote assessments only (RA)
C
C
RA b RA b
C
RA b RA b
C
Dispensing of oral antidepressant (duloxetine, escitalopram, 
sertraline, or venlafaxine XR)
Xh
Drug accountability
Drug accountability (oral antidepressant study medication)
X
Return of subject diary
X
Safety Assessments (Clinician-completed)
Physical examination
X
Vital signs: Blood pressure, pulse, respiratory rate, temperature
X
X
X
Weight
X
C-SSRS: Since last visit version
X c,d
X
X
X
X
X
X
X
PWC-20
X d
X 
Efficacy Assessments (Clinician-completed)
MADRS (performed by independent, remote raters)
X c,d
X
X
X
X
X
X
X
CGI-S 
X
X
X
Efficacy Assessments (Subject-completed)
SDS
X
X
X
GAD-7
X
X
X
EQ-5D-5L
X
X
X
Clinical Laboratory Assessments
Hematology, chemistry
X
Urinalysis
X
Serum pregnancy test
X
Urine pregnancy test
X
X
Biomarker and Expression (RNA) Evaluations e
Blood sample collection (protein) f
X
Blood sample collection (RNA) f
X
Ongoing Subject Review
Concomitant therapy
Ongoing
Adverse events
Ongoing
Footnotes: 
Note: No intranasal study medication will be administered during the Follow-up Phase 
a) The follow-up phase will begin on Day 28, after completion of all study procedures for the double-blind phase. 
No intranasal study medication will be administered during the follow-up phase. Clinical visits or telephone 
contacts will be every week for up to 8 weeks or until relapse.
b) At each “Remote Assessment” visit, site staff will contact the subject by telephone to perform the C-SSRS and to 
obtain information regarding adverse events and concomitant therapies.
c) Performed only if Visit 2.10 and Visit 3.1 do not occur on the same day. 
d) For subjects who withdraw before the end of the double-blind treatment phase, performed only if the EW Visit 
and Visit 3.1 do not occur on the same day.
e) Only for subjects who give written consent to participate in the biomarker, pharmacogenomic (DNA), and 
expression (RNA) component of the study.
f) It is preferred that subjects adhere to a low-fat diet on the day of sample collection.
g) For subjects who complete the 8-week Follow-up Phase or meet criteria for relapse or withdraw before the end 
of the Follow-up Phase for reasons other than withdrawal of consent.
h) For subjects continuing the same oral antidepressant.


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ABBREVIATIONS
AE
Adverse Event
AHI
apnea-hypopnea index
ANCOVA
analysis of covariance
AUC
area under the plasma concentration-time curve
BDNF
brain-derived neurotrophic factor
BMI
body mass index
C
clinic visit
CADSS
Clinician Administered Dissociative States Scale
CGI-S
Clinical Global Impression – Severity
Cmax
maximum plasma concentration
CRF
case report form
C-SSRS
Columbia Suicide Severity Rating Scale
C-VISA
Clinical-Validation Inventory for Study Admission
CYP
cytochrome P450, with any appended letters (2B6, 3A4, etc) indicating subtypes
DBP
diastolic blood pressure
DBS
deep brain stimulation
DNA
deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition)
ECG
electrocardiogram
eCRF
electronic case report form
ECT
electroconvulsive therapy
eDC
Electronic Data Capture
EQ-5D-5L
European Quality of Life (EuroQol-5) dimension-5 level
EQ-VAS
EuroQol group: Visual Analogue Scale
EU
European Union
EW
Early Withdrawal
FDA
United States Food and Drug Administration
FT4
free thyroxine
GAD-7
Generalized Anxiety Disorder 7-item scale
GCP
Good Clinical Practice
HbA1c test
glycated hemoglobin test
HPA
hypothalamus pituitary adrenal
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IM
intramuscular
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
IWRS
interactive web response system
LOCF
last observation carried forward
MADRS
Montgomery-Asberg Depression Rating Scale
MAOI
monoamine oxidase inhibitor
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MGH-ATRQ
Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire
MINI
Mini-International Neuropsychiatric Interview (mental status questionnaire)
MMRM
mixed-effects model for repeated measures
NMDA
N-Methyl-D-Aspartate
PAQ
Patient Adherence Questionnaire
PCP
phencyclidine
PD
pharmacodynamics
PK
pharmacokinetics
PQC
product quality complaint
PWC-20
Physician Withdrawal Checklist; 20-item
QTc
QT interval corrected


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QTcB
QT interval corrected according to Bazett's formula
QTcF
QT interval corrected according to Fridericia's formula
RM
remote assessments only
RNA
ribonucleic acid
SAEs
SAP
serious adverse events
statistical analysis plan
SDS
Sheehan Disability Scale
SmPC
Summary of Product Characteristics
SMQ
standardized MedDRA queries
SNRI
Serotonin and Norepinephrine Reuptake Inhibitors
SSRI
Selective Serotonin Reuptake Inhibitors
SUSARs
suspected unexpected serious adverse reactions
SBP
systolic blood pressure
TEAEs
treatment-emergent adverse events
TRD
treatment-resistant depression
TSH
thyroid-stimulating hormone
US
United States
US FDA
United States Food and Drug Administration
VNS
vagal nerve stimulation
XR
extended release 


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1.
INTRODUCTION
Major depressive disorder (MDD), a serious, recurrent, and disabling psychiatric illness, is the 
second leading cause of years lost to disability worldwide. MDD is associated with excess 
mortality, and with years of potential life lost. About 30% of patients fail to achieve remission 
despite treatment with multiple antidepressant medications and are considered to have treatment-
resistant depression (TRD). There is a significant need to develop novel treatments based upon 
relevant pathophysiologic pathways underlying MDD for the rapid relief of symptoms of 
depression, especially in patients with TRD.
Esketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist. It is the S-enantiomer of 
racemic ketamine and has been shown to have approximately 3- to 4-fold stronger binding affinity 
for the phencyclidine (PCP) site of the N-methyl-D-aspartate (NMDA) receptor than the 
R-enantiomer. The mechanism of action of ketamine and esketamine is distinct from conventional 
monoaminergic antidepressant treatments and ketamine profoundly affects fast excitatory 
glutamate transmission, increases brain-derived neurotrophic factor (BDNF) release, and 
stimulates synaptogenesis.
Janssen Research & Development (JRD) is developing intranasal esketamine as an antidepressant 
therapy. A higher NMDA receptor affinity of esketamine allows a lower volume of medication to 
be administered via the non-invasive, rapidly absorbed intranasal route.
The current study is being conducted to evaluate the efficacy, safety, and tolerability of flexibly 
dosed intranasal esketamine plus a newly initiated oral antidepressant in adult subjects with TRD. 
The study will serve as a Phase 3 short-term efficacy and safety study in support of Chinese 
regulatory agency requirements for registration of intranasal esketamine for the treatment of TRD.
The term “sponsor” used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
1.1.1.
Nonclinical Studies
Safety Pharmacology
The following text is quoted from the United States (US) prescribing information for anesthetic 
Ketalar® (ketamine hydrochloride injection)37 is provided below: Intravenous Ketalar® produces a 
fall in arterial blood pressure in the Rhesus monkey and a rise in arterial blood pressure in the dog. 
In this respect the dog mimics the cardiovascular effect observed in man. The pressor response to 
Ketalar® injected into intact, anaesthetized dogs is accompanied by a tachycardia, rise in cardiac 
output and a fall in total peripheral resistance. The pressor response to Ketalar® is reduced or 
blocked by chlorpromazine (central depressant and peripheral α-adrenergic blockade), by 
β-adrenergic blockade, and by ganglionic blockade.


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Findings from animal studies suggest that the increase in blood pressure produced by 
ketamine/esketamine is due to selective activation of central cardiac stimulating mechanisms 
leading to an increase in cardiac output.
In a 3-month repeat-dose toxicity study with intranasally administered esketamine in dogs, no 
relevant electrocardiogram (ECG) changes were noted up to the highest dose tested, ie, 72 mg/day. 
Heart rate was slightly increased. The cardiovascular safety of racemic ketamine and esketamine 
in humans and animals is summarized in the Investigator's Brochure.34
Toxicology
Repeat-Dose Toxicity Studies
In repeat-dose toxicity studies with intranasally administered esketamine in rats up to 9 mg/day 
for 6 months, and dogs up to 72 mg/day for 3 months of duration, the clinical observations mainly 
related to the central nervous system (eg, changes in activity and gait). No adverse effects were 
noted up to the highest dose tested, ie, 9 mg/day in rats and 72 mg/day in dogs. These observations 
reflected the (exaggerated) pharmacology of the test compound. Minor histologic findings were 
noted in the nasal cavity. These tissue changes were not considered adverse.
In 3- and 9-month repeat-dose toxicity studies with intranasally administered esketamine in dogs, 
no relevant electrocardiogram (ECG) changes were noted up 72 mg/day. Heart rate was slightly 
increased. 
Further details can be found in the Investigator's Brochure.34
Genetic Toxicity
A series of in vitro and in vivo genotoxicity studies was conducted with ketamine and esketamine. 
The weight of evidence indicates that esketamine poses no genotoxic risk to humans.34
Neurotoxicity
Racemic ketamine has been reported to induce neurotoxicity in animal fetuses, and in juvenile, 
adolescent, and adult animals, as evidenced by histopathologic brain lesions and functional 
sequelae. The precise thresholds for dose and duration of exposure causing neurotoxicity in 
animals remain to be established. The relevance to humans of ketamine’s neurotoxic action in 
animals is unknown.
In studies exploring neurotoxic effects of ketamine on juvenile and prenatal monkeys, 
neuroapoptosis was observed to be more widespread in fetal brains than in neonatal brains, after 
administration of ketamine anesthesia IV for 5 hours. In fetal brains, the cerebellum, caudate 
nucleus, putamen, and nucleus accumbens were most severely affected. In neonatal brains, the 
cerebellum was not affected; the strongest neuroapoptotic response was noted in the basal ganglia 
and several thalamic areas.


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In juvenile rodents, ketamine induced apoptotic neurodegeneration was observed that was more 
widespread than in adult rodents, with the developing brain affected in several major regions. 
Neuronal cell death was induced in the dorsolateral thalamus at blood levels of ketamine of 
14 µg/mL (7 times the human anesthetic blood level of approximately 2 µg/mL).
No significant neurotoxic effects occurred in juvenile Rhesus monkeys if the anesthesia was 
administered by IM induction followed by IV maintenance for a duration of 3 hours. Ketamine 
infusion for 9 or 24 hours increased neuronal cell death in the frontal cortex, but no significant 
changes were noted in the hippocampus, thalamus, striatum, or amygdala. Cognitive impairments 
were observed beginning around 10 months of age, and persisted at 3.5 years of age.
The clinical studies will exclude neonates, infants, children, pregnant women, and breastfeeding 
women. Therefore, ketamine’s neurotoxicity in juvenile animals does not represent a safety risk to 
eligible adult subjects. Moreover, the large dosages and prolonged treatment durations associated 
with neurotoxicity in juvenile animals do not suggest a concern.
Chronic treatment with ketamine at high dose levels affected the brain of adolescent monkeys, as 
evidenced by histopathologic lesions and functional impairment. 
The neurotoxicity of ketamine in adult animals is also associated with high dose levels, in contrast 
to the relatively low dose levels of esketamine associated with antidepressant efficacy in humans. 
In single-dose and 14-day repeated-neurotoxicity studies with intranasally administered 
esketamine in rats, no histopathologic brain lesions were noted even upon high exposures, as 
achieved at 54 mg/day in the 14-day study. In the 6-month rat and 9-month dog repeat-dose 
toxicology studies with intranasally administered esketamine, where the animals were of 
adolescent age at initiation of treatment, and in the pre- and post-natal developmental toxicity 
study in rats, no evidence of neurotoxicity was found. Consequently, the risk of neurotoxicity 
associated with intranasal administration of esketamine to adult and adolescent patients is 
considered low.34
Abuse Potential
Animal studies with ketamine suggest that it would have abuse potential in humans. These studies 
included self-administration and withdrawal experiments in several species.34
Reproductive Toxicity
In a rat fertility and early embryonic developmental toxicity study with intranasally administered 
esketamine, no adverse effects on fertility or reproductive capacity or performance were found.
Rat and rabbit embryo-fetal developmental toxicity studies with intranasally administered racemic 
ketamine did not reveal evidence of reproductive toxicity. However, when monkey fetuses were 
exposed in utero to high dose levels of racemic ketamine, neurotoxicity was observed. 
Intranasally administered esketamine did not affect pre- and postnatal development in rats. 
However, high dose levels of racemic ketamine induced neurotoxicity in early postnatal rat pups.34


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Considering the neurotoxic potential of ketamine and esketamine, and the fact that no threshold 
for these effects has been demonstrated, female subjects of childbearing potential should be 
adequately protected from becoming pregnant and pregnant women should not be enrolled.
Cardiovascular toxicity
In guinea pig tissues, ketamine-induced negative inotropic effects and shortening of action 
potential duration at the 0-mV level was observed, likely as a result of the suppression of inward 
calcium current, whereas in rat left atria ketamine-induced positive inotropic effects and 
prolongation of action potential duration at the 0-mV level was observed, likely as a result of a 
decrease in calcium-insensitive transient outward current.20 The inhibitory action on membrane 
currents may partly explain the species and tissue differences in inotropic responses to ketamine.
Blood pressure responses to ketamine also vary with the laboratory species and with experimental 
conditions. Blood pressure is increased in normotensive and renal hypertensive rats with and 
without adrenalectomy and under pentobarbital anesthesia. The US prescribing information for the 
anesthetic Ketalar® (ketamine hydrochloride [HCl] for injection) provides the following guidance. 
Intravenous Ketalar® produces a fall in arterial blood pressure in the Rhesus monkey and a rise in 
arterial blood pressure in the dog. In this respect the dog mimics the cardiovascular effect observed 
in man. The pressor response to Ketalar® injected into intact, unanesthetized dogs is accompanied 
by a tachycardia, rise in cardiac output and a fall in total peripheral resistance. It causes a fall in 
perfusion pressure following a large dose. The tachycardia and increase in myocardial contractile 
force seen in intact animals does not appear in isolated hearts. These observations support the 
hypothesis that the hypertension produced by Ketalar® is due to selective activation of central 
cardiac stimulating mechanisms leading to an increase in cardiac output. 
The dog would be considered the most predictive species in terms of ketamine’s cardiovascular 
effects in humans, but the antidepressant effects of ketamine were studied only in rodent models. 
The myocardial contractility effects and blood pressure responses to ketamine vary between 
species.34 Consequently, a margin of safety could not be reliably derived from the available animal 
data.
Overall Conclusion
The currently available nonclinical safety studies support chronic intranasal administration of 
esketamine in human subjects up to a dosage of 84 mg/day.
Further details can be found in the Investigator's Brochure.34
1.1.2.
Clinical Studies
The clinical program for esketamine includes: a comprehensive clinical pharmacology program in 
healthy volunteers and special populations to fully characterize the product’s pharmacokinetic 
(PK) and pharmacodynamic (PD) activity, including Phase 2 studies with IV esketamine and 
ketamine; a Phase 2 dose response study in adults with TRD; a Phase 2 proof-of-concept study in 
the related condition of MDD with imminent risk for suicide; and data from 5 completed Phase 3 


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studies establishing efficacy and safety in adults with TRD, including those 65 years and older. 
Results from 1 ongoing Phase 2 study and 2 ongoing Phase 3 studies in adults with TRD are not 
available at the time of finalization.
1.1.2.1.
Pharmacokinetics
The following Human Pharmacokinetic (PK) and initial tolerability Phase 1 studies were 
conducted by the sponsor in healthy adult subjects. Further details are available in the Investigator 
Brochure34: 

Intravenous and oral dose of radiolabeled esketamine: 54135419TRD1016.

Intravenous, intranasal and oral esketamine: ESKETINTRD1009 

Intranasal esketamine:

Healthy adult non-Asian and Asian subjects: ESKETINTRD1001, ESKETINTRD1002, 
ESKETINTRD1004, ESKETINTRD1005, ESKETINTRD1006, ESKETINTRD1009, 
ESKETINTRD1010, ESKETINTRD1013, 54135419TRD1020 (Japanese subjects only).

Healthy elderly and younger adult non-Asian and Asian subjects: ESKETINTRD1003, 
ESKETINTRD1012, and 54135419TRD1018 (Japanese subjects only). 

Subjects with a history of allergic rhinitis: ESKETINTRD1007.

Recreational users of perception-altering drugs: 54135419TRD1015

Subjects with hepatic impairment: ESKETINTRD1011

Subjects with renal impairment: 54135419TRD1014

Subjects with MDD; On-Road Driving effects: 54135419TRD1019. 
Human Pharmacokinetics Metabolism
Ketamine (and esketamine) undergoes extensive metabolism by hepatic cytochrome P450 (CYP). 
In humans, N-demethylation to norketamine is the major route of metabolism, which can undergo 
further metabolism to form hydroxynorketamine. Ketamine and norketamine are extensively 
hydroxylated to a series of 6 hydroxynorketamine metabolites and 2 hydroxyketamine 
metabolites.75 Like ketamine, norketamine is a noncompetitive antagonist at the NMDA receptor.19
Norketamine has a half-life in plasma of approximately 5 hours.38 The major human hepatic CYPs 
that catalyze ketamine and esketamine N-demethylation in vitro are CYP2B6 and CYP3A4.29,31,78
The CYP enzymes responsible for the formation of norketamine metabolites include CYP2A6 and 
CYP2B6.53 Published results of a clinical pharmacokinetics (PK) study indicate that esketamine 
does not invert to the R-enantiomer.26
Excretion
Racemic ketamine and its metabolites have been previously shown to be predominantly excreted 
in the urine. An average of 91% and 3% of a tritium-labeled dose (1 mg/kg) administered to 
6 healthy subjects was recovered in urine and feces, respectively.4 Less than 3% of an administered 
dose was excreted in urine as parent drug.75


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Following oral administration of radiolabeled esketamine, approximately 86% and 2% of 
administered radioactivity was recovered in urine and feces, respectively. The recovered 
radioactivity consisted primarily of esketamine metabolites. For the IV and oral routes of 
administration, <1% of the dose was excreted in the urine as unchanged drug. 
A summary of the PK of esketamine administered by the IV and intranasal routes is provided 
below.
Intravenous Esketamine
Subjects with TRD received 0.2 mg/kg or 0.4 mg/kg esketamine as a 40-minute IV infusion during 
Study ESKETIVTRD2001.9 Maximum concentrations of esketamine were observed at the end of 
the infusion. Mean values for maximum plasma concentration (Cmax) and area under the 
concentration-time curve (AUC) increased with an increase in the esketamine dose administered 
(80.9 and 135 ng/mL, respectively, and 150 and 218 ng*h/mL, respectively, for 0.2 mg/kg and 
0.4 mg/kg esketamine). The mean plasma clearance of esketamine was high (109 L/h and 141 L/h 
for the 0.2 mg/kg and 0.4 mg/kg doses, respectively), as it was similar to or exceeded hepatic blood 
flow in humans.8 The large volume of distribution suggests that esketamine distributes widely into 
tissues (236 L and 303 L, respectively). The half-life of esketamine in plasma was 2.14 and 
2.65 hours, respectively, for the 2 doses. 
Intranasal Esketamine
Plasma esketamine PK results from Studies ESKETINTRD1001, ESKETINTRD1002, 
ESKETINTRD1003, and the double-blind phase of Panel A of the ESKETINTRD2003 that inform 
dose selection for the Phase 3 program are described below.5,6,7,10 The results demonstrate that 
plasma esketamine concentrations produced by effective IV regimens (0.2 mg/kg and 0.4 mg/kg 
as 40 minute infusions) may be achieved by the intranasal route. 
Study ESKETINTRD1001 included 3 cohorts of subjects who were healthy male and female 
subjects.5 The intranasal esketamine treatments were self-administered under the direct 
supervision of the investigator or designee. Subjects in Cohorts 1 and 3 received esketamine doses 
that ranged from 28 to 112 mg. The regimens were self-administered in the upright position. No 
instructions were given with regards to sniffing after administration. The reported median time for
Cmax values of esketamine ranged from 0.37 to 0.83 hours from the time the first spray was 
administered (ie, 0.33 to 0.5 hours after the last spray was administered). The doses of 28 to 112 mg 
produced mean Cmax values ranging from 63.3 to 151 ng/mL, whereas mean area under the plasma 
concentration-time curve from time 0 to infinite time (AUC∞) values ranged from 164 to 
565 ng*h/mL. Mean Cmax and AUC values of esketamine increased in a less than dose-proportional 
manner across the dose regimens. Furthermore, there was substantial overlap in the range of 
individual Cmax and AUC values among the 3 doses. The mean terminal half-life of esketamine 
ranged from 5.86 to 9.83 hours across all treatments. Subjects in Cohort 2 received 84 mg in a 
semi-reclined position and were instructed to sniff after each spray. Higher mean Cmax and AUC∞
values were observed in this cohort (174 ng/mL and 437 ng*h/mL, respectively) compared with 
the same esketamine dose self-administered by subjects in Cohort 1 (107 ng/mL and 400 ng*h/mL, 
respectively). The semi-reclined position of the head and the instruction to subjects to sniff gently 


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following intranasal dosing are believed to be the cause for the increase in exposure observed in 
Cohort 2 compared with Cohort 1. As a result, the instructions for self-administration of intranasal 
esketamine were adapted to include the semi-reclined position of the head and sniffing following 
dosing for all future studies.
During the Phase 1 study ESKETINTRD1002, healthy Japanese and Caucasian subjects received 
single intranasal doses of esketamine 28 mg, 56 mg, and 84 mg in a crossover manner.6 On 
average, plasma esketamine Cmax and AUC values were up to 48% higher in Japanese subjects 
compared with Caucasian subjects. In study ESKETINTRD1008, healthy Japanese, Chinese, 
Korean, and Caucasian subjects received a single intranasal dose of 56 mg esketamine. The mean 
esketamine Cmax and AUC values were approximately 40% higher in Japanese subjects compared 
to Caucasian subjects. In general, smaller differences in esketamine and noresketamine exposure 
were observed when comparing other Asian subjects (Hans Chinese and Korean) to Caucasian 
subjects. Mean esketamine Cmax and AUC∞values were 14% and 33% higher, respectively, in Han 
Chinese subjects compared to Caucasian subjects. The incidence and type of treatment-emergent 
adverse events most frequently reported, as defined by system-organ-class, were comparable for 
subjects in all 4 population cohorts. Study ESKETINTRD1003 compared the PK, safety, and 
tolerability of intranasally administered esketamine in healthy elderly (65 years of age) and 
younger adult subjects (18 to 55 years of age, inclusive).7 Subjects received a single intranasal 
treatment of esketamine 28 mg. The Tmax of esketamine was approximately 30 minutes for both 
age groups. The geometric means of Cmax and AUC∞, for esketamine were approximately 21% and 
17% higher, respectively, in the elderly compared with younger adult subjects.
Study ESKETINTRD2003, is a recently completed 2-panel, doubly randomized, double-blind, 
placebo-controlled, multicenter study.55 Panel A was conducted in the United States and Belgium 
and Panel B in Japan. Panel A assessed the efficacy and safety of 3 dose strengths of intranasal 
esketamine (28, 56, and 84 mg) administered twice a week in subjects with TRD. Panel B was 
designed to assess the efficacy and safety of 14 mg and 56 mg dose strengths. Results of a 
preliminary analysis of data from the double-blind phase of Panel A indicate mean (standard 
deviation) esketamine concentrations at 40 minutes postdose were 36.4 ng/mL (16.4), 58.1 ng/mL 
(24.5), and 72.5 ng/mL (34.2), respectively, for the 3 doses (data on file). The mean esketamine 
concentrations in plasma samples collected on Days 1 and 11 were similar, suggesting that the PK 
are consistent after repeated administration.10
1.1.2.2.
Efficacy and Safety Studies
The following Efficacy and Safety Phase 2a and Phase 3 studies were conducted by the sponsor in 
subjects with TRD or MDD who are at imminent risk for suicidal ideation. 

Phase 2a: Intravenous ketamine or esketamine administered to subjects with TRD: 
KETIVTRD2002, KETIVTRD2004 and ESKETIVTRD2001, respectively.

Phase 2a: Intranasal esketamine administered to subjects with TRD: ESKETINTRD2003; 
Intranasal esketamine administered to subjects with MDD who are at imminent risk for 
suicidal ideation: ESKETINSUI2001.


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
Phase 3: Intranasal esketamine administered to subjects with TRD: 

Short-term studies: ESKETINTRD3001, ESKETINTRD3002, and ESKETINTRD3005

Long-term studies: ESKETINTRD3003 and ESKETINTRD3004
For the most comprehensive information regarding these clinical studies, refer to the latest version 
of the Investigator Brochure.34
Pharmacodynamics and Efficacy
The efficacy of subanesthetic doses (0.5 mg/kg IV administered over 40 minutes) of IV ketamine 
has been evaluated in approximately 192 subjects with MDD (cases and controls), and 2 studies 
in bipolar depressed subjects (meta-analyses).25 This recent meta-analysis of studies suggests that 
IV administered ketamine has a rapid onset (within 1 day) of antidepressant efficacy, including in 
those who have not benefitted from other antidepressant treatments, used as monotherapy or in 
combination with oral antidepressant treatments.
Esketamine (0.2 and 0.4 mg/kg administered over 40 minutes) has similar, rapid, and robust
antidepressant effects as that seen with IV ketamine. A double-blind, double-randomization, 
placebo-controlled study (ESKETIVTRD2001) enrolled 30 adult subjects with TRD: 10 in the IV 
placebo group, 9 in the IV esketamine 0.20 mg/kg group, and 11 in the IV esketamine 0.40-mg/kg 
group (based on Day 1 randomization).9 The intent-to-treat (ITT) analysis of the primary efficacy 
variable (change in Montgomery-Asberg Depression Rating Scale [MADRS] total score from 
baseline [Day 1] to Day 2) indicated that the improvement in both IV esketamine dose groups were
statistically significant (1-sided p-value=0.001 in both dose groups) compared with the placebo 
group. The mean (standard deviation) change from baseline [Day 1] to Day 2 in MADRS total 
score was -4.9 (4.72) in the placebo group, -16.8 (10.12) in the IV esketamine 0.20 mg/kg group, 
and -17.8 (9.45) in the IV esketamine 0.40 mg/kg group. 
The studies listed above assessed the efficacy of IV ketamine or IV esketamine after a single dose 
as the primary endpoint. The average duration of response to a single dose of ketamine (0.5 mg/kg) 
was approximately 5 days. An open-label study demonstrated that the response to the first dose 
could be maintained by multiple infusions 3 times a week over 2 weeks. The duration of response 
lasted for approximately 19 days.1
The KETIVTRD2002 study assessed whether multiple doses of IV ketamine given twice a week 
would also maintain the antidepressant response; the data from this study suggest that IV ketamine 
(0.50 mg/kg over 40 minutes) administered twice a week was sufficient for maintaining the initial 
effect over a 4 week treatment period.11
As noted above, Study ESKETINTRD2003 is a 2-panel, doubly randomized, double-blind,
placebo-controlled, multicenter study.10 Panel A was conducted in the United States and Belgium 
and Panel B in Japan. Panel A assessed the efficacy and safety of 3 dose strengths of intranasal
esketamine (28, 56, and 84 mg) administered twice a week in subjects with TRD. Panel B was 
designed to assess the efficacy and safety of 14 mg and 56 mg dose strengths. In Panel A, subjects 
in period 1 (1-week duration) were randomly assigned in a 3:1:1:1 ratio to placebo (33 subjects), 


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esketamine 28 mg (11 subjects), esketamine 56 mg (11 subjects), or esketamine 84 mg 
(12 subjects). Data from the double-blind phase of Panel A indicates that of the 67 subjects 
randomized in Period 1, 63 entered Period 2 (1-week duration), in which 28 placebo subjects who 
were eligible for re-randomization at the end of Period 1, were randomly assigned in a 1:1:1:1 ratio 
to placebo (N=6), esketamine 28 mg (N=8), esketamine 56 mg (N=9), or esketamine 84 mg (N=5). 
Subjects eligible for re-randomization had to have a Quick Inventory of Depressive 
Symptomatology – Self Report (QIDS-SR16) total score >11 at the end of Period 1. 
The improvement (with respect to change in MADRS total score from baseline Day 1 to Day 8) in 
all 3 intranasal esketamine dose groups reached statistical significance (p=0.021, p=0.001, and
p<0.001 for esketamine 28 mg, 56 mg, and 84 mg, respectively) compared with placebo. The 
results of the 2 periods were consistent. The mean differences from placebo on Day 8 (after 1 week 
of treatment), estimated using data from the combined periods, were: 

Esketamine 28 mg:
-4.2 (SE 2.09) 

Esketamine 56 mg: 
-6.3 (SE 2.07) 

Esketamine 84 mg:
-9.0 (SE 2.13)
The effect sizes in Period 1 for esketamine compared with placebo were:

Esketamine 28 mg:
0.43 (CI -0.259-1.118)

Esketamine 56 mg:
0.92 (CI 0.201-1.621)

Esketamine 84 mg:
1.19 (CI 0.473-1.883)
The duration of effect with the 28-mg dose appears to be shorter, with the MADRS total score 
higher on Day 8 than on Day 2. The duration of effect for the 56- and 84-mg doses appears to 
support twice-a-week dosing.
In Panel B, a significant improvement in symptoms of depression as measured by the MADRS 
total score was detected in the esketamine 56 mg treatment group compared with the placebo group 
(-3.7 [SE 2.81]; p=0.096) during Period 1. Smaller improvements in MADRS total score were 
detected in the esketamine 14 mg group compared with the placebo group (+1.8 [SE 2.62]) during 
Period 1.
These data with intranasal esketamine support the hypotheses that intranasal esketamine is
effective as a treatment for depression, that it has rapid onset of effect within 2 hours, and that 
multiple repeated sessions dose-dependently show sustained response throughout the study 
duration. A clear dose response was seen in the double-blind data in Panel A, and the point 
estimates and confidence intervals suggest a high effect size (Cohen’s D) with the 56 mg and 
84 mg dose groups, supporting further development.


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Safety and Tolerability
Ketamine is a rapidly acting general anesthetic that is approved and widely used intravenously or 
intramuscularly for the induction and maintenance of anesthesia in children and adults at a dose of 
1 to 3 mg/kg given as a bolus. Ketamine is marketed as a racemic mixture and in Europe also as 
the S-enantiomer, esketamine. Ketamine was first introduced as an anesthetic in 1963 and is 
considered to have an excellent medical safety profile (Ketalar® Summary of Product 
Characteristics [SmPC] 2011; Ketanest®S SmPC 2011).28,36
Within the US prescribing information for ketamine HCl for injection and the SmPC for 
esketamine HCl for injection, the following adverse reactions were listed as very common, 
common, or frequent occurrences: Emergence or recovery reactions, elevated blood pressure and 
pulse rate, stimulation of respiration, nausea, and vomiting. See the table below for details.
Adverse reactions Listed as very Common, Common, or Frequent Occurrences in the Product Information 
of Anesthetic Ketamine and Esketamine
System Organ 
Class
"Frequent" Adverse Reactions
Per Anesthetic Ketamine USPI, 37a
"Very Common" or "Common" Reactions
Per Anesthetic Esketamine SmPC, 73b
Psychiatric 
disorders
Frequency: Emergence reactions occurred in 
approximately 12% of patients.
Characteristics: Severity varied from pleasant 
dreamlike states, vivid imagery, hallucinations, 
and emergence delirium. Some states were 
accompanied by confusion, excitement, and 
irrational behavior, which some patients recalled 
as an unpleasant experience.
Frequency: Recovery reactions were common. 
When esketamine was the sole anesthetic, up to 
30% of patients displayed dose-dependent recovery 
reactions.
Characteristics: Reactions included vivid dreams 
(including nightmares), nausea and vomiting, 
increased salivation, blurred vision, dizziness, and 
motor restlessness c
Cardiac 
disorders
Blood pressure and pulse rate were frequently 
elevated after administration. However, 
hypotension and bradycardia have been 
observed. Arrhythmia has also occurred.
Common occurrences were temporary tachycardia 
and increase in blood pressure and heart rate 
(approximately 20% of the initial value was 
typical).
Respiratory, 
thoracic, and 
mediastinal 
disorders
Although stimulation of respiration was a 
frequently observed effect, severe depression of 
respiration or apnea also could occur after rapid 
intravenous administration of high doses.
Common effects were increase in vascular 
resistance in pulmonary circulation and increase in 
mucus secretion. Increased oxygen consumption, 
laryngospasms, and temporary respiratory 
depression were common; the risk of respiratory 
depression was noted to depend on dose and 
injection speed.
Gastro-
intestinal 
disorders
No gastrointestinal effects were listed as 
frequent, but the USPI stated that anorexia, 
nausea, and vomiting have been observed.
Common effects included nausea and vomiting.
Abbreviations: SmPC, Summary of Product Characteristics; USPI, United States Prescribing Information
a.
"Frequent" was not defined numerically, except in the case of emergence reactions (12%). The terms "very common" 
and "common" did not appear in the adverse effects section of the USPI.
b. "Very common" was defined in the SmPC as 1/10 and "common" was defined as 1/100 to <1/10.
c.
The incidence of these events can be greatly reduced by the administration of a benzodiazepine.
Source: Investigator's Brochure for esketamine (JNJ-54135419).34


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Adverse Events Associated with Short-term Use of Intranasal Esketamine in Patients with 
MDD
Esketamine has not yet been approved by the FDA for intranasal delivery. Within the SmPC for 
intravenous esketamine,38 the following are reported as common adverse effects: transient 
tachycardia, vivid dreams (including nightmares), nausea and vomiting, increased blood pressure, 
increased salivation, blurred vision, dizziness, motor unrest, increase in vascular resistance in 
pulmonary circulation and increase in mucus secretion, increased oxygen consumption, 
laryngospasms, and temporary respiratory depression. It is reported that the risk of respiratory 
depression typically depends on the dosage and injection speed.36
Administration of intranasal esketamine is associated with adverse events, all of which are 
transient in nature and typically resolve within 2 hours or less from the start of drug administration.
In Panel A of the Phase 2 study with intranasal esketamine (ESKETINTRD2003), the most 
common TEAEs (>10% of subjects in the pooled esketamine treatment groups) during the 
double-blind phase were: Dizziness, headache, dissociation, dysgeusia (metallic taste), nausea, 
dissociative disorder, and oral hypoesthesia.10 Dissociative symptoms were the most typical of 
these adverse events observed post dose and were characterized by feeling unreal or detached from 
reality or by perceptual changes. Transient perceptual changes (dissociation), dizziness, and 
nausea were typically seen immediately after drug administration, resolving by 2 hours.
No deaths were reported in the double-blind or open-label phases of ESKETINTRD2003. There 
was one death (placebo/esketamine 14 mg/OL esketamine treatment group) due to completed 
suicide in Panel B on Study Day 45 during the follow-up phase of the study, 20 days after the 
subject received the last dose of study medication. The investigator considered the event to be ‘not 
related’ to study medication. A total of 3 subjects experienced at least one serious adverse event 
(SAE) during the study. In Panel A, one subject (placebo/placebo treatment group) experienced a 
SAE
of esophagitis
on Study Day 15 during the double-blind phase that was 
considered by the investigator to be ‘not related’ to study medication; one subject 
(esketamine 56 mg/esketamine 56 mg/OL esketamine treatment group), experienced a SAE of 
ectopic pregnancy on Study Day 40 during the open-label phase, which led to withdrawal of study 
medication. The subject subsequently experienced another SAE of general physical health 
deterioration on study Day 44 of the follow-up phase after cessation of study medication. The 
investigator considered that both events were ‘not related’ to study medication. In Panel B, one 
subject experienced a SAE of confusional state during the follow-up phase, 10 days after receiving 
the last dose of study medication. The sponsor considered the event ‘not related’ to study 
medication based on the short half-life of esketamine and the time of onset of the TEAE. A total 
of 4 subjects in Panel A experienced TEAEs which led to withdrawal of study medication. Three 
subjects withdrew during the double-blind phase because of TEAEs. One subject in the esketamine 
28 mg group experienced a TEAE of syncope of severe intensity on Study Day 2 (Period 1), 1 day 
after receiving the first dose of study medication. The investigator considered the event to be 
‘possibly related’ to study medication; the sponsor considered the event ‘not related’ to study 
medication based on the short half-life of esketamine and the onset of the TEAE of syncope. One 
subject in the placebo/esketamine 56 mg group experienced a TEAE of headache of moderate 
intensity on Day 11 (Period 2). The investigator considered the event to be ‘very likely’ related to 


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the study agent. One subject in the esketamine group (84 mg/esketamine 84 mg) experienced a 
TEAE of dissociative disorder of moderate intensity on Study Day 8 (Period 2). The investigator 
considered the event to be very likely related to the study agent. One subject experience an SAE 
of ectopic pregnancy (considered by the investigator as ‘not related’ to study medication; see 
above).63
Dissociative symptoms measured on the Clinician Administered Dissociative States Scale 
(CADSS)3 were dose-dependent, with significant reductions in severity observed on multiple 
dosing, over the 2 weeks. No psychotic symptoms were seen. Transient increases in mean blood 
pressure (systolic and diastolic) were observed post dose following the intranasal esketamine 
administration.
The mean (standard deviation; SD) peak systolic blood pressure after the first administration in 
each dose group was:

Placebo: 124.2 (11.51) mmHg; an increase of 5.4 (7.84) mmHg

Esketamine 28 mg: 131.8 (15.49) mmHg; an increase of 10.4 (10.44) mmHg

Esketamine 56 mg: 130.4 (18.64) mmHg; an increase of 11.2 (15.01) mmHg

Esketamine 84 mg: 146.1 (19.9) mmHg; an increase of 17.1 (15.5) mmHg
Mean (SD) peak diastolic blood pressure after the first administration in each dose group was: 

Placebo: 81.2 (8.36) mmHg; an increase of 3.8 (7.99) mmHg

Esketamine 28 mg: 85.7 (9.16) mmHg; an increase of 6.5 (7.00) mmHg

Esketamine 56 mg: 86.5 (11.34) mmHg; an increase of 7.2 (9.67) mmHg

Esketamine 84 mg: 87.8 (10.62) mmHg; an increase of 8.1 (9.12) mmHg
The blood pressure increase typically resolved within 2 hours. Unlike dissociative symptoms, the 
blood pressure changes observed do not appear to attenuate over time with multiple doses. 
Transient increases in heart rate were also observed in parallel with blood pressure change. There 
was no clinically meaningful change in blood oxygen level.
Adverse Events Associated with Chronic Use of Ketamine
There are no controlled studies of long-term use with esketamine/ketamine in patients with MDD. 
Much of the literature on chronic use of ketamine comes from data gathered from street/illegal use 
of the drug, rather than systematically conducted clinical studies. Data therefore should be 
interpreted with caution, as in many cases, no baseline pre-drug data are available and drug 
exposure is poorly documented. 
In a 1-year longitudinal study, 150 subjects were divided into 5 groups of 30 subjects each: 
Frequent ketamine users (more than 4 times per week), infrequent ketamine users (at least once a 
month), abstinent users (abstinent for at least 1 month), polydrug controls, and non-users of illicit 
drugs.48 Eighty percent of the participants were retested at the end of 1 year. Cognitive deficits 
(including impairment in spatial working memory, pattern recognition memory and category 


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fluency) were mainly observed in frequent users and not with the infrequent users. Short-lasting, 
dose-dependent effects of psychosis were associated with ketamine users. There was no increase 
in symptoms over time, and symptoms were completely reversible upon stopping use of ketamine. 
As noted, these data should be interpreted with caution, as baseline data predating drug use were 
not available. Furthermore, in their recent review, Morgan and Curran report that there is little 
evidence of any link between chronic, heavy use of ketamine and diagnosis of a psychotic 
disorder.47
The principal action of ketamine is at the NMDA receptor, and the consequences of ketamine use 
on cognition have been widely investigated. Several studies have examined cognitive function in 
infrequent and frequent ketamine users.13,46,48,50 Overall, infrequent or recreational ketamine use does 
not appear to be associated with long-term cognitive impairment.48 The most robust findings are that 
frequent ketamine users (more than 5 times a week) exhibit impairments in both short- and long-
term memory.46 Although dosages have varied, dosages reported by ketamine users in this study 
were much higher than the dosages of ketamine or equivalent doses of esketamine intended for use 
in treating TRD. Memory impairments may be reversible when individuals stop using the drug, as 
they were not found in a group of 30 ex-ketamine users who had been abstinent for at least a year.46,47
Ketamine-induced ulcerative cystitis is a recently identified complication.47 The most common 
symptoms are frequency and urgency of urination, dysuria, urge incontinence, and occasionally 
painful hematuria (blood in urine). Computerized tomography scans revealed a marked thickening 
of the bladder wall, a small bladder capacity, and perivesicular stranding consistent with severe 
inflammation. At cystoscopy, all patients had severe ulcerative cystitis. Biopsies in 4 of these cases 
found denuded urothelial mucosa with thin layers of reactive and regenerating epithelial cells, and 
ulcerations with vascular granulation tissue and scattered inflammatory cells. Cessation of 
ketamine use provided some relief of symptoms. Most of the described cases are in near-daily 
users of ketamine for recreational purposes. The prevalence is difficult to determine, as it is seen 
in recreational users who often do not seek help. The majority of cases resolve after stopping 
ketamine use, one-third remaining static.
Abuse Liability, Dependence, and Withdrawal
There are a number of reports of ketamine dependence in the literature33,35,45,52 but no large-scale 
studies, and so the incidence of ketamine dependence is largely unknown.47 An interview study of 
90 ketamine users found that 57% of frequent users, 43% of infrequent users, and 60% of ex-users 
expressed concerns about ketamine addiction.49 The majority of frequent users in that study 
reported using the drug without stopping until supplies ran out, so compulsive patterns of behavior 
are also a concern. Oral ketamine has also been evaluated as a positive control in human abuse 
potential studies, with dosages of 65 mg and 110 mg reported as appropriate for use as positive 
controls for future abuse potential studies of compounds with a similar mechanism of action or 
with possible perception-altering effects.68 There is conflicting evidence of the existence of a 
"withdrawal syndrome" after cessation of ketamine use.47 Cravings seem to be a key problem in 
frequent users: 28 of the 30 daily users in 1 study reported having tried to stop taking the drug but 
failed; all reported ketamine cravings as the reason for failure.47 The same study found that 12 of 
the 30 daily users reported withdrawal symptoms characterized by anxiety, shaking, sweating, and 


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palpitations when they stopped using. A few published case studies also show craving and somatic 
and psychological aspects of anxiety as withdrawal symptoms.12,42 However, a specific ketamine 
withdrawal syndrome has not yet been described.47
Please refer to the Investigator's Brochure for a summary of the adverse events reported in 
ketamine and esketamine studies.34
1.2.
Active Comparator
This study will evaluate the efficacy of switching adult subjects with TRD from a prior 
antidepressant treatment (to which they have not responded) to a flexible dose regimen of 
intranasal esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant, compared with 
switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo. 
In the double-blind treatment phase, subjects will be assigned to receive 1 of 4 commercially 
available oral antidepressant medications from 2 different classes of antidepressant medications, 
selective serotonin reuptake inhibitors (SSRIs: Escitalopram or Sertraline), or serotonin and 
norepinephrine reuptake inhibitors (SNRIs: Duloxetine or Venlafaxine extended release [XR]), 
that the subject has not previously had a non-response to, in the current major depressive episode, 
and has not been previously intolerant to (lifetime). 
The indications and safety information provided below for each oral antidepressant are from the 
US prescribing information.17,21,65,71 For further information, please refer to the appropriate 
package insert applicable to the local country in which the study is being conducted.
In the US, all oral antidepressants include a black box warning in the prescribing information 
regarding suicidality and antidepressant drugs. In China, a similar warning is included in the label.
The black box warning informs the prescriber that antidepressant treatment(s) increase the risk 
compared with placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and 
young adults in short-term studies of MDD and other psychiatric disorders. It states that anyone 
considering using the antidepressant in this population must balance the risk with the clinical need. 
Refer to the US and Chinese prescribing information for the entire content of the black box
warning.17,21,65,71
1.2.1.
Selective Serotonin Reuptake Inhibitors
1.2.1.1.
Escitalopram
Escitalopram is indicated in adults for acute and maintenance treatment of MDD and acute 
treatment of generalized anxiety disorder.21
The starting dosage for MDD in the US prescribing information is 10 mg once daily, and in China, 
the commonly used dosage is 10 mg once daily, with a maximum of 20 mg once daily for both 
countries. If the dosage is increased to 20 mg, this should occur after a minimum of 1 week. No 
additional benefits have been seen at 20 mg/day dose.


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In adult MDD subjects treated with escitalopram, the most commonly observed adverse reactions 
with escitalopram (incidence of approximately 5% or greater and approximately twice the 
incidence in placebo subjects) were insomnia, ejaculation disorder (primarily ejaculatory delay), 
nausea, sweating increased, fatigue, and somnolence.
Contraindications to the use of escitalopram include serotonin syndrome and monoamine oxidase 
inhibitor (MAOI) use (concomitant use with MAOIs intended to treat psychiatric disorders, 
linezolid, or IV methylene blue; use within 14 days of stopping treatment with an MAOI intended 
to treat psychiatric disorders [in addition, an MAOI should not be used within 14 days of stopping 
escitalopram]); concomitant use with pimozide; and known hypersensitivity to escitalopram or 
citalopram or any of the inactive ingredients.
As with most SSRIs, a gradual reduction in the dosage rather than abrupt cessation of escitalopram 
treatment is recommended whenever possible.
1.2.1.2.
Sertraline
Sertraline hydrochloride is indicated in adults for the treatment of MDD, obsessions and 
compulsions in patients with obsessive compulsive disorder, panic disorder (with or without 
agoraphobia), post-traumatic stress disorder, premenstrual dysphoric disorder, and social anxiety 
disorder.65
According to both the US and China prescribing information, sertraline should be administered at 
a dose of 50 mg once daily for the treatment of MDD. While a relationship between dose and effect 
has not been established for MDD, obsessive compulsive disorder, panic disorder, post-traumatic 
stress disorder, or social anxiety disorder, patients were dosed in a range of 50-200 mg/day in the 
clinical trials demonstrating the effectiveness of sertraline for the treatment of these indications. 
Consequently, a dose of 50 mg, administered once daily, is recommended as the initial therapeutic 
dose. Patients not responding to a 50 mg dose may benefit from dose increases up to a maximum 
of 200 mg/day. Given the 24-hour elimination half-life of sertraline, dose changes should not occur 
at intervals of less than 1 week. The maximum dose of sertraline in the current study is 200 mg/day.
Contraindications to the use of sertraline include serotonin syndrome and MAOI use (concomitant 
use with MAOIs intended to treat psychiatric disorders, linezolid, or IV methylene blue; use within 
14 days of stopping treatment with an MAOI intended to treat psychiatric disorders); concomitant 
use with pimozide; and known hypersensitivity to sertraline or any of the inactive ingredients. 
In adult subjects, the most common TEAEs associated with the use of sertraline (incidence of at 
least 5% for sertraline or at least twice that for placebo within at least one of the indications) were 
ejaculation failure, dry mouth, increased sweating, somnolence, tremor, dizziness, fatigue, pain, 
malaise, abdominal pain, anorexia, constipation, diarrhea/loose stools, dyspepsia, nausea, 
agitation, insomnia, and decreased libido.
As with most SSRIs, a gradual reduction in the dosage rather than abrupt cessation treatment is 
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1.2.2.
Serotonin and Norepinephrine Reuptake Inhibitors
1.2.2.1.
Duloxetine
Duloxetine is indicated in adults for MDD, generalized anxiety disorder, diabetic peripheral 
neuropathic pain, fibromyalgia, and chronic musculoskeletal pain.17
The starting dosage for MDD in both the US and China prescribing information is 40 to 60 mg/day. 
The dosage for acute treatment is 40 to 60 mg/day, with maintenance treatment at 60 mg/day. For 
some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to 
adjust to the medication before increasing to 60 mg once daily.74
In the current study, subjects should be initiated with 60 mg/day. Subjects that have in the past 
shown increased sensitivity towards SSRI/SNRIs can, at the discretion of the treating physician, 
be started on a 30 mg dose and up-titrated into the therapeutic range of 60 mg by the start of 
Week-2 of the double-blind treatment phase.
The maximum dosage is 120 mg/day, although there is no evidence that dosages greater than 
60 mg/day confer any additional benefits. The maximum dose to be used in this study is 
60 mg/day.
For pooled studies for all approved indications, the most commonly observed adverse reactions in 
duloxetine-treated subjects (incidence of at least 5% and at least twice the incidence in placebo 
subjects) were nausea, dry mouth, somnolence, fatigue, constipation, decreased appetite, and 
hyperhidrosis. As observed in diabetic peripheral neuropathy studies, duloxetine treatment 
worsens glycemic control in some subjects with diabetes.
Contraindications to the use of duloxetine include use of an MAOI concomitantly or within 
2 weeks of MAOI use; and use in patients with uncontrolled narrow-angle glaucoma.
A gradual reduction in the dosage rather than abrupt cessation is recommended whenever possible.
1.2.2.2.
Venlafaxine Extended-release
Venlafaxine XR is indicated in adults for MDD and social anxiety disorder.71
The starting dosage for MDD in both the US and China prescribing information is 75 mg/day (in 
some patients, 37.5 mg/day for 4 to 7 days), with a dosage increase by 75 mg/day at intervals of 
4 days or longer, and a maximum dosage of 225 mg/day. 
Dosage reductions are recommended for hepatic impairment (including mild) and renal 
impairment.
Contraindications to the use of venlafaxine XR include serotonin syndrome and MAOI use 
(concomitant use with MAOIs intended to treat psychiatric disorders, linezolid, or IV methylene 
blue; use within 14 days of stopping treatment with an MAOI intended to treat psychiatric 
disorders); concomitant use with pimozide; and known hypersensitivity to venlafaxine XR or any 
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In adult subjects with MDD, adverse events in short-term studies that occurred in at least 5% of 
the subjects receiving venlafaxine hydrochloride XR capsules and at a rate at least twice that of 
the placebo group were abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and 
anorexia), central nervous system complaints (dizziness, somnolence, and abnormal dreams), and 
sweating.
Sustained hypertension is noted within the Warnings and Precautions section. Preexisting 
hypertension should be controlled before treatment with venlafaxine XR. It is recommended that 
patients receiving venlafaxine XR tablets have regular monitoring of blood pressure. For patients 
who experience a sustained increase in blood pressure while receiving venlafaxine XR, either 
dosage reduction or discontinuation should be considered.
Across most indications, a dose-related increase in supine systolic and diastolic blood pressure 
was evident in venlafaxine XR-treated patients. Across all clinical studies, 1.4% of subjects in the 
venlafaxine XR-treated groups experienced a ≥15-mmHg increase in supine diastolic blood
pressure, with blood pressure ≥105 mmHg, compared with 0.9% of subjects in the placebo groups. 
Similarly, 1% of subjects in the venlafaxine XR-treated groups experienced a ≥20 mmHg increase 
in supine systolic blood pressure, with blood pressure ≥180 mmHg, compared with 0.3% of 
subjects in the placebo groups. 
A gradual dosage reduction, individualized as necessary, is recommended to avoid discontinuation 
symptoms.
1.3.
Overall Rationale for the Study
The current study is being conducted to evaluate the efficacy, safety, tolerability and 
pharmacokinetics of flexible doses of intranasal esketamine (56 mg or 84 mg) plus a newly 
initiated oral antidepressant in adult subjects with TRD. The study will serve as a Phase 3 efficacy 
and safety study in support of regulatory agency requirements in China for registration of 
intranasal esketamine for the treatment of TRD.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of switching adult subjects with TRD 
from a prior antidepressant treatment (to which they have not responded) to flexibly dosed 
intranasal esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant compared with 
switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in 
improving depressive symptoms, as assessed by the change from
baseline in the 
Montgomery-Asberg Depression Rating Scale (MADRS) total score from Day 1 (pre-
randomization) to the end of the 4-week double-blind treatment phase.


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Secondary Objectives
Key Secondary Objectives
The key secondary objectives are to assess the effect of intranasal esketamine plus a newly initiated 
oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus 
intranasal placebo on the following parameters in adult subjects with TRD:

Change from baseline in the MADRS total score at 24 hours post first dose

Functioning and associated disability
Other Secondary Objectives
To assess the effect of intranasal esketamine plus a newly initiated oral antidepressant compared 
with a newly initiated oral antidepressant (active comparator) plus intranasal placebo on the 
following parameters in adult subjects with TRD:

Onset of clinical response by Day 2 

Depression response rates

Depression remission rates

Overall severity of depressive illness

Anxiety symptoms

Health-related quality of life and health status
To investigate the safety and tolerability of intranasal esketamine plus a newly initiated oral 
antidepressant compared with a newly initiated oral antidepressant (active comparator) plus 
intranasal placebo in adult subjects with TRD, including the following parameters:

Treatment-emergent adverse events (TEAEs), including AEs of special interest

Local nasal tolerability

Effects on heart rate, blood pressure, respiratory rate, and blood oxygen saturation

Dissociative symptoms

Potential effects on suicidal ideation/behavior

Potential withdrawal and/or rebound symptoms following cessation of intranasal 
esketamine treatment.
To assess the pharmacokinetics (PK) of intranasal esketamine in Chinese adult subjects with TRD 
receiving intranasal esketamine plus a newly-initiated oral antidepressant.
Exploratory Objectives
For subjects who receive esketamine during the double-blind treatment phase, the proportion of 
subjects who relapse during the follow-up phase will be evaluated separately for subjects who are 
remitters (MADRS ≤12) at the end of the 4 week double-blind treatment phase and for subjects 


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who are responders but not remitters (≥50% reduction in MADRS total score, but MADRS ˃12) 
at the end of the 4 week double-blind treatment phase.

Time to relapse during the follow-up phase will be evaluated in esketamine subjects who 
remitted 

Time to relapse during the follow-up phase will be evaluated in esketamine subjects who 
are responders but not remitters

To assess the potential relationship of biomarkers with response/non-response to 
intranasal esketamine or oral antidepressant in adult subjects with TRD.
2.1.2.
Endpoints
Primary Endpoint

The primary endpoint is the change in the MADRS total score as measured by the change 
from baseline (Day 1, prior to randomization) to the end of the 4-week double-blind treatment 
phase.
Secondary Endpoints

MADRS: The first key secondary endpoint is the change from baseline (Day 1, predose) to 
24 hours post first dose in depressive symptoms, as measured by the MADRS total score.

Sheehan Disability Scale (SDS): The second key secondary endpoint is the change in SDS 
total score as measured by the change from baseline (Day 1, prior to randomization) to the 
end of the 4-week double-blind treatment phase
Other Secondary Endpoints

Proportion of subjects showing onset of clinical response (≥50% reduction from baseline in 
MADRS total score) by Day 2 that is maintained through the end of the 4-week double-blind 
treatment phase with one excursion allowed.

Proportion of responders (≥50% reduction from baseline in MADRS total score) at the end of 
the 4-week double-blind treatment phase.

Proportion of subjects in remission (MADRS ≤12) at the end of the 4-week double-blind 
treatment phase.

Proportion of subjects who remain in remission (MADRS ≤12) through to the end of the 
follow-up phase.

Change from baseline (Day 1, prior to randomization) to the end of the 4-week double-blind 
treatment phase in:

Severity of depressive illness, using the Clinical Global Impression–Severity (CGI-S);

Anxiety symptoms, using the Generalized Anxiety Disorder (GAD-7);
                                                

Not applicable to China


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
Health-related quality of life and health status, as assessed by the EuroQol-5 dimension-5 
level (EQ-5D-5L).
Exploratory Endpoints

For subjects who receive esketamine during the double-blind treatment phase, the proportion 
of subjects who relapse during the follow-up phase will be evaluated separately for subjects 
who are remitters (MADRS ≤12) at the end of the 4-week double-blind phase and for subjects 
who are responders but not remitters (≥50% reduction in MADRS total score, but MADRS 
˃12) at the end of the 4-week double-blind treatment phase.

Time to relapse during the follow-up phase in esketamine subjects who remitted. 

Time to relapse during the follow-up phase in esketamine subjects who are responders
but not remitters.

To assess the potential relationship of biomarkers with response/non-response to intranasal 
esketamine and oral antidepressant.
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2.
Hypothesis
The hypothesis for this study is that, in adult subjects with TRD, switching from a failed 
antidepressant treatment to intranasal esketamine plus a newly initiated oral antidepressant is 
superior to switching to a newly initiated oral antidepressant treatment (active comparator) plus 
intranasal placebo in improving depressive symptoms.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind, active-controlled, multicenter study in male and female adult 
subjects with TRD to assess the efficacy, safety, tolerability, and pharmacokinetics of flexibly 
dosed intranasal esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant compared 
with a newly initiated oral antidepressant (active comparator) plus intranasal placebo. 
The study has 3 phases;

Screening/Prospective Observational Phase 

Double-blind Treatment Phase

Follow-up Phase 
                                                

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3.1.1.
Overview of Study Phases
Screening/Prospective Observational phase (4-week duration + optional 3-week taper 
period) 
This phase will prospectively assess treatment response to the subject’s current oral antidepressant 
treatment regimen. 
At the start of the screening/prospective observational phase, the subject must have had 
documented non-response to at least 1 antidepressant treatment (based on Massachusetts General 
Hospital–Antidepressant Treatment Response Questionnaire [MGH-ATRQ]) in the current 
episode of depression, and subject is taking a different oral antidepressant treatment (on the 
MGH-ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose. This 
antidepressant treatment, as well as any other ongoing medications being taken for depression at 
screening (including adjunctive/augmentation therapies), will continue from the start of Week 1 
through the end of Week 4 of the screening/prospective observational phase. Dose adjustment is 
permitted per clinical judgment, but the oral antidepressant treatment is to remain at or above the 
minimum therapeutic dose (per the MGH-ATRQ) through the end of Week 4. Antidepressant 
treatment adherence will be assessed using the PAQ. Subjects who report missing ≥4 days of 
antidepressant medication treatment(s) in the prior 2-week period will be considered as screen 
failed due to inadequate adherence.
After 4 weeks, subjects who are non-responders to their current oral antidepressant treatment (as 
assessed by independent, remote raters) may be eligible to proceed to the double-blind treatment 
phase. Non-response at the end of the screening/prospective observational phase is defined as 
≤25% improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total score 
of ≥28 on Week 2 and Week 4.
Eligible subjects who are entering the double-blind treatment phase will discontinue all of their 
current medication(s) being taken for depression (including adjunctive/augmentation therapies), 
and any other prohibited psychotropic medications (including adjunctive atypical antipsychotics). 
Subjects taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of 
lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, zaleplon, 
eszopiclone and ramelteon) during the screening/prospective observational phase, can continue 
these medications during the treatment phase No dose increases beyond the equivalent of 6 mg/day 
of lorazepam or new benzodiazepine medications are permitted during the screening/prospective 
observational phase. If clinically indicated, a subject’s current antidepressant treatment(s) may be 
tapered and discontinued over an additional, optional period of up to 3 weeks per the local 
prescribing information or clinical judgment, or discontinued and switched directly to one of the 
four new oral antidepressant medications on Day 1 of the double-blind treatment phase, per clinical 
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Double-blind Treatment Phase (4-week duration)
Approximately 234 eligible subjects (210 Chinese subjects, 24 non-Chinese subjects) with TRD, 
will be randomly assigned at a 1:1 ratio (n=117 subjects per treatment arm, with approximately 
105 Chinese subjects per arm) to receive double-blind treatment with either intranasal esketamine 
or intranasal placebo. The intranasal treatment sessions (esketamine 56 mg, 84 mg or placebo) will 
occur twice per week for 4 weeks as a flexible dose regimen at the study site. In addition, all 
subjects will initiate a new open-label oral antidepressant on Day 1, that will be taken daily for the 
duration of the double-blind treatment phase. The assigned oral antidepressant will be 1 of 4 oral 
antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine extended release 
[XR]), that the subject has not previously had a non-response to in the current depressive episode, 
has not been previously intolerant to (lifetime), and is available in the participating country.
Subjects who were taking benzodiazepines (at dosages equal to or less than the equivalent of 
6 mg/day of lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, 
zaleplon, eszopiclone and ramelteon) during the screening/prospective observational phase can 
continue these medications 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 (eg, alprazolam, clorazepate, triazolam, lorazepam and temazepam).
Intranasal Treatment Sessions: 
All subjects will self-administer the intranasal study medication (esketamine or placebo) at 
treatment sessions occurring twice a week for 4 weeks at the clinical site. Treatment is assigned 
by the Interactive Web Response System (IWRS). Table 1 in Section 6.2 describes how each 
treatment session will be administered in the double-blind treatment phase.
On Day 1, subjects randomized to intranasal esketamine will start with a dose of 56 mg. On any 
of the subsequent dosing days (Day 4, 8, 11, 15, 18, 22 and 25), the investigator can judge, based 
on efficacy and tolerability, whether to increase the dose of intranasal esketamine to 84 mg or to 
maintain the dose at 56 mg. In the event that an increase in dose is poorly tolerated, the investigator 
may decide to reduce the dose to 56 mg. 
Oral Antidepressant Treatment: 
Starting on Day 1 of the double-blind treatment phase, a new open-label oral antidepressant 
treatment will be initiated in all subjects. The oral antidepressant selected will be 1 of the 4 oral 
antidepressant medications allowed (duloxetine, escitalopram, sertraline, or venlafaxine extended 
release [XR]). The antidepressant medication will be assigned by the investigator based on review 
of MGH-ATRQ and relevant prior antidepressant medication information and will be one that the 
subject has not previously had a non-response to, in the current major depressive episode, has not 
been previously intolerant to (lifetime), and is available in participating country. 


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Dosing of the oral antidepressant will begin on Day 1 and follow a protocol specific titration 
schedule (Attachment 3). The use of the titration schedule provided in the protocol is mandatory. 
Doses are not to exceed the maximum dose defined in the titration schedule. If higher doses are 
not tolerated, a down-titration is permitted based on clinical judgment. 
Refer to the Time and Events Schedule for a list of study evaluations that will be performed during 
the double-blind treatment phase.
If a subject withdraws from the study before the end of the double-blind treatment phase for 
reasons other than withdrawal of consent, an Early Withdrawal visit should be conducted within 
1 week of the date of discontinuation, followed by the follow-up phase.
Follow-up Phase (8-weeks or until relapse)
The follow-up phase will include all subjects who received at least 1 dose of intranasal study 
medication in the double-blind treatment phase. No intranasal study medication will be 
administered during this phase.
At the start of the follow-up phase, further clinical/standard of care for the treatment of depression 
will be arranged by the study investigator and/or the subject’s treating physician and medication 
changes are permitted. The decision to continue the oral antidepressant in this phase will be at the 
discretion of the investigator.
This follow-up phase will provide additional information required to assess the course of the 
subject’s major depressive episode over an 8-week period. Safety and tolerability, including 
potential withdrawal symptoms, following discontinuation of intranasal esketamine will also be 
assessed.
The follow-up phase is completed at the end of the 8-week period or when a subject meets criteria
below for relapse (in remitters and responders), whichever occurs first. 
Relapse is defined as any of the following:

MADRS total score ≥22 for 2 consecutive assessments separated by 5 to 15 days. The date of 
the second MADRS assessment will be used for the date of relapse.

Hospitalization for worsening depression or any other clinically relevant event determined per 
clinical judgment to be suggestive of a relapse of depressive illness such as suicide attempt, 
completed suicide, or hospitalization for suicide prevention. If hospitalized for any of these 
events, the start date of hospitalization will be used for the date of relapse. Otherwise the date 
of the event will be used if the subject is not hospitalized.

In case more than one relapse criteria are met, the earlier date will be defined as the date of 
relapse for this subject. 
The total duration of a subject’s study participation will be up to 19-weeks (including an optional 
3-week taper period) for subjects completing the 8-week follow-up phase.


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A diagram of the study design is provided below in Figure 1.
Figure 1:
Schematic Overview of the Study
AD = antidepressant; CH = Chinese subjects; D/C = discontinue; MDD = major depressive disorder; 
OL = open-label; PBO = placebo. 
The study will end after 8 weeks follow-up clinical/standard of care for treatment of depression, or following
relapse, whichever is earlier. 
3.2.
Study Design Rationale
3.2.1.
Study Population
The study population will consist of approximately 234 subjects (210 Chinese subjects, 
24 non-Chinese subjects) with TRD. After giving informed consent, subjects who are 18 to 
64 years of age (inclusive), will be screened to determine eligibility for study participation. 
Subjects must meet Diagnostic and Statistical Manual of Mental Disorders–Fifth Edition (DSM-5) 
diagnostic criteria for recurrent MDD or single-episode MDD, without psychotic features, based 
upon clinical assessment and confirmed by the Mini International Neuropsychiatric Interview 
(MINI) [DSM-5 diagnostic code 296.23 or 296.33]. An independent rater will conduct the 
MADRS at screening as well as confirming the diagnosis and the validity of the major depressive 
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Treatment-resistant depression is defined as a lack of clinically meaningful improvement after 
treatment with at least 2 different antidepressant agents prescribed in adequate doses for adequate 
duration. At the start of this study, subjects must have had non-response (ie, lack of clinically 
meaningful improvement, defined as ≤25% improvement) to ≥1 but ≤5 (if current episode is 
˃2 years or undefinable, upper limit is only applicable to the last 2 years) oral antidepressant 
treatments, taken at adequate dosage and for adequate duration, as assessed using the MGH-ATRQ 
and documented by records (eg, medical/pharmacy/prescription records or a letter from treating 
physician, etc.) for the current episode of depression. Subjects who have had some initial response 
but then lose the response (eg, tolerance effects/bradyphylaxis) to an antidepressant treatment will 
not be considered to have failed that antidepressant treatment. The use of historical data to define 
non-response to treatment prior to patient enrollment in a treatment study is considered practical 
and valid. The MGH-ATRQ is a validated tool assessing treatment response.
In addition, at the start of the screening/prospective observational phase, subjects must currently 
be taking one of a different oral antidepressant treatment (on the MGH-ATRQ) for at least the 
previous 2 weeks at or above the minimum therapeutic dose. This antidepressant treatment, as well 
as any other ongoing medications being taken for depression at screening (including adjunctive/ 
augmentation therapies), will continue from the start of Week-1 through the end of Week-4 of the 
screening/prospective observational phase. Dose adjustment is permitted per clinical judgment, 
but the oral antidepressant treatment is to remain at or above the minimum therapeutic dose (per 
the MGH-ATRQ) through the end of Week-4. Antidepressant treatment adherence will be assessed 
using the PAQ. Subjects who report missing ≥4 days of antidepressant medication treatment(s) in 
the prior 2-week period will be considered as screen failed due to inadequate adherence.
Non-response at the end of the screening/prospective observational phase is defined as ≤25% 
improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total score of ≥28 
on Week 2 and Week 4.
The subject’s current major depressive episode, depression symptom severity (Week 1 MADRS 
total score ≥28 required), and antidepressant treatment response in their current depressive episode 
(retrospectively assessed) must be deemed valid for participation in the clinical study based on a 
C-VISA. The C-VISA is a tool to facilitate subject selection for MDD clinical studies, with a goal 
to ensure enrollment of subjects who have symptoms that reflect the current state of illness and 
that these symptoms can be reliably measured with appropriate measurement tools, as well as to 
help reduce placebo response.
Potential subjects will be excluded from participating in the study if they have previously 
demonstrated non-response of depressive symptoms to esketamine or ketamine in the current 
major depressive episode, or to all 4 of the oral antidepressant treatment options available for the 
double-blind treatment phase (ie, duloxetine, escitalopram, sertraline, and venlafaxine XR) in the 
current major depressive episode (based on MGH-ATRQ), or an adequate course of treatment with 
electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 
7 treatments with unilateral/ bilateral ECT. Subjects, who in the current depressive episode have 
received vagal nerve stimulation (VNS) or who have received deep brain stimulation (DBS), will 
be excluded. Subjects will also be excluded if they have a current or prior DSM-5 diagnosis of a


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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; if they have homicidal ideation/intent or suicidal ideation with some intent to act within 
6 months prior to the start of the screening/prospective observational phase per the investigator’s 
clinical judgment and/or based on the Columbia Suicide Severity Rating Scale (C-SSRS); or if 
they have a history of moderate or severe substance or alcohol use disorder according to DSM-5 
criteria.
3.2.2.
Study Phases
The Company sponsored phase 3 esketamine studies (ESKETINTRD3001, ESKETINTRD3002, 
ESKETINTRD3003, ESKETINTRD3004 and ESKETINTRD3005)56,57,58,59,60 in subjects with 
treatment resistant depression, all consist of a 4 week screening/prospective observational phase 
plus an optional 3 week taper, and a 4 week induction or treatment phase. The follow-up phase is 
of variable duration.
The 4-week duration of the screening/prospective observational phase will provide adequate time 
to assess subject eligibility according to the study entry criteria while also allowing for a 
prospective confirmation of non-response to the current antidepressant treatment(s) that is 
continued for the duration of this phase. This method of recruitment allows subjects to enter the 
study on a variety of different antidepressant medications that they had been taking, which mimics 
clinical practice and yet allows for prospective demonstration of treatment resistance to the current 
antidepressant treatment. Even though there is no depression rating score available at the start of 
the antidepressant treatment, subjects at screening will have to meet criteria for moderate to severe 
depression. After 4 weeks of prospective observation of continuation of the current antidepressant 
treatment and assessment of treatment response, subjects who meet the predefined non-response 
criteria and are eligible to enter the double-blind treatment phase will discontinue all of the current 
antidepressant treatments, including adjunctive/augmentation therapies, prior to starting the next 
phase. Non-responders who are eligible to enter the double-blind treatment phase are permitted to 
have up to 3 additional weeks to taper and discontinue their current antidepressant treatment prior 
to entry into the double-blind treatment phase per the local prescribing information or clinical 
judgment (eg, tolerability concerns). The optional taper period of up to 3 weeks is expected to 
provide an adequate amount of time for taper and discontinuation.
As described in Section 1.1.2, the duration of the 4-week double-blind treatment phase was 
selected based upon the onset of effect of typical antidepressant treatments and that the duration is 
considered to be sufficiently long to show the antidepressant effects of the active comparator. 
Preliminary findings from an analysis of antidepressant treatments were presented recently, as well 
as a completed analysis of 24 recent MDD studies that compared study durations of 4, 6, and 
8 weeks. Exploratory analyses were conducted for each of the study durations using mixed effects 
model for repeated measures (MMRM) but excluding data beyond the duration of interest. These 
preliminary findings suggest that it is plausible to shorten the study duration down to 4 weeks.40,79
Similarly, it has been demonstrated that improvement of ≥25% on the Hamilton Depression 


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17-item rating scale on Day 14 was a significant cutoff value to predict response after 5 weeks of 
treatment and a lack of improvement (ie, <25%) by Day 14 predicted poor response after 5 weeks 
of treatment.51 All together, these results suggest that a 4-week duration should be adequate to 
assess antidepressant response. 
For subjects entering the follow-up phase, the 8-week duration following the last dose of intranasal 
study medication will allow sufficient time to assess safety and tolerability after cessation of 
intranasal study medication. Given the frequency of esketamine administration, the 8-week 
follow-up should be sufficient to assess potential withdrawal symptoms and reversibility of any 
drug related adverse events and/or laboratory abnormalities. It will provide additional information 
required to assess the course of the subject’s major depressive episode over an 8-week period. 
During this phase, the subject may continue to receive oral antidepressant treatment or follow 
clinical/standard of care, as judged by the study investigator and/or the subject’s treating physician. 
3.2.3.
Blinding and Randomization
Blinded intranasal treatment will be used to reduce potential bias during data collection and 
evaluation of clinical endpoints.
An intranasal placebo control will be used in the double-blind treatment phase to establish the 
frequency and magnitude of changes in clinical endpoints that may occur in the absence of 
intranasal active treatment.
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, to 
increase the likelihood that known and unknown subject attributes (eg, demographic and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups. The randomization will be stratified by country,
class of antidepressant (SNRI or SSRI) and consent to biomarker evaluation(Yes or No) with an 
allocation ratio of 1:1 to placebo or esketamine. The stratification is aimed at balancing treatment 
groups across two countries, class of antidepressant and whether subjects consent to biomarker 
evaluation.
3.2.4.
Treatment Groups and Dose Selection
The 2 treatment groups in the double-blind treatment phase are:

Active comparator (open-label new oral antidepressant) plus intranasal placebo

Intranasal esketamine (56 mg or 84 mg) plus open-label new oral antidepressant
During the double-blind treatment phase, subjects will be randomized to receive intranasal 
treatment with esketamine (56 mg or 84 mg) or placebo. In addition, subjects will simultaneously 
initiate a new, open-label oral antidepressant on Day 1 that will be continued for the duration of 
the 4-week double-blind treatment phase.
                                                
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The treatment groups will allow for evaluation of the efficacy, safety, and tolerability of flexibly 
dosed intranasal esketamine plus a newly initiated oral antidepressant, as compared with a newly 
initiated oral antidepressant treatment (active comparator) plus intranasal placebo, in adult subjects 
with TRD.
Intranasal Study Drug
The dose selection (56 mg and 84 mg) and administration interval (2 treatment sessions per week 
for 4 weeks) for this study were based on the sponsor’s previous clinical data, notably results from 
Studies ESKETIVTRD2001, KETIVTRD2002, ESKETINTRD1001, and Panel A of 
Study ESKETINTRD2003, described above in Section 1.1.2.
The data from Study ESKETINTRD2003 Panel A support the hypotheses that both the 56 mg and 
84 mg doses are effective as a treatment for depression in subjects with TRD, that they have a 
rapid onset of effect, and that 2 treatment sessions per week can sustain the response throughout 
the 4-week duration of the double-blind treatment phase. In addition, the 56 mg and 84 mg dosages 
were generally well tolerated by subjects.
Small differences were observed in the pharmacokinetic profile of esketamine between healthy 
Chinese and Caucasian subjects who were administered a single 56 mg intranasal dose of 
esketamine (ESKETINTRD1008)8. The mean plasma Cmax and AU∞of esketamine were 
approximately 15% and 33% higher, respectively, in Chinese subjects as compared to Caucasian 
subjects. The mean terminal half-life was slightly longer in Chinese subjects (8.8 hours) than in 
Caucasians (6.8 hours). Intranasally administered esketamine 56 mg was well tolerated in both 
cohorts. Based on comparable responses of the two population cohorts to the 56 mg dose, and on 
data from the Caucasian population (ESKETINTRD2003)10, we expected the 84 mg dose to be 
both efficacious and tolerated in the Chinese population.
The use of flexible dosing, rather than using a fixed dose, of intranasal esketamine is considered 
to facilitate improved tolerability by gradually increasing to a higher dose and will also inform 
clinical practice, as many clinicians prefer to gradually increase, and then adjust as clinically 
required, the dose of an antidepressant medication.
Oral Antidepressant
On Day 1 of the double-blind treatment phase, a new, open-label oral antidepressant treatment will 
be initiated in all subjects. Each subject will be assigned to receive 1 of 4 oral antidepressant 
medications from 2 different classes of antidepressant treatments, an SSRI (escitalopram or 
sertraline) or an SNRI (duloxetine or venlafaxine XR). The oral antidepressant medication selected 
are all recommended as standard-of-care treatments for depression, and therefore expected to show 
comparable efficacy.
The antidepressant medication will be assigned by the investigator based on review of 
MGH-ATRQ and relevant prior antidepressant medication information.


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These 2 classes were selected because they are the most commonly prescribed antidepressant 
classes in this population and are generally well-tolerated. The oral antidepressant treatment 
assigned will be one that the subject has not previously had a non-response to in the current 
depressive episode, has not been previously intolerant to (lifetime), and is available in the 
participating country. Dosing of the oral antidepressant will begin on Day 1 and will follow a 
specific titration schedule (Attachment 3). The use of the titration schedule is mandatory. Doses 
are not to exceed the maximum dose defined in the titration schedule. If higher doses are not 
tolerated, a down-titration is permitted based on clinician’s judgment. 
3.2.5.
Efficacy Measures
MADRS
The 10-item clinician-administered MADRS was designed to be used in subjects with MDD to 
measure the overall severity of depressive symptoms.43,44 The MADRS scale has been selected as 
the primary efficacy measure for this study because it is validated, reliable, and acceptable to 
regulatory health authorities as a primary scale to determine efficacy in major depression. The 
MADRS has been validated in Chinese subjects with MDD.81
The primary efficacy endpoint is the change in the MADRS total score from baseline (Day 1, prior 
to randomization) to the end of the 4-week double-blind treatment phase.
In addition to the primary efficacy measure, the change in MADRS total score from baseline 
(Day 1, prior to randomization) to 24 hours post dose (Day 2) will be included as a key secondary 
efficacy endpoint to evaluate rapid reduction of depressive symptoms.
In this study, subjects in any of the 2 treatment groups who respond to the study medication 
(ie, responders) are defined as subjects who meet the criterion for response defined as ≥50% 
reduction in the MADRS total score from baseline (Day 1, pre-randomization) to the end of the 
4-week double-blind treatment phase.
MADRS will also be used to evaluate a secondary objective assessing the onset of clinical response 
(ie, antidepressant effect) by Day 2 that is maintained for the duration of the double-blind treatment 
phase. Onset of clinical response is defined as ≥50% improvement in MADRS total score by Day 2 
(ie, the day after taking the first dose of double-blind intranasal medication) that is maintained 
through the end of the 4-week double-blind treatment phase with one excursion allowed. 
Additionally, MADRS will be used to evaluate a secondary objective assessing the proportion of 
subjects in remission (MADRS total score ≤12) at the end of the 4-week double-blind treatment 
phase; and the proportion who remain in remission (MADRS total score ≤12) through to the end 
of the follow-up phase.
The proportion of subject who relapse during the follow-up phase will be evaluated separately for 
subjects who are remitters (MADRS total score ≤12) at the end of the 4-week double-blind 
treatment phase and for subjects who are responders but not remitters (≥50% reduction in MADRS 
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Sheehan Disability Scale (SDS)
The SDS is a subject-reported outcome measure and is included as an assessment of functional 
impairment and associated disability.41,67 The SDS assessment has been used for many years in 
psychiatric clinical trials in China, and its validity and reliability are well established. Please refer 
to Section 9.2.1.2 for additional information regarding SDS.
Clinical Global Impression–Severity (CGI-S) 
The CGI-S is included to rate the severity of the subject’s illness at the time of assessment, relative 
to the clinician’s past experience with subjects who have the same diagnosis and improvement 
with treatment.27 The CGI-S is widely used in clinical trials in psychiatry in China and has 
demonstrated validity and reliability in Chinese subjects with MDD. Please refer to 
Section 9.2.1.3.1 for additional information regarding CGI-S.
Generalized Anxiety Disorder 7-item Scale (GAD-7)
GAD-7 is included as a brief and validated measure of overall anxiety.69 The GAD-7 has been 
validated in Chinese subjects with MDD.30,80 Please refer to Section 9.2.1.3.2 for additional 
information regarding GAD-7.
EuroQol-5 Dimension-5 Level (EQ-5D-5L)
The EQ-5D-5L is included as a standardized subject-completed instrument for use as a measure of 
health-related quality of life and health status.23,24 The EQ-5D-5L has been validated in Chinese 
subjects with MDD.77 Please refer to Section 9.2.1.3.2 for additional information regarding 
EQ-5D-5L.
3.2.6.
Safety Evaluations
Physical examination, body weight, vital signs (including blood pressure, pulse rate, respiratory 
rate and temperature measurements), 12-lead ECG, pulse oximetry, clinical laboratory tests
(including hematology, serum chemistry, and urinalysis), pregnancy testing (for women of 
childbearing potential) will be performed throughout the study to monitor subject safety. 

Given the potential for treatment emergent transient elevation in systolic and diastolic blood 
pressure, heart rate and blood pressure will be monitored throughout the study and at multiple
time points on dosing days. Specific guidance to be followed on intranasal dosing days is 
provided in Section 6.4 (Guidance on Blood Pressure Monitoring on Intranasal Treatment 
Session Days).
Treatment-emergent adverse events (TEAEs) will be evaluated throughout the course of the study. 
Clinically relevant TEAEs of special interest will be examined separately grouped in the following 
categories as defined by the Standardized Medical Dictionary for Regulatory Activities 
(MedDRA) (version 20.0, or above if applicable) queries [(SMQ): AEs potentially suggestive of 
abuse, increased blood pressure, increased heart rate, transient dizziness/vertigo, impaired 
cognition, anxiety, and cystitis.


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
The preferred terms used to determine TEAEs potentially suggestive of abuse, as defined by 
the Food and Drug Administration’s Assessment of Abuse Potential of Drugs Guidance for 
Industry (January 2017) a , include: Aggression, Confusional state, Decreased activity, 
Disorientation, Dissociation, Dissociative disorder, Dizziness, Drug tolerance, 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, 
Somatic hallucination, Somnolence, Substance use disorder, Substance-induced psychotic 
disorder, and Thinking abnormal. 
Narrative descriptions will be provided for deaths, subjects with serious adverse events, and 
subjects who discontinued study medication due to an adverse event. If applicable, narratives will 
be prepared for subjects with a TEAE of cystitis, with postdose oxygen saturation <93% for 2 or 
more consecutive assessments within the same visit, with post-baseline cases of QTcF >500 msec, 
with clinically significant suicidal ideation (score of 4 or 5 on the C-SSRS) or suicidal behavior 
(scores 6-10 on the C-SSRS), and for subjects who experienced a motor vehicle accident and/or 
who had TEAEs potentially suggestive of abuse.
The following safety evaluations will be performed:

Nasal Examination

Columbia Suicide Severity Rating Scale (C-SSRS), to assess suicidal ideation and behavior 

Clinician Administered Dissociative States Scale (CADSS), to assess treatment-emergent 
dissociative symptoms

Physician Withdrawal Checklist (20-item; PWC-20), to assess potential withdrawal 
symptoms after cessation of esketamine treatment.
On all intranasal dosing days, subjects must remain at the site until study procedures have been 
completed and the subject is ready for discharge and should be accompanied by a responsible adult 
when released from the clinical site. Subjects must not drive a car or work with machines for 
24 hours after receiving intranasal study drug.
A list of prohibited medications is provided in Attachment 1 as general guidance for the 
investigator (but is not all inclusive).
3.2.7.
Other Assessments
Patient Adherence Questionnaire
During the screening/prospective observational phase, the subject-reported Patient Adherence 
Questionnaire (PAQ) will be used to assess how often the subject has taken, and whether he or she 
has made any changes to, his or her antidepressant treatment regimen in the last 2 weeks. This 
                                                
a Federal Disease Associations Assessment of Abuse Potential of Drugs Guidance for Industry. 
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assessment will provide confirmation of medication adherence when evaluating antidepressant 
treatment response. Subjects who report missing ≥4 days of antidepressant medication treatment(s) 
during a 2 week recall period will be considered as screen failed due to inadequate adherence.
3.2.8.
Pharmacokinetic Assessments
Serial pharmacokinetic blood samples (4 mL, each) will be collected from Chinese subjects at all 
clinical sites, at the time points specified in the Time and Events Schedule. Concentration time 
data will allow estimation of individual PK parameters for esketamine, using a population PK 
modeling approach. The timing of PK sample collections was chosen to gather maximal 
information about the PK properties of esketamine while minimizing subject burden. The exact 
dates and times of PK blood sampling must be recorded. The concentrations of esketamine will be 
measured in plasma using a validated liquid chromatography coupled to tandem mass spectrometry 
(LC MS/MS) achiral method. The concentration of other esketamine metabolites may be measured 
in plasma, if required.

Biomarker, Pharmacogenomic (DNA), and Expression (RNA) 
Evaluations
Assessment of biomarkers (protein and RNA) and their potential relationship to the different 
treatment groups and to maintenance/stabilization of response, non-response, and relapse will be 
explored. Blood samples will be collected to measure genetic and epigenetic markers (including 
but not limited to BDNF allelic variants) and protein markers (including but not limited to growth 
factors, inflammation, endocrine, or metabolic). Samples of deoxyribonucleic acid (DNA) and 
biomarkers may be used to help address emerging issues and to enable the development of safer, 
more effective, and ultimately individualized therapies.
Genetic variation can be an important contributory factor to 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 or subgroups that 
are more susceptible to relapse. In addition, pharmacogenomics research may allow for the 
identification of genetic factors that influence the PK, PD, efficacy, safety, or tolerability of the 
different treatment groups, and for the identification of genetic factors associated with TRD or 
MDD. Specifically, genetic and epigenetic changes in genes known to be in pathways relevant to 
depression (eg, hypothalamic pituitary adrenal [HPA] axis, inflammation, growth factors, 
monoamine transporters, ion channels, and circadian rhythm) will be evaluated.
Protein, metabolite, and ribonucleic acid (RNA) biomarkers may aid in the elucidation of the 
mechanism of action of the different treatment groups or help to explain inter-individual variability 
in clinical outcomes or may help to identify population subgroups that respond differently to a 
drug or may help to identify subgroups that are more susceptible to relapse. The goal of the 
                                                

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biomarker analyses is to evaluate the PD of the different treatment groups, and aid in evaluating 
the drug-clinical response relationship.
On the day of biomarker sample collection, it is preferred that subjects adhere to a low fat diet (as 
an alternative to fasting) to reduce the level of postprandial lipemia in blood samples, since 
moderately or grossly lipemic specimens may interfere with assay results.
Subjects who agree to participate in the biomarker, pharmacogenomic (DNA) and expression 
(RNA) component will need to sign a separate written informed consent form.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within a period of at least 28 days before
administration of the study drug. 
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues before 
enrolling a subject in the study. Waivers are not allowed.
For a discussion of the statistical consideration of subject selection, refer to Section 11.2 Sample 
Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
At the time of signing the informed consent form (ICF), subject must be a man or 
woman 18 (or older if the minimum legal age of consent in the country in which the 
study is taking place is ˃18) to 64 years of age, inclusive.
2.
Criterion modified per Amendment 1
2.1 At the start of the screening/prospective observational phase, subject must meet the
Diagnostic and Statistical Manual of Mental Disorders–fifth edition (DSM-5)
diagnostic criteria for recurrent MDD or single-episode MDD, without psychotic 
features, based upon clinical assessment and confirmed by the MINI.
3.
Criterion modified per Amendment 1
3.1 At the start of the screening/prospective observational phase, subject must have had 
non-response (≤25% improvement) to ≥1 but ≤5 (if current episode is >2 years or not 
definable, upper limit is applicable to only the last 2 years) oral antidepressant 
treatments in the current episode of depression, assessed using the MGH-ATRQ and 
confirmed by documented records (eg, medical/ pharmacy/prescription records or letter 
from a treating physician, etc.). In addition, the subject is taking a different oral 


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antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or 
above the minimum therapeutic dose.

For specific tricyclic antidepressants which are ongoing and being taken at a 
dose below the MGH-ATRQ minimum therapeutic dose, a blood level that is 
within the therapeutic (antidepressant) range, is acceptable to establish the 
adequacy of the antidepressant treatment. Note: performing the test depends 
on availability of the kit.

Subjects must be adherent to the continued oral antidepressant treatment 
medication(s) through the screening/prospective observational phase, as 
documented on the Patient Adherence Questionnaire (PAQ). Missing ≥4 days 
of antidepressant medication in the prior 2-week period will be considered as 
screen failed due to inadequate adherence.

Subjects who are non-responders to their current oral antidepressant 
medication(s) from the screening/prospective observational phase (as assessed 
by independent, remote raters) may be eligible for randomization if all other 
entry criteria are met. Non-response at the end of the screening/prospective 
observational phase is defined as ≤25% improvement in the MADRS total 
score from Week 1 to Week 4 and a MADRS total score of ≥28 on Week 2 
and Week 4.
4.
Criterion modified per Amendment 1
4.1 The subject’s current major depressive episode, depression symptom severity 
(Week 1 MADRS total score ≥28 required), and antidepressant treatment response in 
the current depressive episode, must be confirmed using a C-VISA.
5.
Subject must be medically stable on the basis of physical examination, medical history, 
vital signs (including blood pressure), pulse oximetry, and 12-lead ECG performed in 
the screening/prospective observational phase. If there are any abnormalities that are 
not specified in the inclusion and exclusion criteria, they must be consistent with the 
underlying illness in the study population. This determination must be recorded in the 
subject's source documents and initialed or signed by the investigator.
6.
Subject must be medically stable on the basis of clinical laboratory tests performed in 
the screening/prospective observational phase. If the results of the serum chemistry 
panel, hematology, or urinalysis are outside the normal reference ranges, the subject 
may be included only if the investigator judges the abnormalities or deviations from 
normal to be not clinically significant or to be appropriate and reasonable for the 
population under study. This determination must be recorded in the subject's source 
documents and initialed or signed by the investigator.

Subjects with a pre-existing history of thyroid disease/disorder who are treated 
with thyroid hormones must be on a stable dosage for 3 months prior to the 
start of the screening/prospective observational phase. 


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
For any subject (regardless of thyroid history), if the thyroid-stimulating 
hormone (TSH) value is out of range, a free thyroxine (FT4) will be conducted. 
If the FT4 value is abnormal and considered to be clinically significant (after 
discussion with the medical monitor), the subject is not eligible.
7.
Subject must be comfortable with self-administration of intranasal medication and be 
able to follow the intranasal administration instructions provided.
8.
Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical studies.
A woman must be either:
a. Not of childbearing potential defined as: 

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level 
(>40 IU/L or mIU/mL in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy, however in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.

permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, 
bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy.
b. Of childbearing potential and

practicing a highly effective method of contraception (failure rate of <1% per year 
when used consistently and correctly).
Examples of highly effective contraceptives include

user-independent methods:
implantable progestogen-only hormone contraception associated with 
inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-
releasing system (IUS); vasectomized partner; sexual abstinence (sexual 
abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with 
the study drug. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
subject.)

user-dependent methods:
combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal, and transdermal; 
progestogen-only hormone contraception associated with inhibition of 
ovulation: oral and injectable.


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Typical use failure rates may differ from those when used consistently and 
correctly. Use should be consistent with local regulations regarding the use of 
contraceptive methods for subjects participating in clinical studies.
Hormonal contraception may be susceptible to interaction with the study drug, 
which may reduce the efficacy of the contraceptive method.

agrees to use a highly effective method throughout the study and for at least 
6 weeks after the last dose of study drug. 
Note: If the childbearing potential changes after start of the study (eg, woman who is 
not heterosexually active becomes active), a woman must begin a highly effective 
method of birth control, as described throughout the inclusion criteria.
9.
A woman of childbearing potential must have a negative serum (β-human chorionic 
gonadotropin [β-hCG]) at the start of the screening/prospective observational phase and 
a negative urine pregnancy test must be obtained before the first dose of study drug on 
Day 1 of the double-blind phase prior to randomization.
10.
During the study (ie, from Day 1 of the double-blind phase, prior to randomization) and 
for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after 
receiving the last dose of intranasal study medication, a man who is sexually active with 
a woman of childbearing potential 

must be practicing a highly effective method of contraception with his female 
partner from those listed above (see examples of highly effective methods of 
contraception provided for female subjects).

must use a condom if his partner is pregnant.

must agree not to donate sperm.
Note: If the childbearing potential changes after start of the study, a female partner of a 
male study subject, must begin a highly effective method of birth control, as described 
above.
11.
Subject must be willing and able to adhere to the prohibitions and restrictions specified 
in this protocol.
12.
Each subject 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.
13.
For Chinese subjects, the primary spoken language must be Mandarin or subjects must 
be capable of communication fluently in Mandarin.


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4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.
1.
The subject’s depressive symptoms have previously demonstrated non-response to:

Esketamine or ketamine in the current major depressive episode per clinical 
judgment, or

All of the oral antidepressant treatment options available in the respective 
country for the double-blind phase (ie, duloxetine, escitalopram, sertraline, and 
venlafaxine XR) in the current major depressive episode (based on MGH-
ATRQ), or

An adequate course of treatment with electroconvulsive therapy (ECT) in the 
current major depressive episode, defined as at least 7 treatments with 
unilateral/bilateral ECT. 
2.
Subject has received vagal nerve stimulation (VNS) or has received deep brain 
stimulation (DBS) in the current episode of depression.
3. 
Subject has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with 
psychotic features, bipolar or related disorders (confirmed by the MINI), obsessive 
compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes 
315.8, 317, 318.0, 318.1, 318.2 and 319), autism spectrum disorder, borderline 
personality disorder, antisocial personality disorder, histrionic personality disorder, or 
narcissistic personality disorder.
4.
Subject has homicidal ideation/intent, per the investigator’s clinical judgment, or has 
suicidal ideation with some intent to act within 6 months prior to the start of the 
screening/prospective observational phase, per the investigator’s clinical judgment or 
based on the C-SSRS, corresponding to a response of “Yes” on Item 4 (active suicidal 
ideation with some intent to act, without specific plan) or Item 5 (active suicidal 
ideation with specific plan and intent) for suicidal ideation on the C-SSRS, or a history 
of suicidal behavior within the past year prior to the start of the screening/prospective 
observational phase. Subjects reporting suicidal ideation with intent to act or suicidal 
behavior prior to the start of the double-blind treatment phase should be excluded.
5.
Subject has a history of moderate or severe substance or alcohol use disorder according 
to DSM-5 criteria, except nicotine or caffeine, within 6 months before the start of 
screening/prospective observational phase. 

A history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid 
diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) 
hallucinogen-related use disorder is exclusionary.


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6.
Subjects with a current or past history of seizures (uncomplicated childhood febrile 
seizures with no sequelae are not exclusionary).
7.
Subject has one of the following cardiovascular-related conditions:

Cerebrovascular disease with a history of stroke or transient ischemic attack.

Aneurysmal vascular disease (including intracranial, thoracic, or abdominal 
aorta, or peripheral arterial vessels).

Coronary artery disease with myocardial infarction, unstable angina, or 
revascularization procedure (eg, coronary angioplasty or bypass graft surgery) 
within 12 months before the start of the screening/prospective observational 
phase. Subjects who have had a revascularization performed ˃12 months prior 
to screening and are clinically stable and symptom-free, per investigator’s 
clinical judgment, can be included. 

Hemodynamically significant valvular heart disease such as mitral 
regurgitation, aortic stenosis, or aortic regurgitation. 

New York Heart Association (NYHA) Class III-IV heart failure of any 
etiology.
8.
Subject has a history of uncontrolled hypertension despite diet, exercise, or 
antihypertensive therapy, any past history of hypertensive crisis, or ongoing evidence 
of uncontrolled hypertension defined as a supine systolic blood pressure (SBP) 
>140 mmHg 
or 
diastolic 
blood 
pressure 
(DBP) 
>90 mmHg,
during
the
screening/prospective observational phase, which continues to be above this range with 
repeated testing during this phase. [Note: On Day 1 of the double-blind treatment phase 
prior to randomization a supine SBP >140 mm Hg or DBP >90 mmHg is exclusionary].

A potential subject may have his/her current antihypertensive medication(s) 
adjusted during the screening/prospective observational phase and be re-
evaluated to assess their blood pressure control. 
9.
Subject has a current or past history of significant pulmonary insufficiency/condition or 
with an arterial blood oxygen saturation (SpO2) of <93% at the start of the 
screening/prospective observational phase or Day 1 prior to randomization. 
10.
Criterion modified per Amendment 1
10.1 Subject has clinically significant ECG abnormalities at the start of the 
screening/prospective observational phase or on Day 1 of the double-blind treatment 
phase prior to randomization, defined as:

During screening, a QT interval corrected according to Fridericia's formula 
(QTcF): ≥470 msec in males and ≥480 msec in females.


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
On Day 1 (predose), a QT interval corrected according to Fridericia’s formula 
(QTcF): ≥470 msec in males and ≥480 msec in females based on the 
site-evaluated ECG.

Evidence of 2nd and 3rd degree AV block, complete left bundle branch block 
(LBBB), or complete right bundle branch block (RBBB). 

Features of new ischemia.

Arrhythmia (except premature atrial contractions [PACs] and premature 
ventricular contractions [PVCs]).
11.
Subject has a history of additional risk factors for Torsades de Pointes (eg, heart failure, 
hypokalemia, family history of Long QT Syndrome).
12.
Criterion modified per Amendment 1
12.1 Subject has a history of, or symptoms and signs suggestive of, liver cirrhosis 
(eg, esophageal varices, ascites, and increased prothrombin time) OR alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) values 3x the upper limit 
of normal in the screening/prospective observational phase.

Repeat of screening test for abnormal ALT and AST is permitted once during 
the screening period provided per investigator discretion and provided there is 
an alternative explanation for the out of range value.
13.
Criterion modified per Amendment 1
13.1 Subject has positive test result(s) for drugs of abuse at the start of the 
screening/prospective observational phase (including barbiturates, methadone, opiates, 
cocaine, phencyclidine, and amphetamine) or Day 1 of the double-blind treatment phase 
prior to randomization (including cannabinoids, methadone, opiates, cocaine, and 
amphetamine). Note: performing the test, depends on availability of the kit.

Subjects who have a positive test result at screening due to prescribed 
psychostimulants (eg, amphetamine, etc.) taken for an indication other than 
MDD, are permitted to continue to take this medication during the study.

Otherwise, subjects who have a positive test result at screening due to 
prescribed/over-the-counter opiates or barbiturates may be permitted to 
continue in the screening/prospective observational phase if the medication is 
discontinued at least 1 week or 5 half-lives, whichever is longer, before Day 1 
of the double-blind treatment phase (prior to randomization). The result of the 
Day 1 (prior to randomization) test for drugs of abuse must be negative for the 
subject to be randomized.

Retesting is not permitted for positive test result(s), except for reasons stated 
above.


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
Prior intermittent use of cannabinoids prior to the start of the 
screening/prospective observational phase is not exclusionary as long as the 
subject does not meet the criteria for substance use disorder. A positive test for 
cannabinoids at the start of the screening/prospective observational phase is 
not exclusionary however a positive test result for cannabinoids predose on 
Day 1 of the double-blind treatment phase is exclusionary.
14.
Subject has uncontrolled diabetes mellitus, as evidenced by HbA1c >9% in the 
screening/prospective observational phase or history in the prior 3 months prior to the 
start of the screening/prospective observational phase of diabetic ketoacidosis, 
hyperglycemic coma, or severe hypoglycemia with loss of consciousness.
15.
Subject has any anatomical or medical condition that, per the investigator’s clinical 
judgment based on assessment, may impede delivery or absorption of intranasal study 
drug.
16.
Subject has a history of malignancy within 5 years before the start of the 
screening/prospective observational phase (exceptions are squamous and basal cell 
carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that, in the 
opinion of the investigator, with concurrence with the sponsor's medical monitor, is 
considered cured with minimal risk of recurrence).
17.
Subject has known allergies, hypersensitivity, intolerance, or contraindications to 
esketamine/ketamine and/or its excipients or all of the available oral antidepressant 
treatment options for the double-blind treatment phase.
18.
Subject has taken any prohibited therapies that would not permit dosing on Day 1.
19.
Subject is taking a total daily dose of benzodiazepines greater than the equivalent of 
6 mg/day of lorazepam at the start of the screening/prospective observational phase.
20.
Subject has an obstructive sleep apnea (eg, apnea-hypopnea index [AHI] must be <30). 
A subject with obstructive sleep apnea can be included if he or she is using a positive 
airway pressure device or other treatment/therapy that is effectively treating (ie, AHI 
<30) his or her sleep apnea.
21.
Subject has received an investigational drug (including investigational vaccines) or used 
an invasive investigational medical device within 60 days before the start of the 
screening/prospective observational phase, or has participated in 2 or more MDD or 
other psychiatric condition clinical interventional studies (with different investigational 
medication) in the previous 1 year before the start of the screening/prospective 
observational phase, or is currently enrolled in an investigational interventional study.
22.
Subject is a woman who is pregnant, breast-feeding, or planning to become pregnant 
while enrolled in this study or within 6 weeks after the last dose of intranasal study 
drug.


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23.
Subject is a man who plans to father a child while enrolled in this study or within 
12 weeks after the last dose of study drug.
24.
Subject has a diagnosis of acquired immunodeficiency syndrome (AIDS). Human 
immunodeficiency virus (HIV) testing is not required for this study.
25.
Subject has any condition or situation/circumstance for which, in the opinion of the 
investigator, participation would not be in the best interest of the subject 
(eg, compromise the well-being) or that could prevent, limit, or confound the protocol-
specified assessments.
28a.
Subject has had major surgery, (eg, requiring general anesthesia) within 12 weeks 
before the start of the screening/prospective observational phase, or will not have fully 
recovered from surgery, or has surgery planned during the time the subject is expected 
to participate in the study. 
Note: Subjects with planned surgical procedures to be conducted under local anesthesia 
may participate.
29.
Subject is an employee of the investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study site, as 
well as family members of the employees or the investigator.
30.
Subject has severe renal impairment (creatinine clearance <30 ml/min).
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject’s clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 9.1.2, Screening/Prospective Observational Phase describes 
options for retesting. Section 17.4, Source Documentation, describes the required documentation 
to support meeting the enrollment criteria. 
The sponsor will evaluate and approve/reject requests to rescreen an individual subject on a 
case-by-case basis.
                                                
a
In the original protocol the numbering of the exclusion criteria inadvertently skipped 26 and 27. These numbers 
are not being used.


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4.3.
Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and restrictions 
during the course of the study to be eligible for participation:
1.
Refer to Section 8 (Concomitant Therapy) and Attachment 1 (Prohibited Concomitant 
Medications for Intranasal Study Medication [Esketamine or Placebo]) for details regarding 
prohibited and restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the Inclusion 
Criteria (Section 4.1) and Exclusion Criteria (Section 4.2; eg, contraceptive requirements)
3.
Subjects who were taking benzodiazepines at dosages equal to or less than the equivalent of 
6 mg/day of lorazepam and/or permitted non-benzodiazepine sleep medications 
(eg, zolpidem, zaleplon, eszopiclone, and ramelteon) during the screening/prospective 
observational phase can continue these medications 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 (eg, alprazolam, clorazepate, triazolam, 
lorazepam and temazepam). Benzodiazepines and non-benzodiazepine sleeping medication 
(eg, zolpidem, zaleplon, eszopiclone, and ramelteon) are prohibited within 12 hours prior to 
the start of each intranasal treatment session.
4.
A positive urine drug screen for use of cocaine from Day 1 of the double-blind treatment phase 
through the final visit in the double-blind treatment phase will lead to discontinuation. Note: 
performing the test depends on availability of the kit
5.
Subjects must abstain from using alcohol within 24 hours before and after each intranasal 
treatment session. If a subject appears intoxicated, dosing should not occur (delayed per the 
permitted visit window; see the Time and Events Schedule).
6.
On all intranasal study drug dosing days, all subjects must remain at the clinical study site 
until study procedures have been completed and the subject is ready for discharge. Subjects 
should be accompanied by a responsible adult when released from the clinical study site. 
Subjects must not drive a car or work with machines for 24 hours after study drug dosing.
7.
ECT, DBS, transcranial magnetic stimulation (TMS), and VNS are prohibited from study 
entry through the end of the double-blind treatment phase.
8.
Subjects receiving psychotherapy (including cognitive behavioral therapy; CBT) can continue 
receiving psychotherapy; however, CBT must have been ongoing for the last 3 months prior 
to the screening/prospective observational phase. With the exception of new CBT, which is 
prohibited, new psychotherapy is allowed during this study. Any change in existing therapy 
or new therapy must be documented on the concomitant therapies form.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization
Central randomization will be implemented in this study. Subjects will be randomly assigned to 1 
of 2 treatment groups in a 1:1 ratio based on a computer-generated randomization schedule 


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prepared before the study by or under supervision of the sponsor. The randomization will be 
balanced by using randomly permuted blocks and will be stratified by country, class of oral 
antidepressant (SNRI or SSRI) and consent to biomarker evaluation (Yes or No) to be initiated in 
the double-blind treatment phase. The interactive web response system (IWRS) will assign a 
unique treatment code, which will dictate the treatment assignment and matching study drug kits 
for the subject. After the investigator selects the oral antidepressant treatment for the double-blind 
treatment phase, the site will enter this information into IWRS. The requestor must use his or her 
own user identification and personal identification number when contacting the IWRS, and will 
then give the relevant subject details to uniquely identify the subject. 
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (eg, intranasal study drug plasma 
concentrations, treatment allocation) will be handled with special care to ensure that the integrity 
of the blind is maintained and the potential for bias is minimized. This can include making special 
provisions, such as segregating the data in question from view by the investigators, clinical team, 
or others as appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until all subjects have completed the 
study and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment/course of action would be dictated by knowing the treatment status of the 
subject. In such cases, the investigator may in an emergency determine the identity of the treatment 
by contacting the IWRS. It is recommended that the investigator contact the sponsor or its 
designee, if possible, to discuss the particular situation, before breaking the blind. Telephone 
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In the 
event the blind is broken, the sponsor must be informed as soon as possible. The date and time of 
the unblinding will be documented by the IWRS, and reason for the unblinding must be 
documented by the electronic case report form (eCRF) and in the source document. The 
documentation received from the IWRS indicating the code break must be retained with the 
subject's source documents in a secure manner.
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled early withdrawal and follow up visits.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. 
To maintain the blinding of intranasal study medication, the esketamine and placebo intranasal 
devices will be indistinguishable. Please refer to Section 14 (Study Drug Information) for 
information on the physical characteristics of the study drugs and devices. 


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6.
DOSAGE AND ADMINISTRATION
6.1.
Screening/Prospective Observational Phase (4-week duration + optional 
3-week taper period) 
This phase will prospectively assess treatment response to the subject’s current oral antidepressant 
treatment regimen.
At the start of the screening/prospective observational phase, the subject must have had 
documented non-response to at least 1 antidepressant treatment (based on Massachusetts General 
Hospital–Antidepressant Treatment Response Questionnaire [MGH-ATRQ]) in the current 
episode of depression, and subject is taking a different oral antidepressant treatment (on the 
MGH-ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose. This 
antidepressant treatment, as well as any other ongoing medications being taken for depression at 
screening (including adjunctive/augmentation therapies), will continue from the start of Week 1 
through the end of Week 4 of the screening/prospective observational phase. Dose adjustment is 
permitted per clinical judgment, but the oral antidepressant treatment is to remain at or above the 
minimum therapeutic dose (per the MGH-ATRQ) through the end of Week 4. Antidepressant 
treatment adherence will be assessed using the PAQ. Subjects who report missing ≥4 days of 
antidepressant medication treatment(s) in the prior 2-week period will be considered as screen 
failed due to inadequate adherence.
The sponsor will not supply these antidepressant medication(s).
After 4 weeks, subjects who are non-responders to their current oral antidepressant treatment (as 
assessed by independent, remote raters) may be eligible to proceed to the double-blind treatment 
phase. Non-response at the end of the screening/prospective observational phase is defined as 
≤25% improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total score 
of ≥28 on Week 2 and Week 4.
The MADRS interview should be performed in Week 1 (Visit 1.1 or as soon as possible) of the 
screening/prospective observational phase.
Eligible subjects who are entering the double-blind treatment phase will discontinue all current 
medication(s) being used for depression treatment (including adjunctive/augmentation therapies), 
and any other prohibited psychotropic medications (including adjunctive atypical antipsychotics). 
Subjects taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of 
lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, zaleplon, 
eszopiclone and ramelteon) during the screening/prospective observational phase, can continue 
these medications during the treatment phase. No dose increases beyond the equivalent of 
6 mg/day of lorazepam or new benzodiazepine medications are permitted during the 
screening/prospective observational phase. If clinically indicated, a subject’s current 
antidepressant treatment(s) may be tapered and discontinued over an additional optional period of 
up to 3 weeks per the local prescribing information or per clinical judgment or discontinued and
switched directly to one of the four new oral antidepressant medications on Day 1 of the 
double-blind treatment phase, per clinical judgment.


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6.2.
Double-blind Treatment Phase (4-week duration)
Approximately 234 eligible subjects (210 Chinese subjects, 24 non-Chinese subjects) with TRD, 
will be randomly assigned at a 1:1 ratio (n=117 subjects per treatment arm, with approximately 
105 Chinese subjects per arm) to receive double-blind treatment with either intranasal esketamine 
or intranasal placebo. The intranasal treatment sessions (esketamine 56 mg, 84 mg or placebo) will 
occur twice per week for 4 weeks as a flexible dose regimen at the study site. In addition, all 
subjects will initiate a new open-label oral antidepressant on Day 1, that will be taken daily for the 
duration of the double-blind treatment phase. The assigned oral antidepressant will be 1 of 4 oral 
antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine extended release 
[XR]), that the subject has not previously had a non-response to in the current depressive episode, 
has not been previously intolerant to (lifetime), and is available in the participating country.
Subjects who were taking benzodiazepines (at dosages equal to or less than the equivalent of 
6 mg/day of lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, 
zaleplon, eszopiclone and ramelteon) during the screening/prospective observational phase can 
continue these medications 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 (eg, alprazolam, clorazepate, triazolam, lorazepam and temazepam).
Intranasal Treatment Sessions:
All subjects will self-administer the intranasal study medication (esketamine or placebo) at 
treatment sessions occurring twice a week for 4 weeks at the clinical site. Treatment is assigned 
by the Interactive Web Response System (IWRS). The table below describes how each treatment 
session will be administered in the Double-Blind Treatment Phase. 
Table 1:
Intranasal Treatment Sessions in the Double-Blind Treatment Phase 
Intranasal
Treatment
Time of Administration
(Time 0 is defined as the time of the first 100-µL spray)
0 a
5 minutes
10 minutes
Intranasal Device 
b,c
Placebo
1st
1 spray of placebo
to each nostril
2nd
1 spray of placebo
to each nostril
3rd
1 spray of placebo
to each nostril
Esketamine
56 mg
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
1 spray of placebo
to each nostril
Esketamine
84 mg
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
1 spray of esketamine
to each nostril
a.
Time 0 is defined as the time of administration of the first intranasal spray to one nostril from the first intranasal device. 
b.
One device will be used at each time point. Each individual intranasal device contains 2 sprays. The intranasal devices 
containing esketamine deliver 14 mg per spray, for a total of 28 mg per individual device (ie, 2 sprays).
c.
The 3 intranasal devices for each intranasal treatment session should be administered in the medication kit order provided 
by the IWRS
Instructions for use documents (subject and healthcare provider versions) for intranasal study drug 
administration will be provided as separate documents. Details regarding study drug 
administration will be recorded in the source documents and the electronic case report form 
(eCRF).


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Prior to the first intranasal dose on Day 1, subjects will practice spraying (into the air, not 
intranasally) a demonstration intranasal device that is filled with placebo solution.
All subjects will self-administer the intranasal study drug (esketamine or placebo) at treatment 
sessions twice a week for 4 weeks at the study site. The first treatment session will be on Day 1. 
Intranasal treatment sessions should not take place on consecutive days.
On Day 1, subjects randomized to intranasal esketamine will start with a dose of 56 mg. On any 
of the subsequent dosing days (Day 4, 8, 11, 15, 18, 22 and 25), the investigator can judge, based 
on efficacy and tolerance, whether to increase the dose of intranasal esketamine to 84 mg or to 
maintain the dose at 56 mg. In the event that an increase in dose is poorly tolerated, the investigator 
may decide to reduce the dose to 56 mg. Food will be restricted for at least 2 hours before each 
administration of study drug. Drinking of any fluids will be restricted for at least 30 minutes before 
the first nasal spray.
If the subject has nasal congestion on the dosing day, an intranasal decongestant can be used to 
reduce congestion or the dosing day be delayed (per the permitted visit window; see the Time and 
Events Schedule). If an intranasal decongestant is used to reduce congestion, it cannot be used 
within 1 hour prior to intranasal study drug dosing.
On all intranasal treatment sessions, subjects must remain at the clinical site until study procedures 
have been completed and the subject is ready for discharge. On all intranasal treatment session 
days, a site staff member with training in cardiopulmonary resuscitation (eg, Basic Life Support 
course or equivalent course) that is up to date per local regulations, must be present with the subject 
during the intranasal treatment sessions and the postdose observation period. In addition, 
equipment for supportive ventilation and resuscitation needs to be present. Subjects must remain 
at the site until study procedures have been completed and the subject is ready for discharge. At 
the time of discharge, subjects should be accompanied by a responsible adult when released from 
the clinical site. Subjects must not drive a car or work with machines for 24 hours after receiving 
intranasal study drug.
On intranasal dosing days, it is recommended that the oral antidepressant medication not be taken 
until at least 3 hours after an intranasal treatment session, thus providing sufficient time for 
potential side-effects related to esketamine (including dissociation, increase in blood pressure) to 
have resolved.
Oral Antidepressant Treatment: 
Starting on Day 1 of the double-blind treatment phase, a new open-label oral antidepressant 
treatment will be initiated in all subjects. The oral antidepressant selected will be 1 of the 4 oral 
antidepressant medications allowed (duloxetine, escitalopram, sertraline, or venlafaxine extended 
release [XR]). The antidepressant medication will be assigned by the investigator based on review 
of MGH-ATRQ and relevant prior antidepressant medication information and will be one that the 
subject has not previously had a non-response to, in the current depressive episode, has not been 
previously intolerant to (lifetime), and is available in the participating country. 


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Dosing of the oral antidepressant will begin on Day 1 and follow a protocol specific titration 
schedule (Attachment 3). Doses are not to exceed the maximum dose defined in the titration 
schedule. If higher doses are not tolerated, a down-titration is permitted based on clinical judgment. 
Refer to the Time and Events Schedule for a list of study evaluations that will be performed during 
the double-blind treatment phase.
If a subject withdraws from the study before the end of the double-blind treatment phase for 
reasons other than withdrawal of consent, an Early Withdrawal visit should be conducted within 
1 week of the date of discontinuation, followed by the follow-up phase.
6.3.
Follow-up Phase (8-weeks or until relapse)
The follow-up phase will include all subjects who receive at least 1 dose of intranasal study 
medication in the double-blind treatment phase. No intranasal study medication will be
administered during this phase.
At the start of the follow-up phase, further clinical/standard of care for the treatment of depression 
will be arranged by the study investigator and/or the subject’s treating physician and medication 
changes are permitted. The decision to continue the oral antidepressant in this phase will be at the 
discretion of the investigator.
This follow-up phase will provide additional information required to assess the course of the 
subject’s major depressive episode over an 8-week period. Safety and tolerability, including 
potential withdrawal symptoms, following discontinuation of intranasal esketamine will also be 
assessed.
The follow-up phase is completed at the end of the 8-week period or when a subject meets criteria
below for relapse (in remitters and responders), whichever occurs earlier. 

Relapse is defined as any of the following:

MADRS total score ≥22 for 2 consecutive assessments separated by 5 to 15 days. The 
date of the second MADRS assessment will be used for the date of relapse.

Hospitalization for worsening depression or any other clinically relevant event 
determined per clinical judgment to be suggestive of a relapse of depressive illness such 
as suicide attempt, completed suicide, or hospitalization for suicide prevention. If 
hospitalized for any of these events, the start date of hospitalization will be used for the 
date of relapse. Otherwise the date of the event will be used if the subject is not 
hospitalized.

In case more than one relapse criteria are met, the earlier date will be defined as the date 
of relapse for this subject. 
The total duration of a subject’s study participation will be up to 19 weeks for subjects completing 
the follow-up phase.


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6.4.
Guidance on Blood Pressure Monitoring on Intranasal Treatment Session 
Days
Given the potential for treatment emergent transient elevation in systolic and diastolic blood 
pressure, the following guidance should be followed on intranasal dosing days:

If subsequent to fulfilling the inclusion and exclusion criteria on Day 1 (ie, applicable for all 
other intranasal treatment session days after Day 1), a subject’s pre-dose systolic blood 
pressure (SBP) is >140 mmHg and/or diastolic blood pressure (DBP) is >90 mmHg, it is 
recommended to repeat the blood pressure measurement after subject rests in sitting or 
recumbent position. If after rest and repeated measurements, pre-dose SBP is >140 mmHg 
and/or DBP is >90 mmHg, then dosing should be postponed, and the subject scheduled to 
return on the following day or within the given visit window. If the blood pressure elevation 
still persists on the next visit, the subject will be scheduled for a consultation by cardiologist, 
other specialist, or primary care physician, prior to further dosing.

If at any postdose time point on the dosing day, the SBP is ≥180 mmHg but <200 mmHg 
and/or the DBP is ≥110 mmHg but <120 mmHg, further intranasal dosing should be 
interrupted and the subject should be referred to a cardiologist, other specialist, or primary 
care physician for a follow-up assessment.

After the assessment by a cardiologist, other specialist, or primary care physician, if 
recommended by the referring doctor and considered appropriate according to the clinical 
judgment for the subject to continue in the study, the subject may continue with intranasal 
dosing if the pre-dose blood pressure at the next scheduled visit is within the acceptable 
range (see bullet point above).

If at any postdose time point on the dosing day the SBP is ≥200 mmHg and/or the DBP is 
≥120 mmHg, the subject must discontinue from further dosing and the subject should be 
referred to a cardiologist, other specialist or primary care physician for a follow-up 
assessment.
During the double-blind treatment phase, at 1.5 hours postdose, if the SBP is ≥160 mmHg and/or 
the DBP ≥100 mmHg, assessments should continue every 30 minutes until:

the blood pressure is <160 mmHg SBP and <100 mmHg DBP, or 

in the investigator’s clinical judgment, the subject it is clinically stable and can be discharged 
from the study site, or

the subject is referred for appropriate medical care, if clinically indicated, or

if the blood pressure remains ≥180 mmHg SBP and/or ≥110 mmHg DBP, 2 hours after dosing, 
the subject should be referred for immediate medical treatment.
7.
TREATMENT COMPLIANCE
The investigator or designated study-site personnel will maintain a log of all intranasal study drug 
and oral antidepressant medication dispensed and returned. Drug supplies for each subject will be 
inventoried and accounted for throughout the study.


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Subjects will receive instructions on compliance with the oral antidepressant treatment. During the 
course of the study, the investigator or designated study-site personnel will be responsible for 
providing additional instruction to re-educate any subject to ensure compliance with taking the 
oral antidepressant. A subject diary will be provided to capture oral antidepressant study 
medication use.
Antidepressant treatment adherence during the screening/prospective observational phase will be 
assessed using the PAQ. Missing ≥4 days of antidepressant medication in the prior 2-week period 
will be considered screen failed due to inadequate adherence.
Antidepressant treatment compliance during the double-blind treatment and follow-up phases will 
be assessed by performing pill counts (ie, compliance check) and drug accountability.
All doses of intranasal study drug will be self-administered by the subjects at the study site under 
the direct supervision of the investigator or designee and will be recorded.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy non-antidepressant therapies administered up to 30 days before the start of the 
screening/prospective observational phase must be recorded at the start of this phase.
All antidepressant treatment(s), including adjunctive treatment for MDD, taken during the current 
depressive episode (ie, including those taken more than 30 days prior to the start of the 
screening/prospective 
observational 
phase) 
will 
be 
recorded 
at 
the 
start 
of 
the 
screening/prospective observational phase. In addition, information will also be obtained regarding 
any history of intolerance to any of the 4 antidepressant choices (ie, duloxetine, escitalopram, 
sertraline, and venlafaxine XR). Antidepressant treatments which are not listed on the 
MGH-ATRQ but were used, or currently being used, as antidepressant treatment in the current 
depressive episode must be recorded in the ‘Concomitant Therapy’ eCRF.
Any medication that is listed on the MGH-ATRQ and is being taken at the start of the 
screening/prospective observational phase for an indication other than depression (eg, insomnia) 
should be continued during the screening/prospective observational phase but must be 
discontinued before the start of the double-blind treatment phase.
Concomitant therapies must be recorded throughout the study, beginning with signing of the 
informed consent and continuing up to the last visit. Information on concomitant therapies should 
also be obtained beyond this time only in conjunction with new or worsening adverse events until 
resolution of the event.
Subjects should continue to take their permitted concomitant medications (eg, antihypertensive 
medications) at their regular schedule; however, restrictions as outlined in Section 4.3
(Prohibitions and Restrictions) and Attachment 1, should be taken into account. Of note, if a 
subject has routinely taken his/her oral antihypertensive medications in the morning on dosing 
days, the morning dose should be taken prior to intranasal dosing.


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Subjects receiving psychotherapy (including cognitive behavioral therapy; CBT) can continue 
receiving psychotherapy; however, CBT must have been ongoing for the last 3 months prior to the 
start of the screening/prospective observational phase. With the exception of new CBT, which is 
prohibited, new psychotherapy is allowed during the study. Any change in existing therapy or new 
therapy must be documented on the concomitant therapies form.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; nonpharmacologic therapies, such as psychotherapy, electrical stimulation, 
acupuncture, special diets, and exercise regimens) different from the study drug must be recorded 
in the eCRF. Modification of an effective preexisting therapy should not be made for the explicit 
purpose of entering a subject into the study, unless permitted by protocol (eg, adjustment of blood 
pressure medications.
Rescue Medications
Rescue medications will not be supplied by the sponsor. In case of treatment-emergent adverse 
events that cannot be resolved by stopping further administration of intranasal esketamine/placebo, 
the following rescue medications may be considered:

For agitation or anxiety: As required, midazolam (maximum dose 2.5 mg orally or IM) or 
short acting benzodiazepine (eg, alprazolam, clorazepate, triazolam, lorazepam and
temazepam)

For nausea: As required, ondansetron 8 mg sublingually, metoclopramide (10 mg orally or IV 
or IM) or dimenhydrinate (25 to 50 mg, IV or IM)

Unless clinically indicated, it is recommended that transient increases in blood pressure not 
be treated, as the blood pressure typically returns to predose values in 2 hours. The effect of 
any treatment may result in hypotension.
Prohibited Medications
A list of prohibited medications is provided in Section 4.3 and Attachment 1 as general guidance 
for the investigator (but is not all inclusive).
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, PK, biomarker
and pharmacogenomics, health economic, and safety measurements applicable to this study.
                                                
Not applicable to China


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With the exception of postdose assessments, visit-specific subject-reported outcomes assessments 
should be conducted or completed before any tests, procedures, or other consultations for that 
clinic visit to prevent influencing subject perceptions. A recommended order of study procedures 
will be provided to sites as a separate document.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures 
be performed in the following sequence: Collection of urine samples for Clinical laboratory 
assessments and blood samples for PK assessments should be kept as close to the specified time 
as possible. Other measurements may be done earlier than specified timepoints if needed. Actual 
dates and times of assessments will be recorded in the source documentation and eCRF.
The approximate total blood volume to be collected will be 50 mL from each Chinese subject (34 mL 
for eligibility and safety, and 16 mL for PK) and 108.5 mL from each non-Chinese subject (34 mL 
for eligibility and safety, and 74.5 mL for biomarker) (Table 2). The biomarker blood sample 
including protein, DNA and RNA will only be collected from those subjects who give separate 
written informed consent to participate in the biomarker, pharmacogenomic (DNA) and expression 
(RNA) component of the study. Repeat or unscheduled samples may be taken for safety reasons or 
for technical issues with the samples. Additional serum or urine pregnancy tests may be performed, 
as determined necessary by the investigator or as required by local regulation, to establish the 
absence of pregnancy at any time during the subject's participation in the study.


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Table 2:
Volume of Blood to Be Collected from Each Subject
Type of Sample
Volume per 
Sample (mL)
No. of Samples 
per Subject
Total Volume of 
Blood (mL) a
Screening/Prospective Observational Phase
Serum chemistry b
2.5
1
2.5
TSH
3.5
1
3.5
Hematology
2
1
2
Biomarker: protein e
10
1
10
Biomarker: DNA e
6
1
6
Biomarker: RNA e
2.5
1
2.5
Tricyclic Antidepressant Blood level c
9
1
9
FT4 d
3.5
1
3.5
Double-blind Treatment Phase
Serum chemistry
2.5
2
5
Hematology
2
2
4
Pharmacokinetics f
4
4
16
Biomarker: protein e
10
3
30
Biomarker: DNA e
6
1
6
Biomarker: RNA e
2.5
3
7.5
Follow-up Phase
Serum chemistry
2.5
1
2.5
Hematology
2
1
2
Biomarker: protein e
10
1
10
Biomarker: RNA e
2.5
1
2.5
Approximate volume of blood collected during the study
124.5 mL g
Abbreviations: DNA, deoxyribonucleic acid; RNA: Ribonucleic Acid; FT4, free thyroxine; TSH, thyroid-stimulating hormone
a.
Calculated as number of samples multiplied by amount of blood per sample.
b.
Serum chemistry includes serum -hCG pregnancy tests (for women of childbearing potential) and lipid panel.
c.
For specific tricyclic antidepressants which are being taken at a dose below the MGH-ATRQ minimum therapeutic dose, a 
blood level that is within therapeutic (antidepressant) range, is acceptable to establish the adequacy of the antidepressant 
treatment.
d.
For any subject (regardless of thyroid history), if the TSH value is out of range, a free thyroxine (FT4) will be conducted.
e.
Only for subject who has consented to participate in the biomarker, pharmacogenomic (DNA) and expression (RNA) 
component of the study. This applies to US sites only, as not applicable for China.
f.
Only for Chinese subjects.
g.
50 mL for Chinese subjects and 108.5 mL for non-Chinese subjects.
Note: An indwelling IV cannula may be used for blood sample collection.
Note: Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
9.1.2.
Screening/Prospective Observational Phase
Prior to conducting any study procedure, the investigator (or designated study personnel) will 
review and explain the written ICF to each subject. After signing the ICF, subjects who are 18 (or 
older if the minimum legal age of consent in the country in which the study is taking place is >18) 
to 64 years of age (inclusive) will be screened to determine eligibility for study participation 
(please refer to the study entry criteria listed in Section 4). 
Subjects must meet DSM-5 diagnostic criteria for recurrent MDD or single-episode MDD, without 
psychotic features, based upon clinical assessment and confirmed by the MINI. An independent 
blinded rater will conduct the MADRS at screening as well as confirming the diagnosis and the 
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Treatment-resistant depression is defined as a lack of clinically meaningful improvement after 
treatment with at least 2 different antidepressant agents prescribed in adequate dose for adequate 
duration. At the start of the screening/prospective observational phase, subjects must have had 
non-response (ie, lack of clinically meaningful improvement, defined as ≤25% improvement) to 
≥1 but ≤5 (if current episode is >2 years or undefinable, upper limit is applicable to only the last 
2 years) oral antidepressant treatments taken at adequate dosage and for adequate duration, as 
assessed using the MGH-ATRQ and documented by records (eg, medical/ pharmacy/prescription 
records or a letter from treating physician, etc.) for the current episode of depression. In addition, 
at the start of the screening/prospective observational phase, the subject is taking a different oral 
antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or above the 
minimum therapeutic dose. This antidepressant treatment, as well as any other ongoing 
medications being taken for depression (including adjunctive/augmentation therapies), will 
continue from the start of Week 1 through the end of Week 4 of the screening/prospective 
observational phase to confirm non-response prospectively. Dose adjustment is permitted per 
clinical judgment, but the oral antidepressant treatment is to remain at or above the minimum 
therapeutic dose (per the MGH-ATRQ) through the end of Week 4. Antidepressant treatment 
adherence will be assessed using the PAQ. Subjects who report missing ≥4 days of antidepressant 
medication treatment(s) in the prior 2-week period will be considered as screen failed due to 
inadequate adherence.
After 4 weeks, subjects who are non-responders to the current oral antidepressant treatment (as 
assessed by independent, remote raters) may be eligible to proceed to the double-blind treatment 
phase. Non-response at the end of the screening/prospective observational phase is defined as 
≤25% improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total score 
of ≥28 on Week 2 and Week 4. 
Eligible subjects who are entering the double-blind treatment phase will discontinue all current 
medication(s) being taken for depression (including adjunctive/augmentative therapies), and any 
other prohibited psychotropic medications (including adjunctive atypical antipsychotics). Subjects 
taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of lorazepam) 
and/or permitted nonbenzodiazepine sleep medications (eg, zolpidem, zaleplon, eszopiclone and 
ramelteon) during the screening/prospective observational phase can continue these medications 
during the treatment phase. No dose increases beyond the equivalent of 6 mg/day of lorazepam or 
new benzodiazepine medications are permitted during the screening/prospective observational 
phase. If clinically indicated, a subject’s current antidepressant treatment(s) may be tapered and 
discontinued over an additional, optional period of up to 3 weeks per the local prescribing 
information or clinical judgment or discontinued and switched directly to one of the four new oral 
antidepressant medications on Day 1 of the double-blind treatment phase, per clinical judgment.
All other subjects who do not proceed to the double-blind treatment phase will end study 
participation at this time. No further study visits or follow-up is required.


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Optional Antidepressant Taper Period
Since all non-responder subjects will be starting a new oral antidepressant during the double-blind 
treatment phase, no washout or drug-free period is required after discontinuing the current 
antidepressant treatment. However, an additional, optional period of up to 3 weeks is permitted to 
taper and discontinue the current antidepressant treatment(s) after completion of the Week 4 
assessments, per the local prescribing information or clinical judgment. Subjects who do not 
require a taper are eligible to immediately proceed to the double-blind treatment phase.
The taper period should not start until after the completion of 4 weeks of prospective antidepressant 
treatment and assessment of the antidepressant treatment response.
9.1.3.
Double-Blind Treatment Phase
During this phase, all subjects will self-administer the intranasal study medication esketamine 
(56 mg or 84 mg) or placebo, at treatment sessions occurring twice a week for 4 weeks at the study 
site, using a flexible dosing regimen. Treatment is assigned by the Interactive Web Response 
System (IWRS). Table 1 in Section 6.2 describes how each treatment session will be administered 
in the double-blind treatment phase.
Approximately 234 eligible subjects (210 Chinese subjects, 24 non-Chinese subjects) with TRD,
will be randomly assigned at a 1:1 ratio (n = 117 subjects per treatment arm, with approximately 
105 Chinese subjects per arm) to receive double-blind treatment with either intranasal esketamine 
or intranasal placebo. The intranasal treatment sessions (esketamine 56 mg, esketamine 84 mg or 
placebo) will occur twice per week for 4 weeks as a flexible dose regimen at the study site.
In addition, all subjects will simultaneously initiate a new, open-label oral antidepressant (please 
refer to Section 6, Dosage and Administration), on Day 1, that will be taken daily for the duration 
of the double-blind treatment phase. The assigned oral antidepressant will be 1 of 4 oral 
antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine XR). The 
antidepressant medication assigned by the investigator (based on review of the MGH-ATRQ and 
relevant prior antidepressant treatment information) will be one that the subject has not previously 
had a non-response to in the current depressive episode, has not been previously intolerant to 
(lifetime), and is available in the participating country. 
Dosing of the oral antidepressant will begin on Day 1 and follow a protocol specific titration 
schedule (Attachment 3). The use of the titration schedule provided is mandatory. Doses are not 
to exceed the maximum dose defined in the titration schedule. If higher doses are not tolerated, a 
down-titration is permitted based on clinical judgment.
Subjects who were taking benzodiazepines (at dosages equal to or less than the equivalent of 
6 mg/day of lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, 
zaleplon, eszopiclone and ramelteon) during the screening/prospective observational phase can 
continue these medications 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 


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double-blind treatment phase, with the exception of the use of permitted benzodiazepine rescue 
medication (eg, alprazolam, clorazepate, triazolam, lorazepam and temazepam).
For information obtained via telephone contact, written documentation of the communication must 
be available for review in the source documents. During telephone contact visits with the subject 
by site personnel, adverse event and concomitant therapy information will be obtained. In addition, 
specified clinician-administered assessments will be performed by appropriately qualified staff.
At the end of the double-blind treatment phase, subjects will proceed into the follow-up phase.
Early Withdrawal
If a subject withdraws from the study before the end of the double-blind treatment phase for 
reasons other than withdrawal of consent, an Early Withdrawal visit should be conducted within 
1 week of the date of discontinuation, followed by the follow-up phase. If the Early Withdrawal
visit occurs on the same day as a scheduled visit, the early withdrawal visit can be performed on 
the same day and duplicate assessments are not required.
Further clinical/standard of care for the treatment of depression will be arranged by the study 
investigator and/or the subject’s treating physician. The study investigator and/or treating 
physician will determine whether or not the current oral antidepressant medication will continue.
9.1.4.
Follow-up Phase 
The follow-up phase will include all subjects who received at least 1 dose of intranasal study 
medication in the double-blind treatment phase. No intranasal study medication will be 
administered during this phase.
At the start of the follow-up phase, further clinical/standard of care for the treatment of depression 
will be arranged by the study investigator and/or the subject’s treating physician and medication 
changes are permitted. The decision to continue the antidepressant will be at the discretion of the 
investigator. If the subject continues to receive the same antidepressant medication for the duration 
of the follow-up phase, then the antidepressant will be sourced by the sponsor.
This follow-up phase will provide additional information required to assess the course of the 
subject’s major depressive episode over an 8-week period. Safety and tolerability, including 
potential withdrawal symptoms, following discontinuation of intranasal esketamine will be
assessed. 
The follow-up phase is completed at the end of the 8-week period or when a subject meets criteria 
below for relapse (in remitters and responders), whichever occurs earlier.
Relapse is defined as any of the following:

MADRS total score ≥22 for 2 consecutive assessments separated by 5 to 15 days. The date of 
the second MADRS assessment will be used for the date of relapse.


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
Hospitalization for worsening depression or any other clinically relevant event determined per 
clinical judgment to be suggestive of a relapse of depressive illness such as suicide attempt, 
completed suicide, or hospitalization for suicide prevention. If hospitalized for any of these 
events, the start date of hospitalization will be used for the date of relapse. Otherwise the date 
of the event will be used if the subject is not hospitalized.

In case more than one relapse criteria are met, the earlier date will be defined as the date of 
relapse for this subject. 
The total duration of a subject’s study participation will be up to 19-weeks (including an optional 
3-week taper period) for subjects completing the 8-week follow-up phase.
Clinic visits and remote assessment visits will be performed as specified in the Time and Events 
Schedule. 
Telephone contact or clinic visit will be made to determine safety and efficacy assessments and 
any reported adverse events every week for up to 8 weeks after the last dose of study drug, unless 
the subject has died, is lost to follow-up, or has withdrawn consent. If the information is obtained 
via telephone contact, written documentation of the communication must be available for review 
in the source documents. If the subject has died, the date and cause of death will be collected and 
document on 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 endpoint is reached. All 
adverse events and special reporting situations, whether serious or non-serious, will be reported 
until completion of the subject's last study-related procedure.
9.2.
Efficacy Evaluations
9.2.1.
Evaluations
It is recommended that the various subject-reported outcome assessments be completed prior to 
other procedures.
9.2.1.1.
Primary Efficacy Evaluation 
The primary efficacy evaluation will be the MADRS total score. The MADRS will be performed 
by independent remote raters during the study. The Structured Interview Guide for the 
Montgomery Asberg Depression Rating Scale (SIGMA: Williams 2008)76 will be used for each 
administration. 
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 
possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates 
apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability 
to feel (interest level), pessimistic thoughts, and suicidal thoughts. The test exhibits high inter-rater 
reliability. The MADRS has been validated in Chinese subjects with MDD.81


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The typical recall period for the MADRS is 7 days and will be used for the primary efficacy 
evaluation.
9.2.1.2.
Key Secondary Efficacy Evaluation 
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
The MADRS will also be administered using a modified recall period of 24 hours for the key 
secondary efficacy evaluation related to change from baseline to 24 hours. The feasibility of this 
shortened recall period has been confirmed with patients, and physicians, and there are data 
supporting the psychometric properties of this shortened recall period (data on file). 
Sheehan Disability Scale (SDS)
The SDS will be used to assess the secondary objective of functional impact and associated 
disability. The SDS is a subject-reported outcome measure that consists of a 5-item questionnaire 
which has been widely used and accepted for assessment of functional impairment and associated 
disability.41,67 The first three items assess disruption of (1) work/school, (2) social life, and 
(3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items 
are summed to create a total score of 0-30 where a higher score indicates greater impairment. It 
also has one item on days lost from school or work and one item on days when underproductive. 
The recall period for this study is 7 days.
9.2.1.3.
Other Secondary Efficacy Evaluations 
9.2.1.3.1.
Other Secondary Efficacy Evaluations (Clinician-completed)
Clinical Global Impression–Severity (CGI-S)
The CGI-S provides an overall clinician-determined summary measure of the severity of the 
subject’s illness that takes into account all available information, including knowledge of the 
subject’s history, psychosocial circumstances, symptoms, behavior, and the impact of the 
symptoms on the subject’s ability to function.27 The CGI-S evaluates the severity of 
psychopathology on a scale of 0 to 7. Considering total clinical experience, a subject is assessed 
on severity of mental illness at the time of rating according to: 0=not assessed; 1=normal (not at 
all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 
7=among the most extremely ill patients. The CGI-S permits a global evaluation of the subject’s 
condition at a given time.
9.2.1.3.2.
Other Secondary Efficacy Evaluations (Patient-reported Outcomes)
Generalized Anxiety Disorder (GAD-7)
The 7-item subject-reported GAD-7 will be used to measure the secondary objective of symptoms 
of anxiety. The GAD-7 is a brief and validated measure of overall anxiety. Each item is rated on a 
4-point scale (0=not at all; 1=several days; 2=more than half the days; 3=nearly every day).69 Item 
responses are summed to yield a total score (range of 0 to 21), with higher scores indicating more 
anxiety. The recall period is 2 weeks.


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EuroQol-5 dimension-5 level (EQ-5D-5L)
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily 
designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and 
the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L descriptive system comprises the 
following 
5 
dimensions: 
Mobility, 
self-care, 
usual 
activities, 
pain/discomfort 
and 
anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems 
(Level 1 indicating no problem, Level 2 indicating slight problems, Level 3 indicating moderate 
problems, Level 4 indicating severe problems, and Level 5 indicating extreme problems).
The subject selects an answer for each of the 5 dimensions considering the response that best 
matches his or her health “today.” The descriptive system can be represented as a health state. The 
EQ-VAS self-rating records the respondent’s own assessment of his or her overall health status at 
the time of completion, on a scale of 0 to 100. 
The time taken to complete the questionnaire varies with age, health status, and setting but is likely 
to be around 1 minute.
9.3.
Pharmacokinetics (Chinese subjects only)
Whole blood samples will be used to evaluate the PK of esketamine (JNJ-54135419). Plasma 
collected for PK may additionally be used to evaluate safety or efficacy aspects that address 
concerns arising during or after the study period. Genetic analyses will not be performed on these 
blood samples. Subject confidentiality will be maintained.
9.3.1.
Evaluations 
Venous blood samples of approximately 4 mL will be collected from Chinese subjects at all 
clinical sites, for measurement of plasma concentrations of esketamine (JNJ-54135419), (and other 
metabolites, if warranted), at the time points specified in the Time and Events Schedule. The exact 
dates and times of PK blood sampling must be recorded.
9.3.2.
Analytical Procedures
Pharmacokinetics
Serial pharmacokinetic blood samples (4 mL, each) will be collected from Chinese subjects at all 
study sites, at the time points specified in the Time and Events Schedule. Concentration time data 
will allow estimation of individual PK parameters for esketamine using a population PK modeling 
approach. The exact dates and times of PK blood sampling must be recorded. Plasma samples will 
be analyzed to determine concentrations of esketamine using a validated, specific, and sensitive 
liquid chromatography-tandem mass spectrometry (LC-MS/MS) method by or under the 
supervision of the sponsor. If required, some plasma samples may be analyzed to document the 
presence of other analytes (eg, circulating metabolites or denatonium) 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 clinical study report as an appendix.


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9.3.3.
Pharmacokinetic Parameters
The plasma concentration-time data of esketamine will be analyzed using population PK modeling. 
Typical population values of basic PK parameters (eg, esketamine clearance and distribution 
volumes) will be estimated together with the inter-individual variability. Effects of subject 
demographics, laboratory parameter values, and other covariates on the PK of esketamine will be 
explored. The results of the population PK analyses may be reported separately. 
9.4.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations
During the study, blood will be collected for the assessment of biomarkers at the time points 
indicated in the Time and Events schedule. The biomarker blood samples should be collected prior 
to dosing. It is preferred that subjects adhere to a low-fat diet on the day of sample collection.
In blood, biomarkers (protein, metabolite, and ribonucleic acid [RNA]) related to (but not limited 
to) the immune system activity, hypothalamus pituitary adrenal (HPA) axis activation, 
neurotrophic factors, and metabolic factors will be investigated. Biomarkers may be added or 
deleted based on scientific information or technical innovations under the condition that the total 
volume of blood collected will not be increased.
The biomarker data obtained from this study may also be included in an ongoing cross-study 
analysis to investigate the relationship between depression severity and phenotypes and 
biomarkers.
Blood samples for DNA analyses will be collected at the time points indicated in the Time and 
Events Schedule for the assessment of genetic and epigenetic variation in genes in pathways 
relevant to depression (eg, HPA axis, inflammation, growth factors, monoamine transporters, ion 
channels, and circadian rhythm).
Genotyping will be conducted only on the screening sample; pharmacogenomic and epigenetic 
evaluations may be performed on any/all collected samples.
DNA samples will be used for research related to esketamine, oral antidepressants, TRD, or MDD. 
They may also be used to develop tests/assays related to esketamine, oral antidepressants, TRD, 
or MDD. Pharmacogenomic research may consist of the analysis of 1 or more candidate genes or 
of the analysis of genetic markers throughout the genome (as appropriate) in relation to 
esketamine, oral antidepressants, TRD, or MDD clinical endpoints.
Further information regarding handling, shipment, and labeling of biological samples will be 
provided in a separate laboratory manual.
                                                

Not applicable to China


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9.5.
Safety Evaluations
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event 
section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be 
followed by the investigator until resolution or until a clinically stable endpoint is reached.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule.
There may be instances where a subject has started a scheduled clinic visit in which an intranasal 
treatment session is planned, but due to predose vital sign measurements (eg, blood pressure 
value), a decision has been made to postpone/delay the intranasal treatment session within the visit 
window permitted per protocol. In such cases, all time points (including predose) of the following 
assessments must be repeated on the actual intranasal treatment session day: vital sign (ie, blood 
pressure, pulse, respiratory rate, and temperature), 12-lead ECG, C-SSRS (since last visit), pulse 
oximetry, and CADSS.
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or 
the subject's legally acceptable representative) for the duration of the study. Adverse events will 
be followed by the investigator as specified in Section 12, Adverse Event Reporting.
TEAEs of special interest will be examined separately (please refer to Section 3.2.6, Safety 
Evaluations and Section 11.6, Safety Analyses).
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and a urine sample for urinalysis will be 
collected. The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the adverse event section of the eCRF. 
The laboratory reports must be filed with the source documents.
The use of local laboratories is allowed in cases where initiation of treatment or safety follow-up 
is time-critical and the central laboratory results are not expected to be available before the need 
to begin dosing or if actions need to be taken for safety reasons.
The following tests will be performed by the central laboratory, unless noted otherwise:

Hematology Panel
-hemoglobin
-platelet count
-hematocrit
-red blood cell (RBC) count
-white blood cell (WBC) count with differential


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
Serum Chemistry Panel
-sodium
-alkaline phosphatase
-potassium
-creatine phosphokinase (CPK)
-chloride
-calcium
-bicarbonate
-phosphate
-blood urea nitrogen (BUN)
-albumin
-creatinine
-total protein
-glucose
-total bilirubin
-aspartate aminotransferase (AST)
-alanine aminotransferase (ALT)
-gamma-glutamyltransferase (GGT)

Urinalysis
Dipstick
Sediment (if dipstick result is abnormal)
-specific gravity
-red blood cells
-pH
-white blood cells
-glucose
-epithelial cells
-protein
-crystals
-blood
-casts
-ketones
-bacteria
-bilirubin
-urobilinogen
-nitrite
-leukocyte esterase
If dipstick result is abnormal, flow cytometry or microscopy will be used to measure 
sediment. In case of discordance between the dipstick results and the flow cytometric 
results, the sediment will be examined microscopically.
The following tests will be done at time points specified in the Time and Events Schedule or as 
required based on subject status (noted below): 

Serum and urine pregnancy testing (for women of childbearing potential only)

Urine Drug Screen: barbiturates, methadone, opiates, cocaine, cannabinoids (cannabinoids are 
only tested at Day 1 predose), phencyclidine, and amphetamine

at the start of the Screening/Prospective Observational Phase: barbiturates, methadone, 
opiates, cocaine, phencyclidine, and amphetamine

on Day 1 of the Double-blind Treatment Phase prior to randomization: cannabinoids, 
methadone, opiates, cocaine, and amphetamine

on Day 15 and 25 of the Double-blind Treatment Phase: cocaine

Alcohol breath test 

Thyroid-stimulating hormone (TSH)

Free thyroxine (FT4), only if required for abnormal TSH (refer to Inclusion criteria)


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
Calculation of creatinine clearance

Glycated hemoglobin (HbA1c) test

A serum follicle stimulating hormone (FSH) level test, only if required for documentation that 
a female subject is not of childbearing potential (refer to Inclusion Criteria No. 8)
Single, 12-Lead ECG
During the collection of ECGs, subjects should be in a quiet setting without distractions 
(eg, television, cell phones). Subjects should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs.
All ECG tracings will be sent to a central ECG laboratory. The ECGs will be read at the scheduled 
time points and summarized by a central ECG laboratory. The central ECG laboratory will send 
the sponsor an electronic copy of the data for inclusion in the clinical database. In addition, the 
investigator or sub-investigator is required to review all ECGs at the study visit to assess for any 
potential safety concerns or evidence of exclusionary conditions.
A subject must be discontinued from at any time point after baseline (Day 1, predose) if:

QTcF change from baseline is ≥60 msec AND QTcF >480 msec, or

QTCF >500 msec.
Vital Signs (temperature, pulse/heart rate, respiratory rate, 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, please see Guidance on Blood Pressure Monitoring 
on Intranasal Dosing Days (Section 6.4).
Tympanic temperature is recommended.
An automated device will be used for measurement of respiratory rate.
Pulse Oximetry
Pulse oximetry will be used to measure arterial oxygen saturation. On each dosing day, the device 
will be attached to the finger, toe, or ear before the first nasal spray and then, after the first spray 
it will be monitored and documented. Any arterial oxygen saturation (SpO2) <93% should be
confirmed by an additional measurement on another part of the body.


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On intranasal treatment session days, pulse oximetry will be recorded every 15 minutes from 
predose to t=1.5 hours postdose. If oxygen saturation levels are <93% at any time during the 
1.5-hour postdose interval, pulse oximetry will be recorded every 5 minutes until levels return to 
≥93% or until the subject is referred for appropriate medical care, if clinically indicated.
Physical Examination, Height, Body Weight
Physical examinations, body weight, and height will be performed/ measured as per the Time and 
Events Schedule.
Nasal Examinations 
Nasal examinations (including the upper respiratory tract/throat) will be conducted by a qualified 
healthcare practitioner. The objective of the examination at screening is to rule out any subjects 
with anatomical or medical conditions that may impede drug delivery or absorption. 
Subsequent examinations will consist of a visual inspection of the nostrils, nasal mucosa, and 
throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption, and epistaxis, and 
will be graded as follows: Absent, mild, moderate, or severe. 
C-SSRS
The C-SSRS will be performed 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.54 It is a clinical interview 
providing a summary of both suicidal ideation and behavior that can be administered during any 
evaluation or risk assessment to identify the level and type of suicidality present. The C-SSRS can 
also be used during treatment to monitor for clinical worsening.
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 time points (“lifetime” and “in the past 6 months”) and suicidal behavior will be assessed at 
2 time points (“lifetime” and “in the past year”). All subsequent C-SSRS assessments in this study 
will use the Since Last Visit version, which will assess suicidal ideation and behavior since the 
subject’s last visit.
CADSS
The CADSS is an instrument for the measurement of present-state dissociative symptoms,3 and 
will be administered to assess treatment-emergent dissociative symptoms.3
The CADSS consists of 23 subjective items, divided into 3 components: Depersonalization 
(Items 3 to 7, 20, and 23), derealization (Items 1, 2, 8 to 13, 16 to 19, and 21) and amnesia 
(Items 14, 15, and 22). Participant’s responses are coded on a 5-point scale (0=not at all through 
to 4=extremely). CADSS has excellent inter-rater reliability and internal consistency. 


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PWC-20
The PWC-20 will be administered to assess potential withdrawal symptoms following cessation 
of intranasal esketamine treatment. An assessment will be performed on Day 25 to establish a 
baseline prior to discontinuation of intranasal esketamine treatment. In order to better assess 
potential withdrawal symptoms from the intranasal medication it is recommended that the oral 
antidepressant medication be continued for at least the first 2 weeks of the follow up phase unless 
determined as not clinically appropriate.
The PWC-20 is a 20-item simple and accurate method to assess potential development of 
discontinuation symptoms after stopping of study drug. The PWC-20 is a reliable and sensitive 
instrument for the assessment of discontinuation symptoms.61 Discontinuation symptoms occur 
early and disappear rather swiftly, depending upon speed of taper, daily medication dose, and drug 
elimination half-life.
9.6.
Other Evaluations
MINI
Subjects will undergo MINI (a brief, structured diagnostic interview) to confirm the diagnosis of 
MDD and to determine if there are other psychiatric conditions present. It has an administration 
time of approximately 15 minutes.
MGH-ATRQ
The MGH-ATRQ is used to determine treatment resistance in MDD.14
The MGH-ATRQ evaluates the adequacy of duration and dosage of all antidepressant medications 
used for the current major depressive episode. In addition, the MGH-ATRQ assesses the degree of 
improvement on a scale from 0% (not improved at all) to 100% (completely improved). The MGH-
ATRQ will be completed by the clinician in collaboration with the subject.
Clinical Validation Inventory for Study Admission 
Independent psychiatrists/psychologists will perform the Clinical Validation Inventory for Study 
Admission (C-VISA) in the screening/prospective observational phase for all subjects to confirm 
diagnosis of depression and eligibility for the study.70
Further information regarding this assessment will be provided to sites in a separate document.
PAQ
Subjects’ 
adherence 
to 
their 
oral 
antidepressant 
treatment 
regimen 
during 
the 
screening/prospective observational phase will be assessed using the PAQ. It is a brief, 2-item 
subject-report outcome measure that was developed at the University of Texas Southwestern 
Medical Center to assess how often the subject has taken, and whether he or she has made any 
changes to his/her antidepressant treatment regimen in the last 2 weeks. The total score is based 
on the response selected to Question 1 and is interpreted as 0 to 1 =adherent and 2 or 
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9.7.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. If blood samples are collected via an indwelling cannula, an appropriate amount 
(1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock will be 
removed from the cannula and discarded before each blood sample is taken. After blood sample 
collection, the cannula will be flushed with 0.9% sodium chloride, United States Pharmacopeia 
(USP) (or equivalent) and charged with a volume equal to the dead space volume of the lock.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the double-blind treatment phase of the study if he 
or she has completed the MADRS assessment at the end of the 4-week double-blind treatment 
phase (ie, Day 28 MADRS).
Subjects who prematurely discontinue study treatment for any reason before completion of the 
double-blind treatment phase will not be considered to have completed the double-blind treatment 
phase of the study.
Subjects who enter the follow-up phase will be considered to have completed this phase of the 
study if he or she has completed the MADRS assessment at Week 8 of the follow-up phase, or 
when the subject meets criteria for relapse (in remitters and responders), whichever occurs earlier.
10.2.
Discontinuation of Study Treatment or Withdrawal from the Study
Discontinuation of Study Treatment
A subject will not be automatically withdrawn from the study if he or she has to discontinue 
treatment before the end of the treatment regimen.
A subject's study treatment must be discontinued if:

The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the subject to discontinue study treatment

The subject becomes pregnant 
If a subject discontinues study treatment for any reason before the end of the double-blind phase 
(including either treatment with intranasal study drug or oral antidepressant), an early withdrawal 
visit should be conducted within 1 week of the date of discontinuation, followed by progression to 


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the 8-week follow-up phase. End-of-treatment assessments should be obtained during the early 
withdrawal visit, and scheduled assessments should be continued during the follow-up phase.
Withdrawal from the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent (Note: See “Withdraw of Consent” section below; this should only be 
selected as a reason for withdrawal if the subject does not agree to any further study 
assessments or procedures. If the subject is agreeable to participating in the Early Withdrawal 
visit and the follow-up phase, another reason for withdrawal should be selected.)

Violation of protocol procedures (determined on a case-by-case basis)

Blind is broken (double-blind treatment phase)

Lack of efficacy

The investigator or sponsor believes (eg, that for safety or tolerability reasons such as an 
adverse event) it is in the best interest of the subject to discontinue the study. See also guidance 
on blood pressure monitoring on intranasal dosing days (Section 6.4).

At any time point after baseline (Day 1, predose), the subject has a:

QTcF change from baseline 60 msec AND QTcF >480 msec, or

QTcF >500 msec.

Subject becomes pregnant

Death
If the subject withdraws from the study before the end of the double-blind treatment phase, an 
Early Withdrawal visit is to be performed, followed by the follow-up phase.
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. This should include
at least 3 telephone calls, certified letters, email requests, etc. To ensure access to follow-up 
subjects, the study sites should attempt to obtain both primary and secondary telephone contact 
numbers (eg, home, work, and mobile phone numbers), as well as other contact information 
(eg, email addresses) from subjects before randomization. In addition, the study site should 
emphasize the importance of follow-up information to the subject before randomization. The 
measures taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Subjects who withdraw will not be replaced.
Withdrawal of Consent
Every effort will be made in the study to ensure withdrawal of consent is not selected as a reason 
for discontinuation when in fact the subject withdrew for an identifiable reason (eg, due to an 
adverse event or withdrew due to lack of efficacy).


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Subjects who wish to withdraw from the study should be asked if they are agreeable to continue 
to an early withdrawal visit (if withdrawing from the double-blind treatment phase) and the follow-
up phase, or to be contacted to collect follow-up information. Subjects who are not agreeable to 
follow-up contact will be withdrawn from the study as “withdrawal of consent.” Subjects who no 
longer wish to take study drug but agree to provide follow-up information will be withdrawn from 
the double-blind treatment phase with the reason noted as “Other” and will specify the reason why.
For a subject who does “withdrawal of consent”, it is recommended that the subject withdraw 
consent in writing; if the subject refuses or is physically unavailable, the study site should 
document and sign the reason for the subject’s failure to withdraw consent in writing and maintain 
it with the subject’s source records.
The investigator will be responsible for making all required notifications to the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC).
10.3.
Withdrawal from the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, Long 
Term Retention of Samples for Additional Future Research). In such a case, samples will be 
destroyed after they are no longer needed for the clinical study. Details of the sample retention for 
research are presented in the main ICF.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan. 
11.1.
Subject Information
For all subjects who receive at least 1 dose of study drug, descriptive statistics will be provided.
The primary efficacy and safety analysis sets are defined below:
Full Analysis Set: All randomized subjects who receive at least 1 dose of intranasal study 
medication and 1 dose of oral antidepressant in the double-blind treatment phase.
Safety Analysis Set: All randomized subjects who receive at least 1 dose of intranasal study 
medication or 1 dose of oral antidepressant in the double-blind treatment phase.
The efficacy and safety analyses in the double-blind treatment phase will be based on the full 
analysis set and safety analysis set, respectively. Follow-up analysis set which includes all subjects 
who enter follow-up phase will be used for both efficacy and safety analyses in the follow-up 
phase. 
Subjects who discontinue treatment will continue to the follow-up phase.


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Subjects who discontinue treatment but continue with the study assessments will be included in 
the full analysis, safety analysis and follow-up analysis sets and analyzed separately.
11.2.
Sample Size Determination
Assuming a treatment difference for the double-blind phase of 6.5 points in MADRS total score 
between esketamine plus oral antidepressant compared with oral antidepressant plus intranasal 
placebo at the Week 4 endpoint, a standard deviation of 12, a one-sided significance level of 0.025, 
and a drop-out rate of 25%, approximately 117 subjects will be randomized to each treatment arm
to achieve greater than 90% power, and a sample size of 105 Chinese subjects per treatment arm 
(total n = 210) plus 12 non-Chinese subjects per treatment arm (total of n = 24) will be included.
The treatment difference and standard deviation used in this calculation were based on results from 
Panel A of the ESKETINTRD2003 study10 and based on clinical judgment.
11.3.
Efficacy Analyses 
Efficacy analyses will be performed on the full analysis set, which will include all randomized 
subjects who receive at least 1 dose of intranasal study drug and 1 dose of oral antidepressant 
medication, in the double-blind treatment phase.
Primary Endpoint
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined 
by the following 4 components:

Population: subjects with treatment-resistant depression;

Variable: change from Day 1 to end of 4-week double-blind treatment phase;

Intervention Effect: the effect of the initially randomized treatment together with the oral 
antidepressant medication that would have been observed had all subjects remained on 
their treatment throughout the double-blind treatment phase;

Summary Measure: the difference in variable means.
The primary analysis will be based on the full analysis set and the MADRS total scores collected 
during the double-blind treatment phase.
For the primary efficacy analysis, change from baseline in MADRS total score at Week 4 in the 
double-blind treatment phase will be analyzed using a mixed-effects model for repeated measures 
(MMRM). The model will include baseline MADRS total score as a covariate, and treatment,
country, class of antidepressant (Serotonin and Norepinephrine Reuptake Inhibitors [SNRI] or 
Selective Serotonin Reuptake Inhibitor [SSRI]), day, and day-by-treatment interaction as fixed 
effects. Comparison of the esketamine plus oral antidepressant arm to the active comparator (oral 
antidepressant plus intranasal placebo) arm will be performed using the appropriate contrast. 
Missing data will be closely monitored and additional sensitivity analysis for the primary efficacy 
endpoint to assess the robustness of the results to missing data might be performed. The detailed 
assumptions and methods will be provided in the statistical analysis plan (SAP), if necessary.


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Secondary Endpoints
For the analysis of the first of the two key secondary efficacy endpoints, change from baseline in 
MADRS total score at 24 hours post first dose (Day 2), will be analyzed using the same model 
described above for the MADRS total score at Week 4 in the double-blind treatment phase.
The second key efficacy endpoint, change from baseline in SDS total score at Week 4 in the 
double-blind treatment phase, will be analyzed using the same models described above for the 
MADRS total score.
To strongly control Type I error across the primary and the two key secondary efficacy endpoints, 
a fixed sequence approach15,16 will be applied to adjust for multiplicity. The hypotheses will be 
tested sequentially in the following order:

Change in MADRS total score at the end of the 4-week double-blind treatment phase

Change in MADRS total score at 24 hours post first dose

Change in SDS total score
Further details of this approach will be provided in the SAP.
The proportion of subjects showing onset of clinical response by Day 2 (in the event that no 
MADRS was collected on Day 2, a MADRS collected on Day 3 could be used) that is maintained 
for the duration of the double-blind treatment phase (≥50% reduction in MADRS total score by 
the second day after taking the first dose of double-blind medication that continued through the 
end of the double-blind phase) in esketamine arm will be compared with the active comparator 
using a Cochran-Mantel-Haenszel chi-square test adjusting for country and class of antidepressant 
(SNRI or SSRI). Subjects who discontinued the study prior to the end of the double-blind treatment 
phase will not be considered to have maintained clinical response.
Response and remission rates will be summarized at each visit.
The proportion of subjects who remain in remission through to the end of the follow-up phase will 
be presented. 
Change from baseline in GAD-7 total scores at the end of the 4-week double-blind treatment phase 
will be analyzed using an ANCOVA model, with treatment, country and class of antidepressant 
(SNRI or SSRI) as factors, and the respective baseline score as the covariate.
Ranks of change from baseline in CGI-S scores during the 4-week double-blind treatment phase 
will be analyzed using the MMRM for repeat measures, as described for the MADRS and SDS 
total scores. Additional analysis method for CGI-S will be used if necessary and the details will be 
provided in the SAP.
Dimension scores of EQ-5D-5L descriptive system, health status index, and the overall health 
status score will be summarized over time.


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Additionally, scores of all efficacy endpoints will be summarized for all visits in the double-blind 
period. Summaries will be provided to show consistency of effect among relevant subgroups 
(eg, antidepressant class SSRI [escitalopram, sertraline] and SNRI [duloxetine, venlafaxine]).
For subjects who receive esketamine during the double-blind treatment phase, the proportion of 
subjects who relapse during the follow-up phase will be summarized separately for subjects who 
are remitters (MADRS ≤12 at the end of the double-blind phase) and for subjects who are 
responders but not remitters (≥50% reduction in MADRS total score, but MADRS ˃12 at the end 
of the double-blind phase). In addition, the time to relapse during the follow-up phase will be 
estimated by the Kaplan-Meier method separately for subjects who are remitters, and subjects who 
are responders but not remitters. Descriptive statistics (number of relapses, number of censored 
subjects, and median, 25th, and 75th percentile of time to relapse, if estimable) will be provided.
11.4.
Pharmacokinetic Analyses
Plasma esketamine concentrations will be listed for all Chinese subjects. The plasma 
concentration-time data of esketamine will be analyzed using population PK modeling. Data may 
be combined with those of other selected studies to support a relevant structural model. Typical 
population values of basic PK parameters will be estimated together with the inter-individual 
variability. Additional pharmacokinetic parameters, such as post hoc estimates of Cmax and AUC,
may be calculated if deemed appropriate. Effects of subject demographics, laboratory parameter 
values, and other covariates on the PK of esketamine will be explored. The results of the population 
PK analyses may be reported separately.
11.5.
Biomarker and Pharmacogenomic Analyses
Baseline biomarker values and changes from baseline biomarker values to the time points specified 
in the Time and Events Schedule will be summarized if available number is sufficient for analyses. 
Exploratory analyses may include comparison of biomarker measures between the treatment 
groups and correlation with baseline and change from baseline biomarker values in the efficacy 
and other measures. Additional exploratory analyses may also include relationship of baseline and 
change from baseline in biomarker measures to clinical response, maintenance/stabilization of 
response, relapse, and non-response.
Pharmacogenomic analyses may include candidate gene analyses or genome-wide association 
analyses in relation to treatment response, maintenance/stabilization of response, relapse, non-
response, and MDD/TRD. Expression analyses may include testing of known messenger 
RNA/microRNA (mRNA/miRNA) transcripts or transcriptome-wide analysis in relationship to 
antidepressant treatment response and MDD/TRD.
Details of the analysis plan and summary of results from both biomarker and pharmacogenomics 
analyses will be reported separately.
                                                

Not applicable to China


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11.6.
Safety Analyses
Safety data will be analyzed for the double-blind treatment phase using the safety analysis set. The 
safety data from the follow-up phase will be summarized separately.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse events 
(TEAEs) are adverse events with onset during the treatment phase or that are a consequence of a 
pre-existing condition that has worsened since baseline. All reported adverse events will be 
included in the analysis. For each adverse event, the percentage of subjects who experience at least 
1 occurrence of the given event will be summarized by treatment group. In addition, comparisons 
between treatment groups will be provided if appropriate. Adverse events occurring in the follow-
up phase will be summarized separately.
TEAEs of special interest will be examined separately (please refer to Section 3.2.6) AEs of special 
interest will be further listed in the SAP.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and 
at each scheduled time point in each phase of the study. Changes from baseline results will be 
presented. Frequency tabulations of the abnormalities will be provided. Listings of subjects with 
laboratory results outside the reference ranges and markedly abnormal results will also be 
provided.
ECG
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. These tables will include observed values and change from baseline values.
Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will be 
calculated at baseline and for observed values and changes from baseline at each scheduled time 
point. Frequency tabulations of the abnormalities will be made.
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, and 
QTc interval using the following correction methods: QT corrected according to Bazett's formula 
(QTcB) and QTcF.2,32,64 Descriptive statistics of QTc intervals and changes from double-blind 
baseline will be summarized at each scheduled time point. The percentage of subjects with QTc 
interval >450 msec, >480 msec, or >500 msec will be summarized, as will the percentage of 
subjects with QTc interval increases from baseline <30 msec, 30-60 msec, or >60 msec.


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All important abnormalities in ECG waveform that are changes from the baseline readings will be 
reported (eg, changes in T-wave morphology or the occurrence of U-waves).
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, pulse oximetry, and blood 
pressure (systolic and diastolic) (supine) values and changes from baseline will be summarized at 
each scheduled time point. The percentage of subjects with values beyond clinically important 
limits will be summarized.
Nasal Examination
Changes in findings from the baseline nasal examination (including the upper respiratory 
tract/throat) will be listed by treatment group. Examinations will provide ratings (absent, mild, 
moderate, or severe) that are based on a visual inspection of the nostrils, nasal mucosa, and throat 
for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption and epistaxis. A shift 
table for changes from double-blind baseline in ratings for each examination will be presented by 
treatment group.
C-SSRS 
Suicide-related thoughts and behaviors based on the C-SSRS will be summarized by treatment 
group in incidence and shift tables. Separate endpoints for suicidal ideation and suicidal behavior 
will be defined and summarized descriptively by treatment group. Missing scores will not be 
imputed. 
CADSS 
Descriptive statistics of each score and changes from predose will be summarized at each 
scheduled time point.
PWC-20
Descriptive statistics of each score and changes and/or percent changes from baseline will be 
summarized at each scheduled time point.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.


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12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product (definition per International 
Conference on Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and 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 (for example, the subject was at risk of death at the time of the event. “Life 
threatening” does not refer to an event that hypothetically might have caused death if it were 
more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is medically important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
usually be considered serious.


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If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must be 
reported as a serious and unexpected suspected adverse reaction even if it is a component of the 
study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For esketamine, the expectedness of an adverse event will 
be determined by whether or not it is listed in the Reference Safety Information Section of the 
Investigator's Brochure.34
For duloxetine, escitalopram, sertraline, and venlafaxine XR, the expectedness of an adverse event 
will be determined by whether or not it is listed in the SmPC or US prescribing 
information.17,18,21,22,65,66,71,72
Adverse Event Associated with the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed under Attribution Definitions in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant drug(s), 
concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in 
time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).


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12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to the 
sponsor study drug, eg, name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until completion of the subject's last study-related 
procedure (which may include contact for follow-up of safety), with the exception of pregnancy 
which will be reported up to 6 weeks after the last dose of study medication (females) or 90 days 
after the last dose of study medication (partners of male participants). Serious adverse events, 
including those spontaneously reported to the investigator, must be reported using the Serious 
Adverse Event Form. The sponsor will evaluate any safety information that is spontaneously 
reported by an investigator beyond the time frame specified in the protocol.
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. Anticipated events will be 
recorded and reported as described in Attachment 4.


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All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the eCRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. A SUSAR will be reported to regulatory 
authorities unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR 
summary, unless otherwise specified.
For all studies with an outpatient phase, including open-label studies, the subject must be provided 
with a "wallet (study) card" and instructed to carry this card with them for the duration of the study 
indicating the following: 

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site and 
transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious adverse 
event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the subject's participation in the study, must be followed until any of the 
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
The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to study 
conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious 
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs 
during the course of a subject's participation in a study must be reported as a serious adverse event, 
except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such 
as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the eCRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.

For convenience the investigator may choose to hospitalize the subject at times during the 
treatment period.
The cause of death of a subject in a study, whether or not the event is expected or associated with 
the study drug, is considered a serious adverse event.
12.3.3.
Pregnancy 
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel within 
24 hours of their knowledge of the event using the appropriate pregnancy notification form. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered serious adverse events and must be reported using 
the Serious Adverse Event Form. Any subject who becomes pregnant during the study must be 
promptly withdrawn from the study and discontinue further study treatment.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported by the study-site personnel within 24 hours of their 
knowledge of the event using the appropriate pregnancy notification form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.


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12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established 
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting 
of PQC information; all studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to serious adverse event reporting timelines (refer to Section 12.3.2, 
Serious Adverse Events). A sample of the suspected product should be maintained for further 
investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
Intranasal Study Drug
Esketamine will be supplied as a clear, colorless intranasal solution of esketamine hydrochloride 
(16.14% weight/volume [w/v]; equivalent to 14% w/v of esketamine base) in a nasal spray pump. 
The solution will consist of 161.4 mg/mL esketamine hydrochloride (equivalent to 140 mg of 
esketamine base) formulated in 0.12 mg/mL ethylenediaminetetraacetic acid (EDTA) and 
1.5 mg/mL citric acid at a pH of 4.5 in water for injection. It is provided in a nasal spray pump, 
which delivers 16.14 mg esketamine hydrochloride (14 mg esketamine base) per 100 µL spray. 
Each individual nasal spray pump (device) contains a total of 28 mg (ie, 2 sprays). 


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The placebo solution will be supplied as a clear, colorless intranasal solution of water for injection, 
with a bittering agent (denatonium benzoate [Bitrex®] at a final concentration of 0.001 mg/mL) 
added to simulate the taste of the intranasal solution with active drug. The placebo solution will be 
provided in matching nasal spray pump devices. Benzalkonium chloride is added as a preservative 
at a concentration of 0.3 mg/mL. Each individual nasal spray pump (device) contains 2 sprays.
Esketamine and placebo will be manufactured and provided under the responsibility of the 
sponsor. Please refer to the Investigator's Brochure for a list of excipients.34
Oral Antidepressant Medications
Duloxetine
Duloxetine 30 mg will be obtained from commercial stock and provided under the responsibility of 
the sponsor. Please refer to the package insert/SmPC for the physical description and a list of 
excipients.17,18
Escitalopram
Escitalopram 10 mg will be obtained from commercial stock and provided under the responsibility 
of the sponsor. Please refer to the package insert/SmPC for the physical description and a list of 
excipients.21,22
Sertraline
Sertraline 50 mg will be obtained from commercial stock and provided under the responsibility of 
the sponsor. Please refer to the package insert/SmPC for the physical description and a list of 
excipients.65,66
Venlafaxine XR
Venlafaxine 75 mg will be obtained from commercial stock and provided under the responsibility 
of the sponsor. Please refer to the package insert/SmPC for the physical description and a list of 
excipients.71,72
14.2.
Packaging
Intranasal Study Drug
Study drug (ie, intranasal esketamine and placebo solution) will be supplied by the sponsor in a 
bi-dose nasal spray device. The devices will contain 200 µL. Each device delivers 16.14 mg 
esketamine hydrochloride (14 mg esketamine base) or 0.1 µg of denatonium benzoate per 100 µL 
spray.
Each nasal spray device will be individually packaged in a blister tray and subsequently put into a 
carton box. Each carton box constitutes a non-child-resistant subject kit, labeled with a unique 
medication kit number.


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Device for Practicing Intranasal Study Drug Administration
The demonstration intranasal device will also be supplied by the sponsor and will contain placebo 
solution. Subjects will practice spraying into the air and will not spray intranasally.
Oral Antidepressant Medication
Oral antidepressant tablets or capsules will remain in their commercial packaging.
If blisters are supplied, each blister will be packaged into a child-resistant dose pack to constitute 
a subject kit, labeled with a unique medication kit number. These will be labeled according to 
applicable regulatory requirements.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
Study drug will be stored at the study site in a secure area with restricted access until dispensed to 
the subjects. 
All study drug must be stored at controlled temperatures as indicated on the product-specific 
labeling.
Please refer to the pharmacy manual/study site investigational product manual and instructions for 
use documents for additional guidance on study drug preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study.
The dispensing of study drug to the subject, and the return of study drug from the subject (if 
applicable), must be documented on the drug accountability form. Subjects must be instructed to 
return all original containers, whether empty or containing study drug.
The study drug administered to the subject must be documented on the drug accountability form. 
All study drug will be stored and disposed of according to the sponsor's instructions. Study-site 
personnel must not combine contents of the study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label and must 
be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the investigational product destruction form. When the study site is an authorized 
destruction unit and study drug supplies are destroyed on-site, this must also be documented on 
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Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member of 
the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only to 
subjects participating in the study. Returned study drug must not be dispensed again, even to the 
same subject. 
Whenever a subject brings his or her study drug to the study site for pill count (ie, compliance 
check), this is not seen as a return of supplies. 
Study drug may not be relabeled or reassigned for use by other subjects. The investigator agrees 
neither to dispense the study drug from, nor store it at, any site other than the study sites agreed 
upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Practice intranasal devices 

Investigator's Brochure for esketamine

Local prescribing information for oral antidepressant options in double-blind treatment phase

Investigational Product (IP) Binder, including the IP Procedures Manual

Laboratory manual and materials

Clinician-administered and subject-reported outcome assessments:

Paper versions, as applicable

Electronic devices and associated materials

IWRS Manual

ECG equipment and associated materials (eg, manual)

Instructions for Use documents (subject and healthcare provider versions) for intranasal study 
medication

Rater qualifications/requirements for select clinician-administered assessments

Device to measure respiratory rate

Procedural documents for C-VISA

Procedural documents for independent, remote rater interviews

Guidance on recommended order of study procedures

MGH-ATRQ Guidance document

SmPCs of the active comparators: Duloxetine, escitalopram, sertraline, and venlafaxine XR


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
Subject diary
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Clinical Study in Treatment-resistant Major Depression
Major depressive disorder is a common, severe, chronic, and often life-threatening illness. It is 
now the leading cause of disability worldwide. There is a clear need to develop novel and improved 
therapeutics for treatment-resistant depression.
Several clinical studies with esketamine, including the phase 2a global study ESKETINTRD2003,
have shown robust antidepressant effects in patients with MDD, including TRD. Furthermore, 
these clinical studies have shown that esketamine is safe and well tolerated. Based on comparable 
pharmacokinetic profiles of intranasal esketamine between healthy Caucasian and Chinese 
subjects (ESKETINTRD1008)8, and pharmacokinetic, safety and efficacy data from Caucasian 
subjects with TRD (ESKETINTRD2003)10, we expect the selected dose of intranasal esketamine 
to be both efficacious and tolerated in the Chinese population of subjects with TRD.
Selection of Subjects
The primary aim of the study is to evaluate the efficacy of intranasal esketamine plus an oral 
antidepressant for the treatment of TRD. Thus, the study cannot be completed in healthy subjects. 
Potential subjects will be fully informed of the risks and requirements of the study, and during the 
study subjects will be given any new information that may affect their decision to continue 
participation.
For eligibility, subjects must have had non-response to at least 1 prior antidepressant treatment and 
be currently taking an antidepressant treatment at the start of the screening/prospective 
observational phase that will be continued as prospective treatment in the screening/prospective 
observational phase. Only subjects with non-response to their current antidepressant treatment 
after 4 weeks of prospectively observed treatment (for a total duration of antidepressant treatment 
of at least 6 weeks by the end of the screening/prospective observational phase), will be eligible to 
proceed to the double-blind treatment phase, when all subjects will receive a new oral 
antidepressant in addition to intranasal esketamine or placebo. Subjects will receive 4 weeks of 
treatment in the double-blind treatment phase. The oral antidepressant initiated during the double-
blind treatment phase will be continued for a further 8 weeks during the follow-up phase, to 
maintain the antidepressant effect.
Subjects will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.


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Justification for Using Placebo
Intranasal placebo is being used as a double-blind for intranasal esketamine to maintain study 
blinding. All subjects will also receive a newly initiated oral antidepressant during the double-
blind treatment phase. Subjects will not be on placebo alone. Assessment of the potential efficacy 
of a new compound for the treatment of treatment-resistant major depression requires adequate 
and well controlled clinical studies. This superiority study will compare intranasal esketamine plus 
a newly-initiated oral antidepressant to switching to an oral antidepressant as an active comparator.
Recent analyses have shown response to placebo varies considerably, from 10% to 55%. 
Therefore, there is a concern that randomized, controlled studies that rely on comparison with 
standard antidepressant treatments alone will generate unreliable results with limited assay 
sensitivity. However, some have considered it unethical to do placebo-controlled studies in major 
depression due to the potential risk of irreversible harm.62 In a meta-analysis of drug studies 
conducted in MDD, it was reported that adult subjects did not have higher rates of suicide
behaviors or attempts in the placebo group compared with those receiving an active 
antidepressant.39 These studies showed annual suicide rates of 0.8% on the investigational drug, 
0.7% on the active comparator, and 0.4% on placebo. Thus, the risk of irreversible harm was not 
higher in the placebo arm compared with the active control arms. 
Some subjects may decide to not participate in a placebo-controlled study due to the potential for 
increased distress and dysfunction from prolonged depression. 
Therefore, the use of an active-controlled study allows for assessment of efficacy of a new 
compound to allow for scientifically meaningful results. 
Moreover, the duration of the double-blind treatment phase is relatively short (4-week duration). 
Subjects will visit the study site at least twice a week during the double-blind treatment phase and 
their symptoms will be carefully monitored during each study visit. Safety evaluations will include 
evaluation of suicidal ideation/behavior at each clinic visit. At any point in the study, the subject 
may withdraw consent or be removed from the study by the investigator if there are any clinical 
concerns.
Intranasal esketamine may not be available for subjects after the study. 
Precautions to Ensure Subject Safety in the Study 
Subjects may participate in the study only if they have adequate capacity to give consent and after 
fully understanding the potential risks and giving an informed consent. Determination of capacity 
will be made by the study investigator. Subjects may discontinue the study at any time. The 
probability of receiving placebo and the concept of random assignment will be explained to the 
subject. The duration of the study is short, minimizing the time on intranasal placebo (which is 
being administered with a newly-initiated oral antidepressant). Potential disadvantages and 
adverse events of participating in the study and alternative treatment options will be discussed. For 
subjects who do not meet predefined response criteria during the study, clinical care will be 
arranged between the study investigator and their physician.


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Compensation for any procedure will be fair per local standards and approved by the participating 
sites IRB in order to not offer any undue incentive to participate in the study.
Subjects will be carefully monitored during the study and subjects who are unable to tolerate study 
drug during the double-blind treatment phase will be discontinued from the study. If the 
investigator judges it to be necessary to immediately stop study drug, he or she has the option to 
do so. Specific guidance is provided regarding blood pressure monitoring on intranasal dosing 
days (Section 6.4).
Only subjects who had non-response to their current oral antidepressant treatment, where a 
clinician would consider changing it in the future due to lack of response, will be enrolled.
Only qualified and trained investigators will participate in the study.
The total blood volume to be collected is considered to be within the normal range allowed for this 
subject population over this time frame. The approximate blood volume to be collected will be 
124.5 mL from each Chinese subject (34 mL for eligibility and safety, 16 mL for PK, 74.5 mL for 
biomarker) and 108.5 mL from each non-Chinese subject (34 mL for eligibility and safety, and 
74.5 mL for biomarker), which will be less than a Red Cross blood donation.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of human 
subjects. Compliance with this standard provides public assurance that the rights, safety, and 
wellbeing of study subjects are protected, consistent with the principles that originated in the 
Declaration of Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Sponsor-approved training and informational materials


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
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
subjects, data or study conduct), the ICF, applicable recruiting materials, and subject compensation 
programs, and the sponsor has received a copy of this approval. This approval letter must be dated 
and must clearly identify the IEC/IRB and the documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the study 
drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
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At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required. 
The re-approval should be documented in writing (excluding the ones that are purely 
administrative, with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion.
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the study 
has been fully explained. The ICF(s) must be signed before performance of any study-related 
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing 
IEC/IRB and be in a language that the subject can read and understand. The informed consent 
should be in accordance with principles that originated in the Declaration of Helsinki, current ICH 
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw consent 
to participate at any time. They will be informed that choosing to not participate will not affect the 
care the subject will receive for the treatment of his or her disease. Subjects will be told that 
alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow up if needed and that their records may 
be accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject is authorizing such access and agrees to allow his or her study physician 
to re-contact the subject for the purpose of obtaining consent for additional safety evaluations, if 
needed.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. After 
this explanation and before entry into the study, consent should be appropriately recorded by 
means of the subject's personally dated signature. After having obtained the consent, a copy of the 
ICF must be given to the subject.
Where local regulations require, a separate ICF may be used for the required DNA component of 
the study.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be limited 
to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 


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or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original medical 
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and 
regulatory inspection. This consent also addresses the transfer of the data to other entities and to 
other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps will 
be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory PK, biomarker, DNA and RNA research is not conducted under standards appropriate 
for the return of data to subjects. In addition, the sponsor cannot make decisions as to the 
significance of any findings resulting from exploratory research. Therefore, exploratory research 
data will not be returned to subjects or investigators, unless required by law or local regulations. 
Privacy and confidentiality of data generated in the future on stored samples will be protected by 
the same standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand esketamine, oral antidepressants, 
to understand depression, to understand differential drug responders, and to develop tests/assays 
related to esketamine, oral antidepressants, and depression. The research may begin at any time 
during the study or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal from the Use of Samples in Future 
Research).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help 
ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 


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when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be 
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involves only logistic or administrative aspects of the study, the IRB (and IEC where 
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
(see Contact Information page(s) provided separately). Except in emergency situations, this 
contact should be made before implementing any departure from the protocol. In all cases, contact 
with the sponsor must be made as soon as possible to discuss the situation and agree on an 
appropriate course of action. The data recorded in the eCRF and source documents will reflect any 
departure from the protocol, and the source documents will describe this departure and the 
circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

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)


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
Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all sub-investigators

Documentation of sub-investigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentations consistent in the type and level of detail with that 
commonly recorded at the study site as a basis for standard medical care must be available for the 
following: subject identification, eligibility, and study identification; study discussion and date of 
signed informed consent; dates of visits; results of safety and efficacy parameters as required by 
the protocol; record of all adverse events and follow-up of adverse events; concomitant 
medication; drug receipt/dispensing/return records; study drug administration information; and 
date of study completion and reason for early discontinuation of study drug or withdrawal from 
the study, if applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
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The following data will be recorded directly into the eCRF and will be considered source data:

Race

History of smoking (all nicotine use, eg, cigarettes (including e-cigarettes or the equivalent of 
e-cigarettes)

Blood pressure and pulse/heart rate

Height and weight 

Details of physical examination
The minimum source documentation requirements for Section 4.1 (Inclusion Criteria) and 
Section 4.2 (Exclusion Criteria) that specify a need for documented medical history are as follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries

Antidepressant treatment in the current episode of depression
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as the 
clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to the 
CRF in the protocol include the electronic source system but information collected through the 
electronic source system may not be limited to that found in the CRF. Data in this system may be 
considered source documentation.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. All CRF entries, corrections, 
and alterations must be made by the investigator or authorized study-site personnel. The 
investigator must verify that all data entries in the CRF are accurate and correct.
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an eCRF and transmitted in a secure manner 
to the sponsor within the timeframe agreed upon between the sponsor and the study site. The 
electronic file will be considered to be the eCRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documents. All data relating to the study 
must be recorded in eCRFs prepared by the sponsor. Data must be entered into the eCRFs in 
English. Study site personnel must complete the eCRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit.


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The investigator must verify that all data entries in the eCRFs are accurate and correct.
All eCRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or 
study-site personnel must adjust the eCRF (if applicable) and complete the query.
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in either 
of the following ways:

Investigator and study site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, and uploading 
data transfers from external service providers into the sponsor's data base. Written instructions will 
be provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review eCRFs for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
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If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post 
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the eCRFs with the hospital or clinic records (source 
documents); a sample will be reviewed. The nature and location of all source documents will be 
identified to ensure that all sources of original data required to complete the eCRF are known to 
the sponsor and study-site personnel and are accessible for verification by the sponsor study-site 
contact. If electronic records are maintained at the study site, the method of verification must be 
discussed with the study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be provided 
for review of study-related documents. The monitor will meet with the investigator on a regular 
basis during the study to provide feedback on the study conduct.
In addition to on-site monitoring visits, the site monitor may contact the site by telephone for an 
update on study progress. It is expected that study-site personnel will be available to provide an 
update on the progress of the study at the site.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed with the last study assessment for the last subject participating 
in the study. The final data from the study site will be sent to the sponsor (or designee) after 
completion of the final subject assessment at that study site, in the time frame specified in the 
Clinical Trial Agreement.


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17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any reason 
at the sole discretion of the sponsor. Study sites will be closed upon study completion. A study site 
is considered closed when all required documents and study supplies have been collected and a 
study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development

Study is terminated by sponsor due to futility
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the eCRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible for 
being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding 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.


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The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of esketamine, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain eCRF data from all study sites that participated in the study and will represent 
uploaded data transferred from external service providers into the sponsor's database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomic or 
exploratory biomarker analyses performed after the Clinical Study Report has been issued will be 
reported in a separate report and will not require a revision of the Clinical Study Report. Study 
subject identifiers will not be used in publication of results. Any work created in connection with 
performance of the study and contained in the data that can benefit from copyright protection 
(except any publication by the investigator as provided for below) shall be the property of the 
sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data and 
information without approval from the investigator. The investigator has the right to publish study 
site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will 
not mandate modifications to scientific content and does not have the right to suppress information. 
For multicenter study designs and 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 12 months of the availability of the final data (tables, listings, 
graphs), or the sponsor confirms there will be no multicenter study publication. Authorship of 
publications resulting from this study will be based on the guidelines on authorship, such as those 
described in the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, which 
state that the named authors must have made a significant contribution to the design of the study 
or analysis and interpretation of the data, provided critical review of the paper, and given final 
approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of, and the results of clinical studies as required 
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Attachment 1: Prohibited Concomitant Medications with Intranasal Study Medication (Esketamine 
or Placebo)
This list of medications is not all-inclusive; if necessary, please contact the medical monitor for any 
questions regarding a medication(s).
Please refer to the local prescribing information of the subject’s oral antidepressant treatment for 
information regarding prohibited concomitant medications. 
Except where specifically noted, the prohibited medications listed in the following table are prohibited from 
1 week (or 5 half-lives, whichever is longer) prior to the first dose of intranasal study medication until after 
the last dose of intranasal study medication. Note: If a medication is part of the antidepressant treatment 
regimen being taken at the time of signing the ICF (ie, start of screening/prospective observational phase), 
dose adjustment is permitted per clinical judgment, but the oral antidepressant treatment is to remain at or 
above the minimum therapeutic dose (per the MGH-ATRQ) through the end of Week 4. In such cases the 
investigator may choose to taper the relevant medication during the up to 3-week taper period based on 
their clinical judgment.
Note in the following table: N, Prohibited; Y, Permitted, with restrictions (please refer to the column labeled 
“Comments” for additional guidance).
Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for 
Prohibition
Amantadine
N
N
PD interaction
Anorexiants 
(eg, phentermine, 
phendimetrazine)
N
N
Safety
Anticholinesterase 
inhibitors
N
N
Subject 
population is 
excluded
Anticonvulsants
N
N
Subjects with seizures are excluded. 
Use as adjunctive treatment for major 
depressive disorder (MDD) is 
prohibited. 
-Note: Anticonvulsants used for 
indications other than seizures may 
be allowed (eg, valproate for 
migraine; pregabalin)
Safety and PD 
interaction
Antidepressants 
(other than the specific 
antidepressant started in 
the double-blind 
treatment phase of the 
study)
N
N
-Only 1 of the 4 predefined oral 
antidepressant treatment options are 
permitted.
-If a subject is taking a monoamine 
oxidase inhibitor (MAOI) during the 
screening/prospective observational 
phase, there must be a minimum 
washout interval of 2 weeks prior to 
the first dose of intranasal study 
medication.
-Even if used for other indications 
(eg, trazodone for sleep), the use of 
any medication listed on the ATRQ 
is not permitted during the treatment 
phase.
Safety and PD 
interaction
Antipsychotics
N
N
PD interaction


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Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for 
Prohibition
Benzodiazepines (at 
dosages less than or equal 
to the equivalent of 
6 mg/day lorazepam) and 
non-benzodiazepine 
sleeping medication 
(including: zolpidem, 
zaleplon, eszopiclone, 
and ramelteon)
Y
Y
Prohibited within 12 hours prior to the 
start of each intranasal treatment 
session
Safety and PD 
interaction
Benztropine
Y
N
Prohibited if use is continuous.
Safety and PD 
interaction. 
Chloral hydrate, 
melatonin, valerian
N
N
Safety and PD 
interaction
Clonidine
Y
N
Use of blood pressure control is 
allowed
Safety and PD 
interaction
Corticosteroids
(systemic) 
Y
N
Inhaled, intranasal, topical, and 
ophthalmic steroids are not prohibited.
Intermittent IM/IV/oral corticosteroids 
are permitted per sponsor approval
(chronic use prohibited).
PD interaction
Cough/cold 
preparations/nasal 
solutions containing 
vasoconstrictors, 
decongestants
Y
Y
Intranasally-administered 
decongestants (vasoconstrictors) 
should not be used from 1 hour prior to 
each intranasal study medication 
administration.
Pseudoephedrine- containing oral 
products should not be used within 
12 hours prior to an intranasal 
treatment session.
Safety and PD 
interaction
CYP3A4 inducers -
Potent
N
N
Subjects may not take a known potent 
inducer of hepatic CYP3A activity 
within 2 weeks of the first 
administration of intranasal study 
medication until at least 24 hours after 
the last intranasal dose of study 
medication.
Examples (not all-inclusive): 
Efavirenz, nevirapine, barbiturates, 
carbamazepine, glucocorticoids, 
modafinil, oxcarbazepine, 
phenobarbital, phenytoin, rifabutin, 
rifampin, and St. John's wort
PK
Dextromethorphan
N
N
PD interaction
Diphenhydramine
Y
N
Prohibited within 12 hours prior to the 
start of each intranasal treatment 
session
Safety
Ketanserin
N
N
Safety
Lithium
N
N
PD interaction
Memantine
N
N
PD interaction
Methyldopa
N
N
Safety and PD 
Interaction


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Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for 
Prohibition
Metyrosine
N
N
Safety and PD 
interaction
Non-vitamin K 
antagonist oral 
anticoagulation agents 
(eg, dabigatran, 
rivaroxaban, apixaban
N
N
Safety
Opioids
N
N
PD interaction
Psychostimulants 
(eg, amphetamines, 
methylphenidate)
N
Y
Prescribed psychostimulants taken for 
indications other than MDD can be 
continued but must not be taken within 
12 hours prior to the intranasal 
treatment session or for 2 hours after 
the intranasal treatment session.
Cardiovascular 
safety
ADHD medications 
(eg, atomoxetine, 
guanfacine)
N
Y
Can be continued but must not be 
taken within 12 hours prior to the 
intranasal treatment session or for 2 
hours after the intranasal treatment 
session.
Safety
Reserpine
N
N
PD interaction
Scopolamine
N
N
PD interaction
Thyroid hormone 
supplement for treatment 
of thyroid condition only 
(not for depression)
N
Y
Safety
Thyroxine/ 
triiodothyronine (T3), 
thyroid hormone 
prescribed for depression
N
N
PD interaction
Warfarin
N
N
Primary 
condition 
where used is 
excluded
Abbreviations: N, Prohibited; PD, pharmacodynamics; PK, pharmacokinetics; Y, Permitted, with restrictions 
(please refer to the column labeled “Comments” for additional guidance).


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Attachment 2: New York Heart Association Classification of Cardiac Disease
New York Heart Association Classification of Cardiac Disease
Category
Description
Functional Capacity
Class I
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
Class II
Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable 
at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
Class III
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any 
physical activity is undertaken, discomfort is increased.
Objective Assessment
A
No objective evidence of cardiovascular disease.
B
Objective evidence of minimal cardiovascular disease.
C
Objective evidence of moderately severe cardiovascular disease.
D
Objective evidence of severe cardiovascular disease.
Source: Criteria Committee of the New York Heart Association. Functional capacity and objective assessment. In: 
Dolgin M, ed. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels, 9th ed. Boston, 
MA: Little, Brown & Co; 1994, 253-255.


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Attachment 3: Oral Antidepressant Titration Schedule for Double-Blind Treatment Phase
The titration schedule for the 4 oral antidepressants to be used in the current study is provided below. 
Adjustments to the titration schedule may be required in other countries in order to conform to local 
prescribing information.
Global titration schedule 
Oral Antidepressant 
(Active Comparator)
Titration Schedule
Week 1
(Starting Day 1)
Week 2
(Starting Day 8)
Week 3
(Starting Day 15)
Week 4
(Starting Day 22)
Duloxetine
60 mga
60 mg
60 mg
60 mg
Escitalopram
10 mg
20 mg
20 mg
20 mg
Sertraline
50 mg
100 mg
150 mg
200 mg
Venlafaxine XR
75 mg
150 mg
225 mg
225 mg
a
Subjects should be initiated with 60 mg/day. Subjects that have in the past shown increased sensitivity 
towards serotonin reuptake inhibitors (SSRI) /norepinephrine reuptake inhibitors (SNRI) can, at the discretion 
of the treating physician, be started on a 30 mg dose and up-titrated into the therapeutic range of 60 mg by the 
start of Week 2


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Attachment 4: Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease related) or background regimen. For the 
purposes of this study the following events will be considered anticipated events.17,18,21,22,34,65,66,71,72
For esketamine and major depressive disorder (MDD) (including treatment-resistant depression [TRD]; 
based on DSM-5):

Suicidal thinking, ideation, and behavior

Sleep changes, difficulty sleeping, reduced sleep, abnormal sleep, tiredness, fatigue, and reduced 
energy

Difficulty in sexual desire, performance or satisfaction

Reduced appetite and weight changes (loss or increase)

Activation or hypomania/ mania

Irritability, anger, and impulsive behavior

Agitation, tension, panic attacks, and phobia
For esketamine, regarding events related to concomitant therapy with oral antidepressants (from the 
product’s reference safety information/US prescribing information):

Duloxetine

Most commonly observed adverse reactions from pooled studies of all indications (incidence of 
at least 5% and at least twice the incidence in placebo subjects) were nausea, dry mouth, 
somnolence, fatigue, constipation, decreased appetite, and hyperhidrosis (sweating). Duloxetine 
treatment worsens glycemic control in some subjects with diabetes.

Increased the risk compared to placebo of suicidal thinking and behavior; serotonin syndrome; 
hepatotoxicity; hepatic failure; orthostatic hypotension, syncope; abnormal bleeding; severe skin 
reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS); activation of 
mania or hypomania; hyponatremia.

Venlafaxine XR

According to the US prescribing information, adverse events in short-term studies occurring in at 
least 5% of subjects receiving venlafaxine XR and at a rate twice the incidence in placebo 
subjects: abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), 
central nervous system complaints (dizziness, somnolence, and abnormal dreams), and sweating. 
Sustained hypertension is noted within Warnings and Precautions section.

Increased the risk compared to placebo of suicidal thinking and behavior, treatment-emergent 
insomnia and nervousness, activation of mania/hypomania, hyponatremia, mydriasis, abnormal 
bleeding, sustained hypertension, and serotonin syndrome.

Escitalopram

Most commonly observed adverse reactions (incidence of approximately 5% or greater and 
approximately twice the incidence in placebo subjects) were insomnia, ejaculation disorder 
(primarily ejaculatory delay), nausea, sweating increased, fatigue, and somnolence.

Increased the risk compared to placebo of suicidal thinking and behavior, serotonin syndrome, 
activation of mania/hypomania, hyponatremia and abnormal bleeding


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3006 Amendment 2
Confidential – FOIA Exemptions Apply in U.S.
141
Status: Approved, Date: 21 January 2021

Sertraline

Most common treatment-emergent AEs associated with sertraline (incidence of at least 5% for 
sertraline or at least twice the incidence in placebo subjects) were ejaculation failure, dry mouth, 
increased sweating, somnolence, tremor, dizziness, fatigue, pain, malaise, abdominal pain, 
anorexia, constipation, diarrhea/loose stools, dyspepsia, nausea, agitation, insomnia, and 
decreased libido, and serotonin syndrome. 

Increased the risk compared to placebo of suicidal thinking and behavior, activation/mania; 
bleeding events related to SSRI use (have ranged from ecchymosis, hematomas, epistaxis, and 
petechiae to life-threatening hemorrhages), hyponatremia (appears to be the result of the 
syndrome of inappropriate antidiuretic hormone secretion [SIADH]); serotonin syndrome
Reporting of Anticipated Events
All adverse events will be captured on the eCRF and in the database regardless of whether they are 
considered to be anticipated events, and will be reported to the sponsor as described in Section 12.3.1, All 
Adverse Events. Any event that meets serious adverse event criteria will be reported to the sponsor within 
the appropriate timeline as described in Section 12.3.2 Serious Adverse Events. These anticipated events 
are exempt from expedited reporting as individual single cases to Health Authorities. However, if based on 
an aggregate review, it is determined that an anticipated event is possibly related to study drug, the sponsor 
will report these events in an expedited manner.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of pre-specified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug. 
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events Safety 
Monitoring Plan (ASMP).


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3006 Amendment 2
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Status: Approved, Date: 21 January 2021
INVESTIGATOR AGREEMENT
PPD
PPD


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 22 July 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
Protocol Title
A Randomized, Double-blind, Multicenter Active-controlled Study to Evaluate the 
Efficacy, Pharmacokinetics, Safety and Tolerability of Flexible Doses of Intranasal 
esketamine Plus an Oral Antidepressant in Adult Subjects with Treatment-resistant 
Depression
Protocol ESKETINTRD3006; Phase 3
JNJ-54135419 (esketamine)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics,
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact
Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).]
Status:
Approved
Date:
22 July 2020
Prepared by:
Janssen Research & Development, LLC 
EDMS number:
EDMS-RIM-111573, 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL 
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT03434041


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 22 July 2020
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by subjects and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks. 
In alignment with guidance from the China Forums of Clinical Research Capacity Building and 
Human Research Participants Protection (CCHRPP) and any disaster/emergency response/good 
clinical practice (GCP) notification, that the clinical site may have already enforced in line with 
the Central Drug Evaluation (CDE) guidance on Drug Clinical Trial Management under 
COVID-19 Pandemic Situation, the sponsor is providing temporary options for study-related 
subject management in the event of disruption to the conduct of the study. This guidance does not 
supersede any local or government requirements or the clinical judgement of the investigator to 
protect the health and well-being of subjects and site staff. The safety of the subjects and relevant 
study site personnel should be considered as priority. If, at any time, a subject’s safety is considered 
by the investigator to be at risk, study treatment may be discontinued after discussion with the 
sponsor, and study follow-up will be conducted according to GUIDANCE SPECIFIC TO THIS 
PROTOCOL.
Obtaining oral/verbal consent for ongoing subjects: Re-consenting of subjects will be performed 
as applicable for the measures taken (including remote consenting by phone) and according to 
local guidance for informed consent applicable during the COVID-19 pandemic.
Every effort should be made to adhere to protocol-specified assessments for subjects on study 
treatment. Modifications to protocol-required assessments may be permitted after consultation 
between the participant and investigator, and with the agreement of the sponsor. Missed 
assessments/visits will be captured in the clinical trial management system (CTMS) for protocol 
deviations. 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance.
Modifications made to the study conduct as a result of the COVID-19 pandemic will be 
summarized in the clinical study report.


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved, Date: 22 July 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL
These provisions are meant to minimize the risk of exposure to COVID-19 and to safely maintain 
subjects on study treatment while site capabilities are compromised by COVID-19-related 
restrictions. As restrictions are lifted and the acute phase of the COVID-19 pandemic resolves, 
sites should revert to original protocol conduct as soon as feasible.
At each contact, subjects will be interviewed to collect safety data. Subjects will also be questioned 
regarding general health status to fulfill any physical examination requirement.
Evaluate the subject’s situation on a case by case basis and contact the study responsible physician 
for discussion and decision if necessary. Certain measures, such as those listed below, may be 
necessary and should be instituted in accordance with applicable (including local) laws, 
regulations, guidelines, and procedures.
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 delayed 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 as per Exclusion Criterium 25 (see Section 4.2) 
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 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.
Double-blind Treatment Phase
Due to the wide spread of site locations, the risk level of COVID-19 viral infection and restrictions 
might be different at each site. The decision to continue with on-site intranasal dosing or to miss 
intranasal dosing and to conduct a remote phone call visit should be made by the investigator 
taking into consideration the subject's disease status and the potential impact of the COVID-19 
viral infection, and after consultation with the sponsor.
If it is feasible for the subject to be assessed and dosed at the study site, and the subject is willing 
to do so, the original protocol requirements and procedures should be followed. To reduce time 
spent by the subject on site during the dosing day and limit direct contact with multiple site staff 
members, clinician rating scales (Clinical Global Impression – Severity [CGI-S], Columbia 
Suicide Severity Rating Scale [C-SSRS] and Physician Withdrawal Checklist; 20-item [PWC-20]) 
can be completed remotely (via phone). Site staff are advised to wear the necessary personal 
protective equipment when seeing the subject, to ensure that the subject is protected when on site,
and to obtain subject information regarding recent travel or contact history of COVID-19 suspected 
cases.


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved, Date: 22 July 2020
If it is not feasible for the subject to be assessed and dosed at the study site, the following
recommendations should be followed:

The decision to miss the intranasal dosing temporally or to proceed directly to early
withdrawal from the double-blind treatment phase and entry to the follow-up phase should be
at the discretion of investigator and after consultation with the sponsor. The subject should be
contacted for assessments that can be conducted remotely by telephone as specified in the
Time and Events schedule of the protocol.

The subject should continue to take oral antidepressant (AD) as per protocol.

Rating Scales: Every effort should be made to complete the Montgomery-Åsberg Depression
Rating Scale (MADRS) assessment remotely as outlined in the protocol (ie, via telephone by
an independent rater), and within the scheduled timeframe (see Time and Events Schedule).
If this cannot occur, the sponsor medical monitor or delegate should be contacted for
directions. Data obtained from the clinician completed rating scale assessments and patient
report outcome (PRO) that is outlined in the Remote Site Assisted Administration Form
should be collected remotely per the electronic Clinical Outcome Assessments (eCOA)
COVID-19 site administration assistance process.

Safety Assessments: information on adverse events and concomitant therapies should be
obtained and documented at each remote visit as per the visit schedule. If it is determined by
the investigator that it necessary to have laboratory assessments (such as hematology,
chemistry, urine drug screen, urinalysis, urine/serum pregnancy test) and echocardiographic
(ECG) assessments, then these assessments could be done in a nearby hospital/clinic or at a
local laboratory instead of at the central laboratory as stipulated in the protocol. Assessments
that were not conducted will be regarded as missing data. Testing should be resumed as soon
as the conditions permits.
If a subject cannot be contacted for a remote visit, follow procedures in Section 10.2 of the 
protocol.
Follow-up Phase

Further clinical standard of care for the treatment of depression will be arranged by the
investigator. Medication changes are permitted per protocol (see Section 9.1.4). The decision
to continue with oral AD treatment, and the choice of oral AD will be at the discretion of the
investigator taking into consideration the subject's disease status and the potential impact of
the COVID-19 virus infection.

Rating scales/safety assessments can be completed remotely by telephone. Detailed guidance
is specified in the prior section “Double-blind Treatment Phase”

It is recommended that close contact be maintained with study subjects and remote contact
arranged consistent with the subject’s regularly scheduled visit interval.
Study subjects who show worsening or who are at high risk for relapse may require more frequent 
monitoring as per investigator discretion.


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved, Date: 22 July 2020
Exposure to COVID-19

If a subject develops COVID-19 infection during the screening phase, the subject should be
screen failed. After the acute phase of the COVID-19 pandemic, any potential subject who
has had COVID-19 virus and has
fully recovered may be considered for
screening/re-screening following a discussion with the Sponsor’s study responsible physician.

If a subject develops confirmed COVID-19 infection during the double-blind treatment phase,
the principal investigator should contact the sponsor’s medical monitor to discuss the best
course of action based on a risk/benefit assessment.

If a subject develops confirmed COVID-19 infection during the follow-up phase, the principal
investigator should contact the sponsor’s medical monitor. If feasible, the subject, should
complete assessments remotely until recovered.

The subject's COVID-19 infection should be reported to the sponsor following the usual
Adverse Event/Serious Adverse Event reporting requirements.
Data Collection and Documentation
Discontinuations of study treatment and withdrawal from the study due to COVID-19 related 
adverse events (AEs) / serious adverse events (SAEs) should be documented as discontinuation 
due to AE. If a subject has died due to COVID-19, “death” should be selected as the reason for 
treatment discontinuation. Discontinuations for other COVID-19 reasons (eg, site closure) should 
be documented with the prefix “COVID-19-related” in the eCRF.
All relevant communications and discussions applicable to the decision-making processes and 
actions taken in association with the situation related to COVID-19 should be documented in the 
eCRF, including (but not limited to the following examples):

Site rater will verify that the correct subject is being interviewed and document in the source
medical notes of this verification.

For screen failures for a reason related to COVID-19, document the reason under “a violation
for Exclusion Criterion 25” on the Inclusion/Exclusion Criteria form, and also add the
following comment on the Comments form: “Subject is screen failure due to COVID-19
outbreak.”

For early withdrawal for a reason related to COVID-19 (other than AE), document the reason
under “Other” using the following format: “COVID-19 related [and additional details as
appropriate]" in the Disposition form.

Document remote safety assessment for ongoing subject, review of adverse events and
concomitant medications and safety-related scale outcomes. Data obtained from the clinician
completed rating scale assessments and patient report outcome (PRO) that is outlined in the
Remote Site Assisted Administration Form should be collected remotely per the e(COA)
COVID-19 site administration assistance process.

Document treatment status and any changes in standard of care/oral antidepressant treatment
choices.

Document all attempts made by the site personnel to contact the subject, in the event that the
site personnel have not been able to reach the subject.


COVID-19 Appendix
JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved, Date: 22 July 2020

For missed doses of study drug, the dosing form should be inactivated and “COVID-19 related
[and additional details as appropriate]" entered on the Comments form.

Missed / out of window assessments should be documented with “COVID-19-related [and 
additional details as appropriate]” in the comment section of the eCRF. Assessments that 
cannot be performed during the current situation and/or because the subject(s) want to avoid 
any potential risk to COVID-19 exposure, will be regarded as "missing data" and will need to 
be recorded as a related protocol deviation in the source documents. Testing should be 
resumed as soon as the conditions permits. 
All COVID-19-related deviations from the main study protocol will be documented in CTMS 
according to COVID-19 Data Management Guidance. 
Oral/verbal consent for ongoing subjects
Due to changes in this specific guidance in response to the global COVID-19 pandemic, it may 
influence subject’s willingness to continue participating in the study. Below is general guidance 
for capturing enough evidence for an oral/verbal consent. Country specific guidance should be 
followed for alternating consenting methods.
The following should be collected and documented in the relevant subject record that is retained 
at the investigational study site
1.
Who consented: Name of the subject. 
2.
When they consented: The time and date when the consent conversation took place
3.
What they were told at the time: What changes or new aspect of the study the subject agreed 
to (eg., some of scheduled study visits may be conducted by telephone instead of going into 
the study doctor’s office)
4.
How they consented: The consent result, the method used (eg., telephone)
5.
Who captured the oral/verbal consent: Name and signature of the Investigator or staff member 
who captured the subject's consent. 
6.
Impartial witness, if applicable: Who was present as impartial witness and how the impartial 
witness was selected. 
7.
Oral/verbal re consenting will be followed by written consent upon the subject's return to the 
site.
Sites should refer to their continuity plans and local HA/IRB/EC guidance for appropriate methods 
of documenting evidence for verbal and/or other alternate consent methods. The acceptability of 
alternate consenting methods will vary by country based upon local/country guidance, laws, and 
regulations (which take precedence over the above Janssen guidance).
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 ESKETINTRD3006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
7
Status: Approved, Date: 22 July 2020
INVESTIGATOR AGREEMENT
PPD
PPD

SAP_001.pdf: 
1
Approved, Date: 5 February 2021
Janssen Research & Development
Statistical Analysis Plan
A Randomized, Double-blind, Multicenter Active-controlled Study to Evaluate the 
Efficacy, Pharmacokinetics, Safety and Tolerability of Flexible Doses of Intranasal 
Esketamine Plus an Oral Antidepressant in Adult Subjects with Treatment-resistant 
Depression
Protocol ESKETINTRD3006; Phase 3
AMENDMENT 2
JNJ-54135419  (esketamine)
Status:
Approved
Date:
5 February 2021
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-ERI-163890143
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03434041


JNJ-54135419  (esketamine)
Statistical Analysis Plan ESKETINTRD3006
2
Approved, Date: 5 February 2021
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 5
ABBREVIATIONS ........................................................................................................................................ 7
1.
INTRODUCTION.................................................................................................................................. 8
1.1.
Trial Objectives ................................................................................................................................ 8
1.2.
Trial Design ...................................................................................................................................... 9
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 13
1.4.
Sample Size Justification ............................................................................................................... 13
1.5.
Randomization and Blinding .......................................................................................................... 14
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 15
2.1.
Visit Windows................................................................................................................................. 15
2.2.
Analysis Sets.................................................................................................................................. 19
2.2.1.
All Randomized Analysis Set...................................................................................................... 19
2.2.2.
Efficacy Analysis Set(s) .............................................................................................................. 20
2.2.2.1.
Primary Efficacy Analysis Set.................................................................................................. 20
2.2.2.2.
Secondary Efficacy Analysis Set............................................................................................. 20
2.2.3.
Safety Analysis Set..................................................................................................................... 20
2.2.4.
Follow-up Analysis Set ............................................................................................................... 20
2.2.5.
Pharmacokinetics Analysis Set .................................................................................................. 20
2.2.6.
Biomarker and Pharmacogenomics Analysis Set ...................................................................... 20
2.3.
Definition of Subgroups.................................................................................................................. 20
2.4.
Study Day and Relative Day .......................................................................................................... 21
2.5.
Baseline and Endpoint ................................................................................................................... 22
2.6.
Imputation Rules for Missing AE Date/Time of Onset/Resolution ................................................. 22
2.7.
Imputation Rules for Missing Concomitant Medication Dates ....................................................... 24
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 24
4.
SUBJECT INFORMATION................................................................................................................ 24
4.1.
Demographics and Baseline Characteristics ................................................................................. 24
4.2.
Disposition Information................................................................................................................... 25
4.3.
Treatment Compliance................................................................................................................... 26
4.4.
Extent of Exposure......................................................................................................................... 26
4.5.
Protocol Deviations ........................................................................................................................ 27
4.6.
Prior and Concomitant Medications ............................................................................................... 28
5.
EFFICACY ......................................................................................................................................... 28
5.1.
Analysis Specifications................................................................................................................... 29
5.1.1.
Level of Significance................................................................................................................... 29
5.1.2.
Data Handling Rules................................................................................................................... 29
5.2.
Primary Efficacy Endpoint.............................................................................................................. 29
5.2.1.
Definition..................................................................................................................................... 29
5.2.2.
Estimand..................................................................................................................................... 30
5.2.3.
Analysis Methods........................................................................................................................ 30
5.3.
Major Secondary Endpoints........................................................................................................... 33
5.3.1.
MADRS total score at 24 hours .................................................................................................. 33
5.3.1.1.
Analysis Methods .................................................................................................................... 33
5.3.2.
Sheehan Disability Scale (SDS) ................................................................................................. 34
5.3.2.1.
Definition.................................................................................................................................. 34
5.3.2.2.
Analysis Methods .................................................................................................................... 34
5.4.
Other Efficacy Variables................................................................................................................. 34
5.4.1.
Onset of Clinical Response ........................................................................................................ 34


JNJ-54135419  (esketamine)
Statistical Analysis Plan ESKETINTRD3006
3
Approved, Date: 5 February 2021
5.4.1.1.
Definition.................................................................................................................................. 34
5.4.1.2.
Analysis Methods .................................................................................................................... 34
5.4.2.
Responders ................................................................................................................................ 35
5.4.2.1.
Definition.................................................................................................................................. 35
5.4.2.2.
Analysis Methods .................................................................................................................... 35
5.4.3.
Improvement of at Least 30% MADRS Total Score................................................................... 35
5.4.3.1.
Definition.................................................................................................................................. 35
5.4.3.2.
Analysis Methods .................................................................................................................... 36
5.4.4.
Remitters .................................................................................................................................... 36
5.4.4.1.
Definition.................................................................................................................................. 36
5.4.4.2.
Analysis Methods .................................................................................................................... 36
5.4.5.
CGI-S.......................................................................................................................................... 36
5.4.5.1.
Definition.................................................................................................................................. 36
5.4.5.2.
Analysis Methods .................................................................................................................... 36
5.4.6.
GAD-7......................................................................................................................................... 37
5.4.6.1.
Definition.................................................................................................................................. 37
5.4.6.2.
Analysis Methods .................................................................................................................... 37
5.4.7.
EuroQol Group; 5 Dimension; 5 level (EQ-5D-5L) ..................................................................... 37
5.4.7.1.
Definition.................................................................................................................................. 37
5.4.7.2.
Analysis Methods .................................................................................................................... 38
5.4.8.
SDS in the Follow-up Phase....................................................................................................... 38
5.4.8.1.
Definition.................................................................................................................................. 38
5.4.8.2.
Analysis Methods .................................................................................................................... 38
5.4.9.
Relapse....................................................................................................................................... 39
5.4.9.1.
Definition.................................................................................................................................. 39
5.4.9.2.
Analysis Methods .................................................................................................................... 39
5.4.10.
Six-Item MADRS subscale (MADRS6)....................................................................................... 39
5.4.10.1.
Definition.................................................................................................................................. 39
5.4.10.2.
Analysis Methods .................................................................................................................... 39
6.
SAFETY............................................................................................................................................. 39
6.1.
Adverse Events .............................................................................................................................. 40
6.2.
Clinical Laboratory Tests................................................................................................................ 42
6.3.
Vital Signs, Weight and BMI .......................................................................................................... 43
6.4.
Electrocardiogram.......................................................................................................................... 44
6.5.
Other Safety Parameters ............................................................................................................... 45
6.5.1.
Nasal Examination...................................................................................................................... 45
6.5.2.
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................... 46
6.5.3.
Clinician Administered Dissociative States Scale (CADSS)....................................................... 47
6.5.4.
Physician Withdrawal Checklist (PWC-20)................................................................................. 47
7.
PHARMACOKINETICS ..................................................................................................................... 47
8.
BIOMARKER, PHARMACOGENOMIC (DNA), AND EXPRESSION (RNA) EVALUATIONS ........ 48
REFERENCES............................................................................................................................................ 49
ATTACHMENTS......................................................................................................................................... 50


JNJ-54135419  (esketamine)
Statistical Analysis Plan ESKETINTRD3006
4
Approved, Date: 5 February 2021
LIST OF IN-TEXT TABLES
Table 1: 
Visit Windows............................................................................................................................ 15
Table 2: 
Definition of Subgroups............................................................................................................. 21
Table 3: 
Demographic Variables............................................................................................................. 25
Table 4: 
Psychiatric History at Baseline Variables ................................................................................. 25
Table 5: 
Efficacy Variables ..................................................................................................................... 28
Table 6:
Analysis Types and Assumptions ............................................................................................. 31
Table 7: 
Clinically Important Abnormalities in Vital Signs....................................................................... 43
Table 8:
Limits for HR, PR, QRS and QT Interval Abnormality .............................................................. 45
Table 9:
Criteria for Abnormal QTc Values and Changes from Baseline ............................................... 45
Table 10:
CADSS Scoring ........................................................................................................................ 47
LIST OF IN-TEXT FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 13


JNJ-54135419  (esketamine)
Statistical Analysis Plan ESKETINTRD3006
5
Approved, Date: 5 February 2021
AMENDMENT HISTORY
SAP Version
Issue Date
Original SAP
May 8, 2019
Amendment 1
May 25, 2020
Amendment 2
February 2, 2021
Amendments below are listed beginning with the most recent amendment.
Amendment 2 (02 Feb 2020)
The overall reason for the amendment: to change the first key secondary endpoint according to protocol 
amendment 2.
Applicable Section(s)
Description of Change (s)
Section 1.1 Trial Objectives
Change the first key secondary objective to ‘Change from baseline in the MADRS 
total score at 24 hours post first dose’. The current first key secondary endpoint is
changed to an “Other Secondary Endpoint”.
Section 2.1 Visit Windows
For Pulse oximetry, ‘End point(DB)’ is removed since Pulse ox is only done on 
dosing days.
Section 2.2.5 
Pharmacokinetics analysis 
Set
The definition of PK analysis set is added.
Section 2.3 Definition of 
subgroup
History of hypertension is removed. Based on clinical experience, it is not an 
important factor for the efficacy. 
Section 4.1 Demographics 
and Baseline Characteristics
‘Duration of current episode’ and ‘Duration of current episode categorize (<=2 
years, >2 years)’ are added in psychiatric history at baseline variables.
Section 5 Efficacy
Key secondary endpoint is updated accordingly in table 5 (efficacy variables) and 
fixed sequence approach.
Section 5.2.2
Estimand is updated based on latest version of ICH E9
Section 5.3 Major 
Secondary Endpoints
Change the first key secondary objective to ‘Change from baseline in the MADRS 
total score at 24 hours post first dose’. And use the same methods (MMRM) as the 
primary endpoint.
Section 5.4 Other Efficacy 
Variables
The current first key secondary endpoint (Onset of clinical response) is changed to 
an “Other Secondary Endpoint”.
Section 5.4.6 GAD-7
Analysis is added according to protocol
Section 6.1 Adverse Events
AE of special interest has been updated to follow global study TRD3008
Section 6.3 Vital Signs, 
Weight and BMI and 
Section 6.5.1 Nasal 
Examination
Minor corrections are made:
The information for hypertension status is updated based on current eCRF
Phase information is corrected based on protocol


JNJ-54135419  (esketamine)
Statistical Analysis Plan ESKETINTRD3006
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Approved, Date: 5 February 2021
Amendment 1 (25 May 2020)
The overall reason for the amendment: 
Applicable Section(s)
Description of Change (s)
Section 1 Introduction
Since the biomarker application was rejected by the Human Genetic Resource 
Administration Office of China (HGRAO), biomarker samples will be collected for 
subjects from the US sites only. The biomarker analysis plan will be developed 
based on the availability of sufficient number of subjects. 
Section 1 Introduction:
General description of potential analysis due to impact of COVID-19 is added.
Section 2.1 Visit Windows
The time window for a visit during the follow-up phase has been modified relative 
to the last intranasal dose of study drug, instead of the start date of the follow-up 
phase, to better reflect the Time & Event schedule within the protocol. 
Section 2.3 Definition of 
subgroups
Duration of current episode ，Number of classes of prior antidepressant 
medications and Individual oral drug (duloxetine, escitalopram, venlafaxine XR, 
sertraline) have been added in order to better understand the depression history of 
the subject in interpreting the data.
Section 2.4 Study Day and 
Relative Day
Clarified the purpose of using two relative days for the follow-up phase, one relative 
day to assign the time window relative to the date of last intranasal dose of study 
drug and the other relative day relative to the start date of follow-up phase to be 
presented in the listing.
Section 4.1 Demographics 
and Baseline Characteristics
Number of depressive episodes, Duration of Current Episode and Number of oral 
antidepressant drug classes have been added to better present baseline 
characteristics.
Section 5.4 Other efficacy 
Variables
By country efficacy analyses have been added for the MADRS total score 
(including responders, remitters), CGI-S, and SDS analysis, in order to improve on 
data presentation between subjects in China and the US
Section 5.4.2 Improvement 
of at least 30% in the 
MADRS Total Score
An improvement at least 30% in the MADRS total score from baseline has been 
added as an exploratory endpoint in order to better understand the data
Section 5.4.9 Six-item 
MADRS subscale
The six-item MADRS subscale has been added as exploratory endpoint in order to 
better understand data.
Section 6.1 Adverse events
By country safety analysis has been added for the adverse event summary tables to 
better display data.
Section 6.5.3 Clinician 
Administered Dissociative 
States Scale (CADSS)
By country analyses have been added for CADSS in order to better display data.


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ABBREVIATIONS
AD
antidepressant
AE
adverse event
ALT/SGPT
alanine aminotransferase
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic Class
AUC
area under the curve
BMI
body mass index
CADSS
Clinician Administered Dissociative States Scale
CGI-S
Clinical Global Impression –Severity
CMH
Cochran-Mantel-Haenszel
Cmax
maximum concentration
CRF
case report form
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
coefficient of variation
DB
Double-blind
ECG
electrocardiogram
eCRF
electronic case report form
EQ-5D-5L
EuroQol Group; 5 dimension; 5 level
EQ-VAS
EuroQol Group: visual analogue scale
FAS
full analysis set
FDA
Food and Drug Administration
F/U
Follow-up
GAD-7
Generalized Anxiety Disorder 7-item scale
ICH
International Conference on Harmonization
IVRS
interactive voice response system
LLOQ
lower limit of quantification
MADRS
Montgomery-Asberg Depression Rating Scale
MCMC
Markov Chain Monte Carlo
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
MINI
Mini International Neuropsychiatric Interview
MGH-ATRQ
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire
MMRM
Mixed-effects model using repeated measures
MRD
minimum required dilution
PD
pharmacodynamic
PK
pharmacokinetic(s)
PP
per protocol
PWC-20
Physician Withdrawal Checklist; 20 item
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SDS
Sheehan Disability Scale
SE
Standard error
SNRI
Serotonin and Norepinephrine Reuptake Inhibitors
SSRI
Selective Serotonin Reuptake Inhibitors
TEAE
treatment-emergent adverse event
TEMA
treatment-emergent markedly abnormal
TRD
Treatment Resistant Depression
ULN
Upper limit of normal


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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 JNJ54135419-ESKETINTRD3006.
Pharmacokinetic analyses using population PK modeling will be provided in a separate plan. In 
addition, if the available number of subjects is sufficient for analysis, the analysis plan for 
biomarker and pharmacogenomic analyses will be provided separately.
In considering the COVID-19 pandemic has potential impact on the study outcomes, additional 
analysis may be implemented if applicable.
1.1.
Trial Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of switching adult subjects with TRD 
from a prior antidepressant treatment (to which they have not responded) to flexibly dosed 
intranasal esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant, compared with 
switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in 
improving depressive symptoms, as assessed by the change from baseline in the Montgomery-
Asberg Depression Rating Scale (MADRS) total score from Day1 (pre-randomization) to the end 
of the 4-week double-blind treatment phase. 
Key Secondary Objectives
The key secondary objectives are to assess the effect of intranasal esketamine plus a newly initiated 
oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus 
intranasal placebo on the following parameters in adult subjects with TRD: 

Change from baseline in the MADRS total score at 24 hours (Day 2) post first dose

Functioning and associated disability
Other Secondary Objectives 
To assess the effect of intranasal esketamine plus a newly initiated oral antidepressant compared 
with a newly initiated oral antidepressant (active comparator) plus intranasal placebo on the 
following parameters in adult subjects with TRD: 

Onset of clinical response by Day 2

Depression response rates

Depression remission rates 

Overall severity of depressive illness 

Anxiety symptoms 

Health-related quality of life and health status


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To investigate the safety and tolerability of intranasal esketamine plus a newly initiated oral 
antidepressant compared with a newly initiated oral antidepressant (active comparator) plus 
intranasal placebo in adult subjects with TRD, including the following parameters: 

Treatment-emergent adverse events (TEAEs), including AEs of special interest 

Local nasal tolerability 

Effects on heart rate, blood pressure, respiratory rate, and blood oxygen saturation 

Dissociative symptoms 

Potential effects on suicidal ideation/behavior 

Potential withdrawal and/or rebound symptoms following cessation of intranasal 
esketamine treatment. 
To assess the pharmacokinetics (PK) of intranasal esketamine in Chinese adult subjects with TRD 
receiving intranasal esketamine plus a newly-initiated oral antidepressant.
Exploratory Objectives
For subjects who receive esketamine during the double-blind treatment phase, the proportion of
subjects who relapse during the follow-up phase will be evaluated separately for subjects who are 
remitters (MADRS ≤12) at the end of the 4 week double-blind treatment phase and for subjects 
who are responders but not remitters (≥50% reduction in MADRS total score, but MADRS ˃12) 
at the end of the 4 week double-blind treatment phase. 

Time to relapse during the follow-up phase will be evaluated in esketamine subjects who 
remitted 

Time to relapse during the follow-up phase will be evaluated in esketamine subjects who 
are responders but not remitters
To assess the potential relationship of biomarkers with response/non-response to intranasal 
esketamine or oral antidepressants in adult subjects with TRDa.
a: Not applicable to China
1.2.
Trial Design
This is a randomized, double-blind, active-controlled, multicenter study in male and female adult 
subjects with TRD to assess the efficacy, safety, tolerability, and pharmacokinetics of flexibly 
dosed intranasal esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant compared 
with a newly initiated oral antidepressant (active comparator) plus intranasal placebo. 
The study has 3 phases;

Screening/Prospective Observational Phase 

Double-blind Treatment Phase 

Follow-up Phase


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Screening/Prospective Observational phase (4-week duration + optional 3-week taper 
period) 
This phase will prospectively assess treatment response to the subject’s current oral antidepressant 
treatment regimen. 
At the start of the screening/prospective observational phase, the subject must have had 
documented non-response to at least 1 antidepressant treatment (based on Massachusetts General 
Hospital–Antidepressant Treatment Response Questionnaire [MGH-ATRQ]) in the current 
episode of depression, and subject is taking a different oral antidepressant treatment (on the MGH-
ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose. This 
antidepressant treatment, as well as any other ongoing medications being taken for depression at 
screening (including adjunctive/augmentation therapies), will continue from the start of Week 1 
through the end of Week 4 of the screening/prospective observational phase. Dose adjustment is 
permitted per clinical judgment, but the oral antidepressant treatment is to remain at or above the 
minimum therapeutic dose (per the MGH-ATRQ) through the end of Week 4. Antidepressant 
treatment adherence will be assessed using the PAQ. Subjects who report missing ≥4 days of 
antidepressant medication treatment(s) in the prior 2-week period will be considered as screen 
failed due to inadequate adherence.
After 4 weeks, subjects who are non-responders to their current oral antidepressant treatment (as 
assessed by independent, remote raters) may be eligible to proceed to the double-blind treatment 
phase. Non-response at the end of the screening/prospective observational phase is defined as 
≤25% improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total score 
of ≥28 on Week 2 and Week 4.
Eligible subjects who are entering the double-blind treatment phase will discontinue all of their 
current medication(s) being taken for depression (including adjunctive/augmentation therapies), 
and any other prohibited psychotropic medications (including adjunctive atypical antipsychotics). 
Subjects taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of 
lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, zaleplon, 
eszopiclone and ramelteon) during the screening/prospective observational phase, can continue 
these medications during the treatment phase. No dose increases beyond the equivalent of 
6 mg/day of lorazepam or new benzodiazepine medications are permitted during the 
screening/prospective observational phase. If clinically indicated, a subject’s current 
antidepressant treatment(s) may be tapered and discontinued over an additional, optional period of 
up to 3 weeks per the local prescribing information or clinical judgment, or discontinued and 
switched directly to one of the four new oral antidepressant medications on Day 1 of the double-
blind treatment phase, per clinical judgment.
Double-blind Treatment Phase (4-week duration) 
Approximately 234 eligible subjects (210 Chinese subjects, 24 non-Chinese subjects) with TRD, 
will be randomly assigned at a 1:1 ratio (n=117 subjects per treatment arm, with approximately 
105 Chinese subjects per arm) to receive double-blind treatment with either intranasal esketamine 
or intranasal placebo. The intranasal treatment sessions (esketamine 56 mg, 84 mg or placebo) will 


JNJ-54135419  (esketamine)
Statistical Analysis Plan ESKETINTRD3006
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Approved, Date: 5 February 2021
occur twice per week for 4 weeks as a flexible dose regimen at the study site. In addition, all 
subjects will initiate a new open-label oral antidepressant on Day 1, that will be taken daily for the 
duration of the double-blind treatment phase. The assigned oral antidepressant will be 1 of 4 oral 
antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine extended release 
[XR]), that the subject has not previously had a non-response to in the current depressive episode, 
has not been previously intolerant to (lifetime), and is available in the participating country.
Subjects who were taking benzodiazepines (at dosages equal to or less than the equivalent of 
6mg/day of lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, 
zaleplon, eszopiclone and ramelteon) during the screening/prospective observational phase can 
continue these medications 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 (eg, alprazolam, clorazepate, triazolam, lorazepam and temazepam).
Intranasal Treatment Sessions: 
All subjects will self-administer the intranasal study medication (esketamine or placebo) at 
treatment sessions occurring twice a week for 4 weeks at the clinical site. Treatment is assigned 
by the Interactive Web Response System (IWRS). 
On Day 1, subjects randomized to intranasal esketamine will start with a dose of 56 mg. On any 
of the subsequent dosing days (Day 4, 8, 11, 15, 18, 22 and 25), the investigator can judge, based 
on efficacy and tolerability, whether to increase the dose of intranasal esketamine to 84 mg or to 
maintain the dose at 56 mg. In the event that an increase in dose is poorly tolerated, the investigator 
may decide to reduce the dose to 56 mg. 
Oral Antidepressant Treatment: 
Starting on Day 1 of the double-blind treatment phase, a new open-label oral antidepressant 
treatment will be initiated in all subjects. The oral antidepressant selected will be 1 of the 4 oral 
antidepressant medications allowed (duloxetine, escitalopram, sertraline, or venlafaxine extended 
release [XR]). The antidepressant medication will be assigned by the investigator based on review 
of MGH-ATRQ and relevant prior antidepressant medication information, and will be one that the 
subject has not previously had a non-response to, in the current major depressive episode, has not 
been previously intolerant to (lifetime), and is available in participating country. 
The use of the titration schedule provided in the protocol is mandatory. Doses are not to exceed 
the maximum dose defined in the titration schedule. If higher doses are not tolerated, a down-
titration is permitted based on clinical judgment. 
If a subject withdraws from the study before the end of the double-blind treatment phase for 
reasons other than withdrawal of consent, an Early Withdrawal visit should be conducted within 
1week of the date of discontinuation, followed by the follow-up phase.


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Follow-up Phase (8 weeks or until relapse) 
The follow-up phase will include all subjects who received at least 1 dose of intranasal study 
medication in the double-blind treatment phase unless the subjects will directly roll over to 
study 54135419TRD3008 after completing the 4-week treatment phase. No intranasal study 
medication will be administered during this phase.
Subjects participating in the 
ESKETINTRD3006 study, at US sites only, following completion of the 4-week double-blind 
treatment phase, and based on the clinical judgement of the investigator may proceed directly to 
the 54135419TRD3008 open label extension safety study, without entering the follow-up phase of 
the ESKETINTRD3006 study. Please refer to the 54135419TRD3008 protocol for full details.
At the start of the follow-up phase, further clinical/standard of care for the treatment of depression 
will be arranged by the study investigator and/or the subject’s treating physician and medication 
changes are permitted. The decision to continue the oral antidepressant in this phase will be at the
discretion of the investigator.
This follow-up phase will provide additional information required to assess the course of the 
subject’s major depressive episode over an 8-week period. Safety and tolerability, including 
potential withdrawal symptoms, following discontinuation of intranasal esketamine will also be 
assessed.
The follow-up phase is completed at the end of the 8-week period or when a subject meets the 
criteria below for relapse (in remitters and responders), whichever occurs first.
Relapse is defined as any of the following:

MADRS total score ≥22 for 2 consecutive assessments separated by 5 to 15 days. The 
date of the second MADRS assessment will be used for the date of relapse. 

Hospitalization for worsening depression or any other clinically relevant event 
determined per clinical judgment to be suggestive of a relapse of depressive illness such 
as suicide attempt, completed suicide, or hospitalization for suicide prevention. If 
hospitalized for any of these events, the start date of hospitalization will be used for the 
date of relapse. Otherwise the date of the event will be used if the subject is not 
hospitalized.

In case more than one relapse criteria are met, the earlier date will be defined as the date 
of relapse for this subject. 
The total duration of a subject’s study participation will be up to 19 weeks (including an optional 
3-week taper period) for subjects completing the 8-week follow-up phase.
A diagram of the study design is provided below in Figure 1.


JNJ-54135419  (esketamine)
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Figure 1:
Schematic Overview of the Study
-
AD = antidepressant; CH = Chinese subjects; D/C = discontinue; MDD = major depressive disorder; 
-
OL = open-label; PBO = placebo. 
-
The study will end after 8 weeks follow-up clinical/standard of care for treatment of depression, or following
relapse, whichever is earlier. 
1.3.
Statistical Hypotheses for Trial Objectives
The primary efficacy endpoint is the change in the MADRS total score as measured by the change 
from baseline (Day 1 prior to randomization) to the end of the 4-week double-blind treatment 
phase. The hypothesis for this study is that, in adult subjects with TRD, switching from a failed 
antidepressant treatment to intranasal esketamine plus a newly initiated oral antidepressant is 
superior to switching to a newly initiated oral antidepressant treatment (active comparator) plus 
intranasal placebo in improving depressive symptoms based on the primary efficacy endpoint.
1.4.
Sample Size Justification
Assuming a treatment difference for the double-blind phase of 6.5 points in MADRS total score 
between esketamine plus oral antidepressant compared with oral antidepressant plus intranasal 
placebo at the Week 4 endpoint, a standard deviation of 12, a one-sided significance level of 0.025, 
and a drop-out rate of 25%, approximately 117 subjects will be randomized to each treatment arm
to achieve greater than 90% power, and a sample size of 105 Chinese subjects per treatment arm 
(total n = 210) plus 12 non-Chinese subjects per treatment arm (total n = 24) will be included. The 
treatment difference and standard deviation used in this calculation were based on results from 
Panel A of the ESKETINTRD2003 study and based on clinical judgment.


JNJ-54135419  (esketamine)
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Approved, Date: 5 February 2021
1.5.
Randomization and Blinding
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, to 
increase the likelihood that known and unknown subject attributes (eg, demographic and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups.
Central randomization will be implemented in this study. Subjects will be randomly assigned to 1 
of 2 treatment groups in a 1:1 ratio based on a computer-generated randomization schedule 
prepared before the study by or under supervision of the sponsor. The randomization will be 
balanced by using randomly permuted blocks and will be stratified by country, class of oral 
antidepressant (SNRI or SSRI) and consent to biomarker evaluation (Yes or No) to be initiated in 
the double-blind treatment phase. The interactive web response system (IWRS) will assign a 
unique treatment code, which will dictate the treatment assignment and matching study drug kits 
for the subject. After the investigator selects the oral antidepressant treatment for the double-blind 
treatment phase, the site will enter this information into IWRS. The requestor must use his or her 
own user identification and personal identification number when contacting the IWRS, and will 
then give the relevant subject details to uniquely identify the subject.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (eg, intranasal study drug plasma 
concentrations, treatment allocation) will be handled with special care to ensure that the integrity 
of the blind is maintained and the potential for bias is minimized. This can include making special 
provisions, such as segregating the data in question from view by the investigators, clinical team, 
or others as appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until all subjects have completed the 
study and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment/course of action would be dictated by knowing the treatment status of the 
subject. In such cases, the investigator may in an emergency determine the identity of the treatment 
by contacting the IWRS. It is recommended that the investigator contact the sponsor or its 
designee, if possible, to discuss the particular situation, before breaking the blind. Telephone 
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In the 
event the blind is broken, the sponsor must be informed as soon as possible. The date and time of 
the unblinding will be documented by the IWRS, and reason for the unblinding must be 
documented by the electronic case report form (eCRF) and in the source document. The 
documentation received from the IWRS indicating the code break must be retained with the 
subject's source documents in a secure manner.
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled early withdrawal and follow up visits.


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In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. 
To maintain the blinding of intranasal study medication, the esketamine and placebo intranasal 
devices will be indistinguishable. An intranasal placebo control will be used in the double-blind 
treatment phase to establish the frequency and magnitude of changes in clinical endpoints that may 
occur in the absence of intranasal active treatment.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
As subjects 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 Study Day 1 (definition in section 2.4). If a subject has 2 or more 
actual visits in one visit window, the visit closest to the target day will be used as the protocol visit 
for that visit window. The other additional visit(s) will not be used in the summaries or analyses,
but they can be used for determination of clinically important endpoints. If 2 actual visits are 
equidistant from the target day within a visit window, the later visit is used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point except for the endpoint. Listed below 
(Table 1) are the visit windows and the target days for each visit defined in the protocol.
Table 1:
Visit Windows
Parameter
Analysis Phase
Scheduled Visit 
Number
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Timea Point 
(Day)
MADRS
Screening
1.1
Week 1 (SC)
1.2
Week 2 (SC)
1.3
Week 4 (SC)
DB
2.1
Baseline
≤1
1
2.2
Day 2 
2-3
2
2.4
Day 8
4-11
8
2.6
Day 15
12-18
15
2.8
Day 22
19-24
22
2.10
Day 28
25 to end of DB
28
DB final visit
End Point (DB) 
2 to end of DB
Follow-up
3.1
Week 1 (F/U)
1- 10
7
3.2
Week 2 (F/U)
11-17
14
3.3
Week 3 (F/U)
18-24
21
3.4
Week 4 (F/U)
25-31
28
3.5
Week 5 (F/U)
32-38
35
3.6
Week 6 (F/U)
39-45
42
3.7
Week 7 (F/U)
46-52
49
3.8
Week 8 (F/U)
53 to end of F/U
56
F/U final visit
End point (F/U)
2 to end of F/U


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Table 1:
Visit Windows
Parameter
Analysis Phase
Scheduled Visit 
Number
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Timea Point 
(Day)
SDS
Screening
1.1
Week 1 (SC)
DB
2.1
Baseline
≤1
1
2.6
Day 15 
12-21
15
2.10
Day 28
22 to end of DB
28
DB final visit
End Point (DB) 
2 to end of DB
Follow-up
3.2
Week 2 (F/U)
1-24
14
3.5
Week 5 (F/U)
25-40
35
3.8
Week 8 (F/U)
41 to end of F/U
56
F/U final visit
End point (F/U)
2 to end of F/U
CGI-S
Screening
1.1
Week 1 (SC)
DB
2.1
Baseline
≤1
1
2.3
Day 4
2-6
4
2.4
Day 8
7-9
8
2.5
Day 11
10-13
11
2.6
Day 15
14-18
15
2.8
Day 22
19-24
22
2.10
Day 28
25 to end of DB
28
DB final visit
End Point (DB) 
2 to end of DB
Follow-up
3.2
Week 2 (F/U)
1-24
14
3.5
Week 5 (F/U)
25-40
35
3.8
Week 8 (F/U)
41 to end of F/U
56
F/U final visit
End point (F/U)
2 to end of F/U
GAD-7
Screening
1.1
Week 1 (SC)
DB
2.1
Baseline
≤1
1
2.10
Day 28
2 to end of DB
28
DB final visit
End Point (DB) 
2 to end of DB
Follow-up
3.2
Week 2 (F/U)
124
14
3.5
Week 5 (F/U)
25-40
35
3.8
Week 8 (F/U)
41 to end of F/U
56
F/U final visit
End point (F/U)
2 to end of F/U
EQ-5D-5L
Screening
1.1
Week 1 (SC)
DB
2.1
Baseline
1
1
2.6
Day 15 
2-21
15
2.10
Day 28
22 to end of DB
28
DB final visit
End Point (DB) 
2 to end of DB
Follow-up
3.2
Week 2 (F/U)
124
14
3.5
Week 5 (F/U)
2540
35
3.8
Week 8 (F/U)
41 to end of F/U
56
F/U final visit
End point (F/U)
2 to end of F/U
Vital Signs
(TEMP [predose at each 
visit], BPb, HR, RESP 
[at each visit, predose, 
40M, 1H, 1.5H])
DB
2.1
Baseline
Day 1: Predose
Day 1: 40M
Day 1: 1H
Day 1: 1H30M
≤1/predose
1
2.3
Day 4: Predose
Day 4: 40M
Day 4: 1H
Day 4: 1H30M
2-6
4
2.4
Day 8: Predose
Day 8: 40M
Day 8: 1H
Day 8: 1H30M
7-9
8
2.5
Day 11: Predose
Day 11: 40M
Day 11: 1H
Day 11: 1H30M
10-13
11


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Table 1:
Visit Windows
Parameter
Analysis Phase
Scheduled Visit 
Number
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Timea Point 
(Day)
2.6
Day 15: Predose
Day 15: 40M
Day 15: 1H
Day 15: 1H30M
14-16
15
2.7
Day 18: Predose
Day 18: 40M
Day 18: 1H
Day 18: 1H30M
17-20
18
2.8
Day 22: Predose
Day 22: 40M
Day 22: 1H
Day 22: 1H30M
21-23
22
2.9
Day 25: Predose
Day 25: 40M
Day 25: 1H
Day 25: 1H30M
24 to end of DB
25
DB final visit
End Point (DB)
Day 1: 40M to 
end of DB
Follow-up
3.2
Week 2 (F/U)
1-24
14
3.5
Week 5 (F/U)
25-45
35
3.8
Week 8 (F/U)
46 to end of F/U
56
F/U final visit
End point (F/U)
2 to end of F/U
Weight and BMI
DB
2.1
Baseline
≤1
1
2.10
Day 28
2 to end of DB
28
DB final visit
End Point (DB) 
2 to end of DB
Follow-up
3.8
Week 8 (F/U)
46 to end of F/U
56
F/U final visit
End point (F/U)
2 to end of F/U
ECG
DB
2.1
Baseline
≤1/Predose
1
2.1
Day 1: 1H
1
1
2.4
Day 8: 1H
2-16
8
2.9
Day 25: 1H
17 to end of DB
25
DB final visit
End Point (DB) 
2 to end of DB
Lab
(Hematology, 
Chemistry)
DB
2.1
Baseline
≤1/predose
1
2.10
Day 28
2 to end of DB
28
DB final visit
End Point (DB) 
2 to end of DB
Follow-up
3.2
Week 2 (F/U)
2 to end of F/U
14
Lab
(Urinalysis)
DB
2.1
Baseline
≤1/predose
1  
2.6
Day 15
2-21
15
2.10
Day 28
22 to end of DB
28
DB final visit
End Point (DB) 
2 to end of DB
Follow-up
3.2
Week 2 (F/U)
2 to end of F/U
14
C-SSRS
Screening
1.1
Week 1 (SC)
1.2
Week 2 (SC)
1.3
Week 4 (SC)
DB
2.1
Baseline
≤1
1
2.3
Day 4
2-6
4
2.4
Day 8
7-9
8
2.5
Day 11
10-13
11
2.6
Day 15
14-16
15
2.7
Day 18
17-20
18
2.8
Day 22
21-23
22
2.9
Day 25
24-26
25
2.10
Day 28
27 to end of DB
28
DB final visit
End Point (DB) 
1 to end of DB
Follow-up
3.1
Week 1 (F/U)
1-10
7
3.2
Week 2 (F/U)
11-17
14
3.3
Week 3 (F/U)
18-24
21


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Table 1:
Visit Windows
Parameter
Analysis Phase
Scheduled Visit 
Number
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Timea Point 
(Day)
3.4
Week 4 (F/U)
25-31
28
3.5
Week 5 (F/U)
32-38
35
3.6
Week 6 (F/U)
39-45
42
3.7
Week 7 (F/U)
4652
49
3.8
Week 8 (F/U)
53 to end of F/U
56
F/U final visit
End point (F/U)
2 to end of F/U
PWC-20
DB
2.9
Day 25
2 to end of DB
25
DB final visit
End Point (DB) 
2 to end of DB
Follow-up
3.1
Week 1 (F/U)
1-10
7
3.2
Week 2 (F/U)
11 to end of F/U
14
F/U final visit
End Point (F/U) 
2 to end of F/U
Nasal exam
DB
2.1
Baseline
≤1
1
2.10
Day 28
2 to end of DB
28
DB final visit
End Point (DB) 
2 to end of DB
CADSS
DB
2.1
Day 1: predose
Day 1: 40M
Day 1: 1H30M
≤1/predose
1
2.3
Day 4: predose
Day 4: 40M
Day 4: 1H30M
2-6
4
2.4
Day 8: predose
Day 8: 40M
Day 8: 1H30M
7-11
8
2.6
Day 15: predose
Day 15: 40M
Day 15: 1H30M
12-18
15
2.8
Day 22: predose
Day 22: 40M
Day 22: 1H30M
19-23
22
2.9
Day 25: predose
Day 25: 40M
Day 25: 1H30M
24 to end of DB
25
Pulse oximetry
(every 15 minutes from 
predose to t=1.5 hours 
postdose)c
DB
2.1
Day 1 : Predose
Day 1: 15M
Day 1：30M
Day 1: 45M
Day 1: 1H
Day 1: 1H15M
Day 1: 1H30M
≤1/predose
1
2.3
Day 4 : Predose
Day 4: 15M
Day 4：30M
Day 4: 45M
Day 4: 1H
Day 4: 1H15M
Day 4: 1H30M
2-6
4
2.4
Day 8: Predose
Day 8: 15M
Day 8：30M
Day 8: 45M
Day 8: 1H
Day 8: 1H15M
Day 8: 1H30M
7-9
8
2.5
Day 11: Predose
Day 11: 15M
Day 11：30M
Day 11: 45M
Day 11: 1H
10-13
11


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Table 1:
Visit Windows
Parameter
Analysis Phase
Scheduled Visit 
Number
Time Interval
(label on output)
Time Intervala
(Day)
Target 
Timea Point 
(Day)
Day 11: 1H15M
Day 11: 1H30M
2.6
Day 15: Predose
Day 15: 15M
Day 15：30M
Day 15: 45M
Day 15: 1H
Day 15: 1H15M
Day 15: 1H30M
14-16
15
2.7
Day 18: Predose
Day 18: 15M
Day 18：30M
Day 18: 45M
Day 18: 1H
Day 18: 1H15M
Day 18: 1H30M
17-20
18
2.8
Day 22: Predose
Day 22: 15M
Day 22：30M
Day 22: 45M
Day 22: 1H
Day 22: 1H15M
Day 22: 1H30M
21-23
22
2.9
Day 25: Predose
Day 25: 15M
Day 25：30M
Day 25: 45M
Day 25: 1H
Day 25: 1H15M
Day 25: 1H30M
24 to end of DB
25
a For double-blind (DB) treatment phase, time interval is relative to the date of Study Day 1 of the DB phase. For the follow-up 
(F/U) phase, since the scheduled visits are related to the last intranasal dose, accordingly time interval is relative to the date of the
last intranasal dose.
b During the DB phase, at 1.5 hours post dose if the SBP is ≥160 mmHg and/or DBP is ≥100 mmHg, assessments should 
continue every 30 minutes until the blood pressure is <160 mmHg and/or <100 mmHg or investigator’s clinical judgment the 
subject it is clinical stable and can be discharged from the clinical site.
c If oxygen saturation levels are <93% at any time during the 1.5 hour postdose interval, pulse oximetry will be recorded every 
5 minutes until levels return to ≥93% or until the subject is referred for appropriate medical care, if clinically indicated.
2.2.
Analysis Sets
2.2.1.
All Randomized Analysis Set
The all randomized analysis set includes all subjects who were randomized in the study
(i.e., subjects who reported a randomization date, or were assigned a randomization number) 
regardless of whether or not treatment was received. This analysis set will be used for summarizing 
the overall study completion/withdrawal information.


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2.2.2.
Efficacy Analysis Set(s)
2.2.2.1.
Primary Efficacy Analysis Set
Full analysis set (FAS) is the primary efficacy analysis set, which includes all randomized subjects 
who received a least 1 dose of intranasal study medication and 1 dose of oral antidepressant 
medication during the double-blind treatment phase. FAS will be used for all efficacy analysis.
2.2.2.2.
Secondary Efficacy Analysis Set
Per-protocol set is the secondary efficacy analysis set, which includes a subset of subjects in the 
FAS who is in-compliance with the protocol. Compliance is defined as no major protocol 
deviations. List of major protocol deviations is specified in Section 4.5. Per-protocol set will be 
used as sensitivity analyses for the primary efficacy analyses.
2.2.3.
Safety Analysis Set
The safety analysis set is defined for the double-blind treatment phase. The safety analysis set 
includes all randomized subjects who received at least 1 dose of intranasal study medication or 
1 dose of oral antidepressant medication during the double-blind treatment phase. Analyses of 
change from baseline will include only subjects who have both baseline and at least 1 postbaseline 
observation during that phase. Screen failures and randomized subjects who received no double-
blind study medication will be excluded from the safety analysis set. Subjects who received an 
incorrect treatment will be analyzed under the planned treatment. This analysis set will be used for 
safety analyses.
2.2.4.
Follow-up Analysis Set
The Follow-up analysis set is defined as all subjects who enter the follow-up phase. This analysis 
set will be used for both efficacy and safety analyses.
2.2.5.
Pharmacokinetics Analysis Set
The pharmacokinetic population will consist of all subjects who received at least 1 dose of 
intranasal study medication and have at least 1 post treatment sample collected during treatment.  
2.2.6.
Biomarker and Pharmacogenomics Analysis Set
The definition of analysis set and analyses will be provided in a separate document if the available 
number of subjects is sufficient.
2.3.
Definition of Subgroups
Definition of subgroups are presented in Table 2.


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Table 2:
Definition of Subgroups
Subgroup
Definition
Country
China
US
Age Group
Adults
18-44 years
45-64 years
Sex
Female
Male
Number of Previous Treatment Failures in Current Episode
Based on ATRQ
Functional Impairment based on Baseline SDS Total Score
No impaired (0-3)
Mile (4-11)
Moderate (12-19)
Marked (20-26)
Extreme (27-30)
Baseline MDRS total Score
≤median
> median
Class of antidepressant study medication
SSRI
SNRI
BMI
≤median (kg/M2)
> median (kg/M2)
Employee Status
Employment
Unemployment
Duration of current episode
≤2 years
> 2 years
Number of classes of prior failed antidepressant medications
< 2
≥2
Individual antidepressant study medication
Duloxetine
Escitalopram
Sertraline
Venlafaxine extended release (XR)
2.4.
Study Day and Relative Day
Study Day
Study Day 1 or Day 1 refers to the earlier of date of the first dose of intranasal study medication, 
or the oral antidepressant study drug (study Day 1 is not available for screened subjects who did 
not take any intranasal study drug or oral antidepressant study drug). All efficacy and safety 
assessments at all visits will be assigned a day relative to the date of Study Day 1.
Study day for a visit is defined as:

Visit date - (date of Study Day 1) +1, if visit date is ≥date of Day 1

Visit date - Date of Day 1, if visit date <date of Day 1
There is no 'Day 0'.
Relative Day
The start date of the double-blind treatment phase (referred to as ‘DB start date’) is the same as 
date of Study Day 1. The start date/time of the double-blind treatment phase (referred to as, ‘DB 
start date/time’) is the DB start date and the time of the first dose of intranasal study medication. 


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If no intranasal study medication is administered or it is administered after the start of oral 
antidepressant, then the time will be left blank.
The start date of the follow-up phase (referred to as ‘F/U start date’) is the day after the DB end 
date.
Relative day to the analysis phase start date for a visit is defined as:

Visit date - (analysis phase start date) +1, if visit date is ≥analysis phase start date

Visit date - analysis phase start date, if visit date is < analysis phase start date
Time window for a follow-up phase is assigned based on the relative day to the date of last 
intranasal dose, which the relative day is defined as:

Visit date - (the last intranasal dose date) +1, if visit date is ≥the last intranasal dose date

Visit date - the last intranasal dose date, if visit date is < the last intranasal dose date
Note that the relative day to F/U start date will be presented in the listing but not be used to derive 
the time window of follow-up phase.
The double-blind treatment phase end date (referred to as ‘DB end date’) is the date of 
completion/withdrawal from the double-blind treatment phase.
The follow-up phase end date (referred to as ‘F/U end date’) is the maximum of the last follow-up 
visit date or end of trial date.
2.5.
Baseline and Endpoint
Baseline is defined as the last observation before receiving the first dose of any study medication 
in the double-blind treatment phase. Baseline is defined for each parameter/assessment.
The double-blind endpoint is defined as the last available postbaseline result during the double-
blind treatment phase. Unscheduled visit results are included in this definition and will be 
considered as the endpoint value if the unscheduled visit result is the last postbaseline result 
available within the analysis period.
2.6.
Imputation Rules for Missing AE Date/Time of Onset/Resolution
Treatment-emergent adverse events (TEAEs) for the double-blind treatment phase are those events 
with an onset date/time on or after the start of study medication and occurred on or before the end 
of the double-blind phase. Adverse events (AEs) for the follow-up phase are those events with an 
onset date on or after the start of the follow-up phase and occurred on or before the end of the 
follow-up phase. A conservative approach will be used to handle the missing dates for adverse 
events.


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Onset Date
Partial AE onset dates will be imputed as follows:

If the onset date of an adverse event is missing day only, it will be set to:

First day of the month that the AE occurred, if month/year of the onset of AE is different 
than the month/year of the DB start date

The day of DB start date, if the month/year of the onset of AE is the same as month/year 
of the DB start date and month/year of the AE resolution date is different

The day of DB start date or day of AE resolution date, whichever is earliest, if month/year 
of the onset of AE and month/year of the DB start date and month/year of the AE 
resolution date are same

If the onset date of an adverse event is missing both day and month, it will be set to the earliest 
of:

January 1 of the year of onset, as long as this date is on or after the DB start date

One day after the DB start date, if this date is the same year that the AE occurred

Last day of the year if the year of the AE onset is prior to the year of the DB start date,

The AE resolution date.

Completely missing onset date of an adverse event will be set to the DB start date.
Resolution Date
Partial AE resolution dates not marked as ongoing will be imputed as follows:

If the resolution date of an adverse event is missing day only, it will be set to the earliest of 
the last day of the month of occurrence of resolution, the day of withdrawal, study completion, 
or the day of the date of death, if withdrawal, study completion, or death occurred in that 
month.

If the resolution date of an adverse event is missing both day and month, it will be set to the 
earliest of the date of withdrawal, study completion, December 31 of the year, or the day and 
month of the date of death, if the death occurred in that year.

Completely missing resolution dates will not be imputed.
Time
AE onset/resolution dates with missing times will be imputed as follows:

A missing time of onset of an adverse event will be set as follows:

00:00 as long as the onset date is after the DB start date

00:00 if the date is the same as DB start date, but the intranasal study medication in the 
double-blind treatment phase was started after the oral antidepressant medication in this 
phase


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
The time of intranasal medication start in the double-blind treatment phase if the date is 
the same as DB start date, and the intranasal medication was started on or before the oral 
antidepressant medication in this phase.

The missing time of resolution of an adverse event will be set to 23:59.
If a missing time is associated with a partial or missing date, the date will be imputed first prior to 
imputing the time.
2.7.
Imputation Rules for Missing Concomitant Medication Dates
If a partial date is reported, it is assumed the medication (or therapy) was taken in all phases that 
overlap with the partial date. If both start and end dates are missing but this concomitant 
medication was taken both prior to the study entry and still ongoing at study end, it is assumed 
medication was taken in all phases.
The rules for estimating an incomplete concomitant medication start date are as follows:

If the month of the concomitant medication start date is equal to the month of the start of the 
Double-Blind phase, then the estimated start date is the DB start date; 

If the month of the concomitant medication start date is greater than the month of the start of 
the Double-Blind phase and earlier than the study end date, then the estimated start date of the 
concomitant medication is the first day of the month; 

If the month of the concomitant medication start date is greater than the month of the study 
end date, then no imputation will be done; 

If the month and year of the concomitant medication start date are known and the DB start 
date is after the month of the concomitant medication start date, then no imputation will be 
done; 

If either the month or year of the concomitant medication start date is missing, no imputation 
is to be performed.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
No interim analysis is planned in this study.
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Demographic and baseline characteristics (Table 3) and psychiatric history at baseline (Table 4) 
will be summarized by treatment group and overall for the Safety and Full analysis sets.  In 
addition, a separate summary will be presented by treatment group and country (China, non-China) 
for Safety and Full analysis sets.


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Table 3:
Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median and 
range [minimum and maximum]).
Baseline Weight (kg)
Baseline Height (cm)
Baseline Body Mass Index (BMI) (kg/m2)
Categorical Variables
Age (18-44 years and 45-64 years)
Frequency distribution with the number 
and percentage of subjects in each 
category.
Sex (male, female, undifferentiated)
Race (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or other Pacific Islander, White, Other, Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
Baseline BMI ([underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, overweight 25-
<30 kg/m2, obese ≥30 kg/m2])
Employment Status
Hypertension Status
Class of antidepressant (SSRI/SNRI)
Oral antidepressant
Country
aIf multiple race categories are indicated, the Race is recorded as 'Multiple'
Table 4: 
Psychiatric History at Baseline Variables
Continuous Variables:
Summary Type
Baseline MADRS total score
Descriptive statistics (N, mean, 
standard deviation [SD], median and 
range [minimum and maximum]).
Baseline CGI-S score
Age (years) when diagnosed with MDD
Duration of current episode 
Categorical Variables
Baseline CGI-S score
Frequency distribution with the number 
and percentage of subjects in each 
category.
Screening C-SSRS category (no event, suicidal ideation, suicidal behavior)
Duration of current episode categorize (<=2 years, >2 years)
Antidepressant treatment history (number of medications with non-response taken 
for at least 6 weeks during the current episode as obtained in the MGH-ATRQ)
Number of depressive episodes
Number of classes of prior failed antidepressant medications
Family history of
-
Depression
-
Anxiety Disorder
-
Bipolar Disorder 
-
Schizophrenia 
-
Alcohol Abuse
-
Substance Abuse
4.2.
Disposition Information
The distribution of the number of subjects who are randomized, receive double-blind treatment 
and complete the double-blind treatment phase will be presented by treatment group for overall
population. A separate summary will be presented by treatment group and country (China, US).
In addition, the distribution of reasons for discontinuation will be presented. These summaries will 
be provided for the All Randomized and Safety analysis sets. A subject will be considered to have 
completed the double-blind treatment phase if the subject has completed assessment through 
Day 28. The distribution of the number of subjects who enter the follow-up phase and complete 
all follow-up visits will be presented by treatment group for China population. The reasons for 


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discontinuation will be presented. In addition, the number of subjects who enroll in 
study ESKETINTRD3008 will be provided.
The number of subjects in each analysis set will be presented by treatment group for overall
population. The distribution of screened subjects will be presented by country and site ID.
Screened subjects and reason for screen failures will be summarized for overall population.
A listing of subjects will be provided for the following categories:

Subjects who discontinued the double-blind treatment phase

Subjects who discontinued the study

Subjects who were unblinded during the double-blind treatment phase

Subjects who were randomized yet did not receive study medication.
4.3.
Treatment Compliance
Doses of oral AD will be summarized using descriptive statistics of the mean dose (days on drug),
mode dose (days on drug) and the final dose, by each type of oral AD for both the double-blind 
treatment and follow-up phases. In addition, percent compliance of the oral AD will be calculated 
as, days actually dosed/days expected to be dosed*100, and summarized.
4.4.
Extent of Exposure
Extent of exposure in terms of total duration of exposure and number of dosing sessions of 
intranasal study medication and oral AD will be summarized for the Full analysis set and the Safety 
analysis set.
The total duration of exposure for the intranasal study drug and for each type of oral antidepressant 
(AD) during the double-blind treatment phase is defined as (date of last dose of each type of study 
medication – date of first dose of each type of study medication) +1.
Descriptive statistics (N, mean, SD, median, minimum and maximum) of total duration of 
exposure of intranasal study drug will be presented. The total duration of intranasal study drug 
exposure in the double-blind treatment phase will be presented using the following categories: 
≤7 days, 8-14 days, 15-21 days, 22-25 days, >25 days. A frequency distribution of the total number 
of dosing sessions of intranasal study medication during the double-blind treatment phase will be 
presented. A frequency distribution of dose level will be presented for each dosing session.
The total duration of exposure of oral AD will be summarized similarly to the intranasal study 
drug, however the following categories will be used for the double-blind treatment phase: ≤7 days, 
8-14 days, 15-21 days, 22-28 days, >28 days and for the follow-up phase: ≤7 days, 8-14 days, 
15-21 days, 22-28 days, 29-35 days, 36-42 days, 43-49 days, 50-56 days, >56 days. Each type of 
oral AD will be summarized separately.


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Modal dose for a subject is defined as the most frequently taken dose by a subject. Mean dose of 
a subject is calculated as the sum of doses during the double-blind treatment phase divided by the 
total number of days exposed. The final dose is the last non-zero dose received during the double-
blind treatment phase. The calculation of mean, mode and final dose will exclude days off study 
drug. 
Descriptive statistics (N, mean, SD, median, minimum and maximum) of modal dose, mean and 
final dose of intranasal study drug will be presented. Doses of oral AD will be summarized using 
descriptive statistics of the mean dose (days on drug), mode dose (days on drug) and the final dose, 
by each type of oral AD for both the double-blind treatment and follow-up phases.
A summary of descriptive statistics that will be done for the double-blind treatment phase are 
listed:

Total duration of exposure of intranasal study drug for double-blind treatment phase

Total duration of exposure of oral AD for both the double-blind treatment phase and follow-
up phase

Modal dose, mean and final dose of intranasal study drug

Modal dose, mean and final dose of oral AD
Summary of other analyses include:

Frequency distribution of the total number of dosing sessions of intranasal study medication 
during the double-blind treatment phase

Frequency distribution of dose level will be presented for each dosing session

Doses of oral AD
4.5.
Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
subjects’ rights, safety or well-being, or the integrity and/or result of the clinical study. Subjects 
with major protocol deviations will be identified prior to database lock and the subjects with major 
protocol deviations will be summarized by category. More categories may be included depending 
on the nature of the protocol deviation.

Developed withdrawal criteria but not withdrawn

Entered but did not satisfy criteria

Received a disallowed concomitant treatment

Received wrong treatment or incorrect dose

Other
Minor protocol deviations related to COVID-19 will be included in the listing.


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4.6.
Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Prior medications are defined as any therapy used before the day of first 
dose of study agent. Concomitant medications are defined as any therapy used on or after the same 
day as the first dose of study agent, including those that started before and continue on after the 
first dose of study agent.
Antidepressant medications taken prior to the baseline visit will be summarized by treatment group 
for the Safety analysis set.
Summaries of concomitant medications will be presented by treatment group, and study phase for 
the Safety analysis set and for the Follow-Up analysis set. The proportion of subjects who receive 
each concomitant medication will be summarized as well as the proportion of subjects who receive 
at least one concomitant medication. 
5.
EFFICACY
The efficacy data will be summarized by treatment group in each study phase. Primary and key 
secondary efficacy analyses will be presented for overall and China populations, separately. 
Analysis population for other endpoints will be overall population unless otherwise specified.
The efficacy variables for this study are listed in Table 5.
Table 5: 
Efficacy Variables
Efficacy Variable
Endpoint
MADRS

Change in MADRS from Baseline to Day 28 (DB) 
Primary 

Change in MADRS from Baseline to 24 hours (Day 2)
Key Secondary

Onset of Clinical Response (achieving at least 50% 
improvement with onset by Day 2 that is maintained to Day 
28 with one excursion) 
Secondary

Proportion of responders (≥50% reduction from baseline in 
MADRS total score) at the end of the 4 week double-blind 
treatment phase.
Secondary

Proportion of subjects in remission (MADRS ≤12) at the end 
of the 4 week double-blind treatment phase
Secondary

Proportion of subjects who remain in remission (MADRS 
≤12) through to the end of the follow-up phase
Secondary

Proportion of subjects who remain as responders (≥50% 
reduction from baseline in MADRS total score) through to 
the end of the follow-up phase
Secondary

Response rates over time (at least 50% improvement from 
baseline) 
Secondary

Remission rates over time (MADRS≤12)
Secondary

Time to sustained response (first occurrence of response that 
is maintained through Day 28 with one excursion)
Secondary

Time to sustained remission (first occurrence of remission 
that is maintained through Day 28 with one excursion)
Secondary

Proportion of subjects ≥30% reduction from baseline in 
MADRS total score at the end of the 4-week double-blind 
treatment phase
Exploratory

Change in MADRS6 subscale from Baseline to Day 28 (DB)
Exploratory


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Table 5: 
Efficacy Variables
Efficacy Variable
Endpoint
SDS

Change in SDS from Baseline to Day 28 
Key Secondary

Change in SDS during the F/U phase
Secondary

Response based on SDS over time
Secondary

Remission based on SDS over time
Secondary
CGI-S

Change in CGI-S from Baseline to Day 28
Secondary
GAD-7

Change in GAD-7 from Baseline to Day 28 or End Point 
(DB)
Secondary
EQ-5D-5L, 

Change from Baseline to Day 28 or End Point (DB)
Secondary
Relapse

Time to relapse during the F/U phase for subjects who are 
remitters at the end of DB phase
Exploratory

Time to relapse during the F/U phase for subjects who are 
responders but not remitters
Exploratory

Proportion of subjects who relapse during the F/U phase for 
subjects who are remitters 
Exploratory

Proportion of subjects who relapse during the F/U phase for 
subjects who are responders but not remitters
Exploratory
5.1.
Analysis Specifications
5.1.1.
Level of Significance
Statistical analysis tests will be conducted at a 2-sided 0.05 level of significance unless specified 
otherwise.
A serial gatekeeping (fixed sequence) approach will be applied to adjust for multiplicity and to 
strongly control type I error across the primary and the 2 key secondary efficacy endpoints (onset 
of clinical response, change in SDS total score. The 2 key secondary endpoints will be analyzed 
sequentially and will be considered statistically significant at the 2-sided 0.05 level only if the 
endpoint is individually significant at the 2-sided 0.05 level and previous endpoints in the hierarchy 
were significant at the 2-sided 0.05 level, including the primary endpoint. If the primary endpoint 
is statistically significant, the selected secondary endpoints will be assessed in the following order:

Change in MADRS total score at 24 hours post first dose

Change in SDS total score from Baseline to Day 28
5.1.2.
Data Handling Rules
The last post baseline observation during the double-blind treatment phase will be carried forward 
as the “End Point” for that phase. Imputation of the MADRS total score is described in 
Section 5.2.1. For all other scales where multiple items are summed to create a total, if any item 
of the scale is missing at a visit, the total score for that scale at that visit will be left blank.
5.2.
Primary Efficacy Endpoint
5.2.1.
Definition
The primary efficacy endpoint is the change in MADRS total score from Day 1 to Day 28. The 
MADRS is a clinician-rated scale designed to measure depression severity and to detect changes 
due to antidepressant treatment6. The scale consists of 10 items, each of which is scored from 0 
(item is not present or is normal) to 6 (severe or continuous presence of the symptoms), for a total 


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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, interest 
level, pessimistic thoughts, and suicidal thoughts. The test exhibits high inter-rater reliability.
If 2 or more items are missing, no imputation will be performed and the total score will be left 
missing. Otherwise, the total score will be calculated as sum of the non-missing items multiplied 
by the ratio of the maximum number of items (i.e., 10) to the number of non-missing items.
5.2.2.
Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined 
by the following 5 components:
Treatment: Active comparator (open-label new oral antidepressant) plus intranasal placebo and 
Intranasal esketamine (56 mg or 84 mg) plus open-label new oral antidepressant
Population: subjects with treatment-resistant depression as defined through appropriate 
inclusion/exclusion criteria to reflect the targeted patient population
Variable: change from baseline to Day 28 in the MADRS total score
Intercurrent events and corresponding strategies:

Treatment discontinuation (including COVID-19 related discontinuation) –
Hypothetical Strategy: the effect of the initially randomized treatment together with 
the oral antidepressant medication that would have been observed had all subjects 
remained on their treatment throughout the double-blind treatment phase

Major protocol violations and COVID-19 related minor protocol violations –
Treatment Policy Strategy: use all measures, regardless of whether or not major 
protocol violations or COVID-19 related minor protocol violations had occurred.
Population-level summary: the difference in variable least square means
The primary analysis will be based on the full analysis set, as described in Section 2.2.2.1, and the 
MADRS total scores collected during the DB treatment phase.
5.2.3.
Analysis Methods
The primary efficacy variable, change from baseline in MADRS total score at Day 28 in the 
double-blind treatment phase, will be analyzed using a Mixed-Effect Model for Repeated 
Measures (MMRM) based on observed case data. The models will include baseline MADRS total 
score as a covariate, and treatment, country, class of antidepressant (SNRI or SSRI), day (see 
Table 1), and day-by-treatment interaction as fixed effects. The within-subject covariance between 
visits will be estimated via an unstructured variance-covariance matrix. In case of convergence 
problems, alternative variance-covariance structures will be tried in the following order, with the 
first structure that converges being used in the analysis: heterogeneous Toeplitz, standard Toeplitz, 
and AR(1) with separate subject random effect. Comparison of the esketamine plus oral 
antidepressant arm versus oral antidepressant plus intranasal placebo will be performed using the 


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appropriate contrast. Lease squares mean changes in MADRS total score over time and cumulative 
percent response for change from baseline to 28 days in MADRS total score will be graphically 
presented.
Model Diagnostics
The normality and equal variance assumptions will be assessed graphically for the MADRS total 
score at end point. Residuals from the primary models will be plotted against the predicted values 
and a QQ plot of the residuals versus the expected quantiles of the standard normal distribution 
will be presented. If either the equal variance or the normality assumption appears to be grossly 
violated, other methods like an appropriate transformation of the primary endpoint might be 
considered.
Missing Data Sensitivity Analysis 
The following table (Table 6) shows the assumptions of each considered analysis for the primary 
efficacy endpoint, all applied to the same full analysis set defined in Section 2.2.2.1:
Table 6:
Analysis Types and Assumptions
Analysis Type
Analysis Method
Assumption
Primary Analysis 
MMRM 
Missing at Random – MAR
Sensitivity Analysis
Delta worsening adjustment applied to 
standard multiple imputation regression
Efficacy scores worsen after study 
discontinuation
To evaluate the robustness of the MMRM analysis to increasing deviations from the MAR 
assumption, a delta adjustment multiple imputation method will be used for sensitivity analysis. 
This type of method is regarded to be an informative sensitivity analysis in clinical trials 
(2010 National Research Council report on missing data7 and T Permutt8).
This method will employ the following 3 steps:
Step 1 –Multiple Imputation (MI)
Note: Most missing data will be a result of subjects dropping out of the study and having 
observations at every scheduled visit up to the point they dropped but no observations thereafter. 
This is a monotone missing data pattern. Some subjects may have ‘intermediate missing’ data 
between non-missing observations. This is a non-monotone missing data pattern.
If there are subjects 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 the 
MCMC (Markov Chain Monte Carlo) method. This will be done using SAS PROC MI and the 
MCMC statement with the following specifications:
PROC MI DATA=INPUT NIMPUTE=500 SEED=234 
OUT=IN_MCMC; VAR …; (treatment group, country, class of antidepressant (SNRI or SSRI), and the preceding 
non-missing values in the order of clinical visits: baseline, Day 2, Day 8, Day 15, Day 22 and Day 28) 


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MCMC CHAIN=SINGLE NBITER=200 NITER=100 IMPUTE=MONOTONE; 
RUN; 
Note: Graphical diagnostic tools available in the MCMC statement (TIMEPLOT(WLF) and ACFPLOT(WLF)) 
will be used to assess if convergence has not been achieved.
If all subjects have a monotone missing data pattern (either directly from the study or created by 
the previous step), the MAR-based multiple imputation with the regression option will be used to 
impute missing values. This analysis will be performed using SAS PROC MI with the 
MONOTONE statement and the REGRESSION option with the following specifications: 
PROC MI DATA=IN_MCMC NIMPUTE=1 (see note) SEED=234 OUT=OUTPUT; 
VAR …; (treatment group, country, class of antidepressant (SNRI or SSRI), 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…;(treatment 
group, country, class of antidepressant (SNRI or SSRI)) MONOTONE REGRESSION; 
RUN; 
Note: NIMPUTE=500 if MCMC was NOT applied at the previous step.
Step 2 –Delta Adjustments 
The imputed values for subjects who discontinued will be adjusted by adding  to the imputed 
values for subjects randomized to placebo and adding  to the imputed values for subjects 
randomized to an active esketamine arm. Delta-adjusted fully imputed datasets will be generated 
for different combinations of  and  values as defined below:

 = 0 and  = 0 	
 ∆
∗in increments of 1 (active-only adjustment analysis)

 = /2 and  = 0 	
 ∆
∗in increments of 1 (analysis with a control adjustment that is 
half of the active adjustment)

 =  = 0 	
 ∆
∗in increments of 1 (all arms adjustment analysis) 
Adding positive values results in higher (worse) scores. ∆
∗, ∆
∗and ∆
∗represent the adjustments 
leading to the ‘tipping point’, so the smallest delta adjustments values at which conclusions change 
from favorable to drug (i.e. statistically significant: one-sided p-value ≤0.025) to unfavorable 
(acceptance of the null hypothesis of no treatment difference).
Step 3 –Analysis and Pooling
For each (,) combination:

Same MMRM as described for the primary efficacy analysis will be performed for each set of 
the adjusted fully imputed datasets; 


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
Multiple imputation combining rules in PROC MIANALYZE will be applied to the MMRM 
results from the imputed datasets to produce final inferences.
Between-group comparisons to placebo at Day 28 (e.g., p-values, point estimates for treatment
difference) will be displayed graphically for each considered (,) combination, up to the 
‘tipping point’ adjustment.
The delta adjustment MI method as described above will be applied to all subjects who 
discontinued from the DB treatment phase and have missing efficacy scores in this phase. In 
addition, another version of this method will be applied. In this version, the delta adjustments from 
Step 2 will be applied to all subjects who discontinued, except those with a discontinuation reason 
that was not considered related to the study drug, including Lost to Follow-Up, Withdrawal by 
Subject or Other. A process is in place to obtain clarification on reasons of Withdrawal by Subject 
and Other to confirm they are not related to the study drug.
Additional Sensitivity Analysis
MMRM will be used for primary efficacy endpoint as described above with the exclusion of 
5 subjects from 1 site in the US as a sensitivity analysis due to a potential unblinding issue.
Subgroup Analysis
Forest plots will be provided displaying analysis results for each subgroup listed in Section 2.3. 
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 baseline MADRS total score as a covariate, and treatment, country, class of 
antidepressant (SNRI or SSRI), day, subgroup, day-by-treatment interaction, treatment-by
subgroup and day-by-treatment-by-subgroup interaction as fixed effects. The terms in the models 
will be adjusted for the subgroups of country and 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.
5.3.
Major Secondary Endpoints
5.3.1.
MADRS total score at 24 hours 
5.3.1.1.
Analysis Methods
The first key efficacy endpoint, change from baseline in MADRS total score at 24 hours post first 
dose (Day 2), will be analyzed using the same model (MMRM) described above for the MADRS 
total score at Week 4 in the double-blind treatment phase in Section 5.2.3. The models will include 
baseline MADRS total score as a covariate, and treatment, country, class of antidepressant (SNRI 
or SSRI), day (see Table 1), and day-by-treatment interaction as fixed effects.


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5.3.2.
Sheehan Disability Scale (SDS)
5.3.2.1.
Definition
The SDS is a subject-reported outcome measure and is a 5-item questionnaire which has been 
widely used and accepted for assessment of functional impairment and associated disability. The 
first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home 
responsibilities using a 0-10 rating scale. The scores for the first three items are summed to create 
a total score of 0-30 where a higher score indicates greater impairment. It also has one item on 
days lost from school or work and one item on days when underproductive. The recall period for 
this study is 7 days. Scores ≤4 for each item and ≤12 for the total score are considered response. 
Scores ≤2 for each item and ≤6 for the total score are considered remission. If any of the first three 
items are missing, the total score will be set to missing as well as response and remission status.
5.3.2.2.
Analysis Methods
The second key efficacy endpoint, change from baseline in SDS total score at Week 4 in the 
double-blind treatment phase, will be analyzed using the same model (MMRM) described above 
for the MADRS total score in Section 5.2.3. Least squares mean changes and arithmetic means for 
SDS total score over time will be presented graphically. The proportion of subjects who achieve 
response and remission over time will also be summarized.
Graphs for arithmetic mean change from baseline over time will be provided by country.
5.4.
Other Efficacy Variables
5.4.1.
Onset of Clinical Response
5.4.1.1.
Definition
A subject is defined as having a clinical response if there is at least 50% improvement from 
baseline in the MADRS total score with onset by Day 2 (in the event that no MADRS was collected 
on Day2, a MADRS collected on Day 3 could be used) that is maintained to Day 28. Subjects are 
allowed one excursion (non-response) on Days 8, 15 or 22, however the score must show at least 
25% improvement. Subjects who do not meet such criterion, or discontinue during the study before 
Day 28 for any reason will be considered as non-responders and will be assigned the value of 0 
(ie, no).
5.4.1.2.
Analysis Methods
The proportion of subjects showing onset of clinical response by Day 2 that is maintained for the 
duration of the double-blind treatment phase in the esketamine plus oral antidepressant arm will 
be compared with the oral antidepressant plus intranasal placebo arm using a Cochran-Mantel 
Haenszel (CMH) chi-square test adjusting for country and class of antidepressant (SNRI or SSRI).
The odds ratio, calculated as the odds of achieving clinical response on esketamine plus oral 
antidepressant arm divided by the odds of achieving clinical response on oral antidepressant plus 
intranasal placebo will be provided, along with the 95% confidence interval for the odds ratio.


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The proportion of subjects who achieve clinical response will be summarized by class of 
antidepressant study medication (SNRI or SSRI).
5.4.2.
Responders
5.4.2.1.
Definition
The percentage change from baseline at Day X is calculated as 100*(MADRS total score at 
Day X-Baseline MADRS total score)/(Baseline MADRS total score). Negative percent changes 
in MADRS total score indicate improvement (e.g., percent change ≤-50% indicates improvement 
≥50%).
A subject is defined a responder (yes=1 and no=0) at a given time point if the percent improvement 
in MADRS total score is ≥50%.
5.4.2.2.
Analysis Methods
The proportion of subjects who achieve a response will be summarized by treatment group at each 
time point during the double-blind treatment and follow-up phases. The proportion of subjects who 
achieve a response will also be summarized by class of antidepressant study medication (SNRI or 
SSRI) and by country separately at each time point. Graphs for response rate over time will be 
provided by country.
The cumulative response rate, defined as the percentage of subjects experiencing at least a given 
value of percent reduction from baseline to Day 28 in MADRS total score will be presented 
graphically.
The cumulative distribution function of the time to sustained response will be estimated by the 
Kaplan-Meier method. Time to sustained response will be summarized (number of sustained 
responders, number of censored subjects, median, 25th and 75th percentile, if estimable) by 
treatment group. Sustained response is defined as the first occurrence of response that is 
maintained through the Day 28 assessment. Subjects are allowed one excursion (non-response) on 
a subsequent visit prior to Day 28, however the score must show at least 25% improvement. 
Subjects who discontinue early are not considered to have sustained response.
5.4.3.
Improvement of at Least 30% MADRS Total Score
5.4.3.1.
Definition
The percentage change from baseline at Day X is calculated as 100*(MADRS total score at 
Day X-Baseline MADRS total score)/(Baseline MADRS total score). Negative percent changes 
in MADRS total score indicate improvement (e.g., percent change ≤-30% indicates improvement 
≥30%).
A subject is defined an improvement of ≥30% MADRS total score (yes=1 and no=0) at a given 
time point if the percent improvement in MADRS total score is ≥30%.


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5.4.3.2.
Analysis Methods
The analysis will be for overall population and by country separately.
The proportion of subjects who achieve an improvement of ≥30% MADRS total score will be 
summarized by treatment group at each time point during the double-blind treatment and follow-
up phases. Graphs over time will be provided by country. The proportion of subjects who achieve 
an improvement of ≥30% MADRS total score will also be summarized by class of antidepressant 
study medication (SNRI or SSRI) and by country separately at each time point.
5.4.4.
Remitters
5.4.4.1.
Definition
Subjects who have a MADRS total score of ≤12 at a visit will be considered remitters.
5.4.4.2.
Analysis Methods
The proportion of subjects who achieve remission will be summarized by treatment group at each 
time point during the double-blind treatment and follow-up phases. The proportion of subjects who 
achieve remission will also be summarized by class of antidepressant study medication (SNRI or 
SSRI) and by country separately at each time point.
The cumulative distribution function of the time to sustained remission will be estimated by the 
Kaplan-Meier method. Time to sustained remission will be summarized (number of sustained 
responders, number of censored subjects, median, 25th and 75th percentile, if estimable) by 
treatment group. Sustained remission is defined as the first occurrence of remission that is 
maintained through the Day 28 assessment. Subjects are allowed one excursion (MADRS total 
score >12) on a subsequent visit prior to Day 28. Subjects who discontinue early are not considered 
to have sustained remission.
5.4.5.
CGI-S
5.4.5.1.
Definition
The Clinical Global Impression of Severity (CGI-S) provides an overall clinician-determined 
summary measure of the severity of the subject’s illness that takes into account all available 
information, including knowledge of the subject’s history, psychosocial circumstances, symptoms, 
behavior, and the impact of the symptoms on the subject’s ability to function4. The CGI-S 
evaluates the severity of psychopathology on a scale of 0 to 7. Considering total clinical experience, 
a subject is assessed on severity of mental illness at the time of rating according to: 0=not assessed; 
1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 
6=severely ill; 7=among the most extremely ill patients. The CGI-S permits a global evaluation of 
the subject’s condition at a given time.
5.4.5.2.
Analysis Methods
Descriptive statistics (N, median, minimum, and maximum) of actual values and changes from 
baseline by treatment group will be provided for observed data for overall population and by 


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country. Frequency distributions will be provided at each assessment time point during the double-
blind and follow-up phases for overall population and by country. Graphs over time will be 
provided by country.
The change from baseline for CGI-S in the double-blind treatment phase will be analyzed at each 
time point using the same MMRM as described for primary efficacy endpoint in Section 5.2.3.
Graphs over time will be provided by country.
5.4.6.
GAD-7
5.4.6.1.
Definition
The GAD-7 (Generalized Anxiety Disorder - 7 Items) is a brief and validated 7-item self-report 
assessment of overall anxiety. Subjects respond to each item using a 4 point scale with response 
categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day10. 
Item responses are summed to yield a total score with a range of 0 to 21, where higher scores 
indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as 
follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15-21).
5.4.6.2.
Analysis Methods
Descriptive statistics of actual values and changes from baseline by treatment group will be 
provided for observed case data at all time points in the double-blind treatment and follow-up 
phases. A frequency distribution will also be provided for GAD-7 severity categories at all time 
points.
The change from baseline for the GAD-7 total score in the double-blind phase will be analyzed 
using an ANCOVA model with treatment, country and class of antidepressant (SNRI or SSRI) as 
factors, and the baseline score as the covariate.
5.4.7.
EuroQol Group; 5 Dimension; 5 level (EQ-5D-5L)
5.4.7.1.
Definition
The EQ-5D-5L (EuroQol Group - 5 Dimension - 5 Level2,3) is a standardized 2-part instrument for 
use as a measure of health outcome, primarily designed for self-completion by respondents. It 
essentially consists of the EQ-5D-5L descriptive system and the EQ visual analogue scale 
(EQ-VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is 
divided into 5 levels of perceived problems (Level 1 indicating no problem, Level 2 indicating 
slight problems, Level 3 indicating moderate problems, Level 4 indicating severe problems, and 
Level 5 indicating extreme problems).
The subject selects an answer for each of the 5 dimensions considering the response that best 
matches his or her health “today.” The descriptive system can be represented as a health state. The 
EQ-VAS self-rating records the respondent’s own assessment of his or her overall health status at 


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the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the best health 
you can imagine). 
The time taken to complete the questionnaire varies with age, health status, and setting but is likely 
to be around 1 minute.
Individual scores from the 5 dimensions will be used to obtain a weighted health status index as 
shown below: 
(i)
Scores from each dimension will be combined to obtain a 5L profile score or health state: 
eg, a score of 1 for each dimension will give a 5L profile score of 11111. Dimension scores 
will be combined in the following order: Mobility, Self-Care, Usual Activities, 
Pain/Discomfort, Anxiety/Depression 
(ii)
The value set of the Health Status Index for various values of 5L profile scores is published 
for Canada in the following website: 
https://www.ncbi.nlm.nih.gov/pubmed/26492214
(iii)
The Canadian value set will be used to get the HSI values for all the countries participating 
in the study.
In addition, a sum score will be derived as follows: The scores of the five dimensions (values 1-5) 
will be added (sums between 5 and 25). From this score, subtract 5 (range 0-20) and multiply by 
5(range 0-100).
5.4.7.2.
Analysis Methods
Descriptive statistics of actual values and changes from baseline by treatment group will be 
provided for the weighted EQ-5D health status index, the EQ-VAS, and the sum score at each time 
point for the double-blind and follow-up phases.
Individual dimension responses will also be summarized at each visit using a frequency 
distribution by treatment group for the double-blind and follow-up phases.
5.4.8.
SDS in the Follow-up Phase
5.4.8.1.
Definition
Definition of SDS is described in Section 5.3.2.1.
5.4.8.2.
Analysis Methods
Descriptive statistics of actual values and changes from baseline will be provided at each time 
point by treatment group for the follow-up phase.


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5.4.9.
Relapse
5.4.9.1.
Definition
During the follow-up phase, relapse (in remitters and responders) is defined as any of the following:

MADRS total score ≥22 for 2 consecutive assessments separated by 5 to 15 days. The date of 
the second MADRS assessment will be used for the date of relapse. 

Hospitalization for worsening depression or any other clinically relevant event determined per 
clinical judgment to be suggestive of a relapse of depressive illness such as suicide attempt, 
completed suicide, or hospitalization for suicide prevention. If hospitalized for any of these 
events, the start date of hospitalization will be used for the date of relapse. Otherwise the date 
of the event will be used if the subject is not hospitalized. 

In case more than one relapse criteria are met, the earlier date will be defined as the date of 
relapse for this subject.
5.4.9.2.
Analysis Methods
For subjects who receive esketamine during the double-blind treatment phase, the proportion of 
subjects who relapse during the follow-up phase will be summarized separately for subjects who 
are remitters (MADRS ≤12 at the end of the double-blind phase) and for subjects who are 
responders but not remitters (≥50% reduction in MADRS total score, but MADRS ˃12 at the end 
of the double-blind phase).
In addition, the time to relapse during the follow-up phase will be estimated by the Kaplan-Meier 
method separately for subjects who are remitters, and subjects who are responders but not remitters. 
Descriptive statistics (number of relapses, number of censored subjects, and median, 25th, and 75th 
percentile of time to relapse, if estimable) will be provided.
5.4.10.
Six-Item MADRS subscale (MADRS6)
5.4.10.1.
Definition
MADRS6[14] is a six-item core depression subscale of MADRS, which contains the following 
items: apparent sadness, reported sadness, inner tension, lassitude, inability to feel, and pessimistic 
thoughts.
5.4.10.2.
Analysis Methods
Change from baseline in MADRS6 total score at Day 28 in the double-blind treatment phase will 
be analyzed using the same model (MMRM) described above for the MADRS total score in 
Section 5.2.3. Least squares mean changes and arithmetic means for MADRS6 total score over 
time will be presented graphically. 
6.
SAFETY
All safety summaries for the double-blind treatment phase will be based on the Safety analysis set. 
Safety summaries for the follow-up phase will be based on the Follow-up analysis set. Unless 
otherwise specified, the safety data will be summarized for overall population.


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6.1.
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 agent during the treatment phase through the day of last dose until 
end of double-blind phase is considered to be treatment emergent. 
Treatment-emergent adverse events (TEAEs) are defined as follows for each study phase:

TEAEs in Double-Blind treatment phase:

If AE onset time is not missing:
a.
If intranasal study medication was started on the same day as the oral antidepressant: 
DB start date/time <= AE onset date and time <= DB end date
b.
If intranasal study medication was not taken or was started after oral antidepressant: 
DB start date <= AE onset date <= DB end date

If AE onset time is missing: DB start date <= AE onset date <= DB end date

AEs in Follow-up phase: F/U start date <= AE onset date <= F/U end date

For the AEs that have both day and month missing, treatment-emergent flag is assigned based 
on the rules presented in Section 2.6.
For each adverse event, the number and percentage of subjects who experience at least 1occurrence 
of the given event will be summarized by treatment group and system organ class and preferred 
term. The same analysis for the double-blind treatment phase will be provided by country. In 
addition, comparisons between treatment groups will be provided if appropriate.
Summary tables in the double-blind treatment phase will be provided for:

TEAEs

Serious TEAEs 

TEAEs leading to discontinuation of intranasal drug

TEAEs leading to discontinuation of oral antidepressant

TEAEs by severity

TEAEs by relationship to intranasal drug

AEs by relationship to oral antidepressant

TEAEs leading to dose reduction
Adverse events occurring in the follow-up phase will be summarized by treatment group 
separately.

AEs

Serious AEs 

AEs leading to discontinuation of oral antidepressant


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
AEs leading to termination of study participation

AEs by severity
In addition to the summary tables, listings will be provided for subjects who:

Had SAEs

Had AEs leading to discontinuation of study medication/termination of study participation
In addition, TEAEs will be summarized by severity and relationship to study medication using the 
preferred term. For the summaries of TEAEs by severity/relationship to study medication, the 
observation with the most severe occurrence/closest relationship to study medication will be 
chosen if there is more than one incident of an AE reported during the analysis phase by the subject.
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 subjects who died will be provided. Actual treatment 
received, cause of death and relationship to study agent (yes/no) will be presented.
Adverse Events of Special Interest
Incidence of other treatment-emergent adverse events of clinical special interest will be 
summarized.
Clinically relevant TEAEs of special interest will be examined separately grouped in the following 
categories: 

Drug abuse Potential: 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, 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); 


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
Anxiety (Anticipatory anxiety, Anxiety, Anxiety disorder, Agitation, Fear, Feeling jittery, 
Irritability, Nervousness, Panic attack, Tension).

Events potentially related to suicidality (Completed suicide, Depression suicidal, Intentional 
overdose, Intentional self-injury, Multiple drug overdose intentional, Poisoning deliberate, 
Self-injurious behavior, Self-injurious ideation, Suicidal 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)

symptoms of dissociation persisting beyond the typical ≤2 hour post esketamine 
administration (dissociation)

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)
The number and percentage of subjects taking concomitant medication for dissociation events 
(preferred term of Dissociation) at any time during the double-blind phase will be provided
6.2.
Clinical Laboratory Tests
Descriptive statistics (N, mean, median, minimum, and maximum) for values and changes from 
baseline will be provided for clinical laboratory tests (hematology, chemistry and urinalysis) at 
each scheduled time point in the double-blind treatment and follow-up phases. Baseline laboratory 
result is defined as the last result collected prior to Day 1 predose. This will be used to calculate 
change for the double-blind treatment phase summary. Changes from baseline for the follow-up 
phase will also be calculated using the double-blind baseline.


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Clinical laboratory tests that meet the criteria for markedly abnormal will be listed by subject for 
the double-blind treatment phase. The incidence of treatment-emergent markedly abnormal 
(TEMA) laboratory values that occurred at any time during the double-blind treatment phase will
be presented. Clinical laboratory test values will be considered TEMA using the criteria defined 
by the Sponsor (Janssen Research & Development, LLC) listed in Attachment 1. The identification 
of TEMA laboratory values is based on the postbaseline value being out of range while the baseline 
value is either missing or within the range given in Attachment 1. If postbaseline laboratory results 
are above the upper limit and the baseline value is below the lower limit, then the post-baseline 
abnormality will also be considered TEMA. The same applies to the postbaseline value being 
below the lower limit with the baseline value being above the upper limit.
The incidence of subjects with ALT or AST values > 3*upper normal limit (ULN) will be 
presented for each study phase. Additionally, incidence of hepatic toxicity (Hy’s Law11) defined 
as ALT or AST values >3*ULN AND total bilirubin values >2*ULN will be presented for the
double-blind treatment and follow-up phases. Similar to the markedly abnormal analysis, only 
subjects with baseline ALT or AST values ≤3*ULN (AND baseline total bilirubin values 
≤2*ULN for hepatic toxicity) (or if baseline value is missing) will be eligible for these analyses.
6.3.
Vital Signs, Weight and BMI
Descriptive statistics for values and changes from baseline at each scheduled time-point during the 
double-blind treatment phase will be presented for temperature, systolic blood pressure, diastolic 
blood pressure, pulse rate, respiratory rate, oxygen saturation, weight, and BMI. In addition, 
descriptive statistics of pulse rate and blood pressure (systolic and diastolic) values, changes and 
percent changes from predose will be provided for each dosing day. These summaries will also be 
provided by hypertension status (history of hypertension recorded in medical history, Yes/No). 
Frequency distributions of maximum percent change increase from predose and time of maximum 
percent change increase will also be presented for blood pressure. Descriptive statistics of 
maximum increase and maximum percent increase from predose will be provided for blood 
pressure for each dosing day. Note that if the maximum value within a phase occurs at multiple 
time points, the earliest time point is selected. 
The proportion of subjects who have a treatment-emergent abnormality, as defined in Table 7
below, during the double-blind treatment phase will be presented. Both the double-blind baseline 
and the predose assessment will be used to determine abnormal values. A listing of subjects 
meeting any of the criteria will also be provided for the double-blind treatment phase.
Table 7: 
Clinically Important Abnormalities in Vital Signs
Vital Parameter
Post-baseline value outside of normal limit if:
Abnormally low
Abnormally high
Pulse (bpm)
A decrease from baseline of 15 to a value 
50
An increase from baseline of 15 to a value 
100
Systolic BP (mmHg)
A decrease from baseline of 20 to a value 
90
An increase from baseline of 20 to a value 
180
Diastolic BP (mmHg)
A decrease from baseline of 15 to a value 
50
An increase from baseline of 15 to a value 
105


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The proportion of subjects who experienced treatment-emergent markedly elevated blood pressure 
(systolic BP≥180 or diastolic BP≥110) at any time during the double-blind treatment phase will 
be summarized by treatment group and hypertension status.
Mean (+/-SE) values for systolic BP, diastolic BP and heart rate will be summarized and presented 
graphically over the double-blind treatment phase by treatment group and hypertension status. In 
addition, for subjects with hypertension who receive antihypertensive medication, the same tables 
and graphs will be summarized by medication type (beta-blockers, multiple agents (beta 
blockers+others), all other agents).
A listing of subjects with oxygen saturation less than 93% will be provided.
A separate summary for China population of blood pressure data will be presented for the China 
population:

Mean maximum increases from each predose over time

Frequency of subjects with treatment-emergent abnormal vital signs relative to baseline or 
predose

Graph of arithmetic mean

Frequency of subjects with treatment-emergent markedly elevated blood pressure 
6.4.
Electrocardiogram
ECG variables that will be analyzed include heart rate, RR, PR interval, QRS interval, QT interval 
and QTc intervals. The corrected QT (QTc) intervals will include QTcB (Bazett) and QTcF 
(Fridericia).
The maximum post-baseline value during the double-blind treatment phase will be computed for 
each ECG parameter using data from both scheduled and unscheduled visits.
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. Summary tables for observed values and changes from baseline will be 
presented by treatment at each scheduled timepoint during the double-blind treatment and follow-
up phases.
The frequency of treatment-emergent abnormalities will be tabulated and presented for the double-
blind treatment phase. The identification of treatment-emergent abnormal ECG values is based on 
the post-baseline value (a value occurring after the first study drug administration) being out of 
range while the baseline value is either missing or within the limits given in Table 8. If post-
baseline ECG results are above the upper limits (abnormally high) and the baseline value is below 
the lower limits (abnormally low), then the post-baseline abnormality will also be considered 
treatment-emergent. The same applies to the post-baseline value being below the lower limits 
(abnormally low) with the baseline value being above the upper limits (abnormally high). The 
average predose value will be used as baseline for the double-blind treatment summary. Abnormal 
ranges for the HR, PR, QRS and QT intervals are given in Table 8.


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Table 8:
Limits for HR, PR, QRS and QT Interval Abnormality
ECG parameter
Abnormally Low
Abnormally High
HR (bpm)
≤ 50
≥ 100
PR interval (msec)
--
≥ 210
QRS interval (msec)
≤ 50
≥ 120
QT interval (msec)
≤ 200
≥ 500
Based on the maximum QTc value for each subject during a given phase (separate for each QTc 
correction) the incidence of abnormal QTc values and changes from baseline will be summarized 
by treatment group. Criteria for abnormal corrected QT values and changes from baseline are given 
in Table 9 and are derived from the ICH E14 Guidance495 (the same criteria apply to all QT 
corrections).
Table 9:
Criteria for Abnormal QTc Values and Changes from Baseline
Parameter
Classification
Criteria
Clinically Significant QTc Value
No
500
Yes
>500
QTc change from baseline a
No concern
30
Concern
>30 – 60
Clear concern
> 60
QTc value
Normal
450
> 450 – 480
>450 - 480
> 480 – 500
>480 – 500
> 500
> 500
These criteria are based on ICH E14 Guideline
a Baseline is defined as the average pre-dose for the double-blind and follow-up phases.
The proportion of subjects with treatment emergent abnormalities will be presented for the double-
blind treatment phase. A listing of subjects with abnormalities will also be provided.
6.5.
Other Safety Parameters
6.5.1.
Nasal Examination
Targeted nasal examinations (including the upper respiratory tract/throat) will be conducted by a 
qualified healthcare practitioner. The objective of the examination at Screening is to rule out any 
subjects with anatomical or medical conditions that may impede drug delivery or absorption.
Subsequent examinations will consist of a visual inspection of the nostrils, nasal mucosa, and 
throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption and epistaxis and 
graded as follows: absent, mild, moderate, or severe. 
Changes in findings from the double-blind baseline for each examination (including the upper 
respiratory tract/throat) will be listed for the double-blind phase by treatment group.


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6.5.2.
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS (Columbia Suicide Severity Rating Scale) 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 treatment9. It is a semi structured clinician-administered questionnaire designed to 
solicit the occurrence, severity, and frequency of suicide-related ideation and behaviors during the 
assessment period. Using the C-SSRS, potentially suicide-related events will be categorized using 
the following scores:
Suicidal Ideation (1-5) 
1: Wish to be Dead 
2: Non-specific Active Suicidal Thoughts
3: Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
4: Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
5: Active Suicidal Ideation with Specific Plan and Intent
Suicidal Behavior (6-10)
6: Preparatory Acts or Behavior 
7: Aborted Attempt 
8: Interrupted Attempt 
9: Actual Attempt (non-fatal) 
10: Completed Suicide
If no events qualify for a score of 1 to 10, a score of 0 will be assigned (0=“no event that can be 
assessed on the basis of C-SSRS”). 
The summaries of the C-SSRS outcomes will be based on the Safety analysis set for subjects who 
have at least 1 post-baseline C-SSRS measurement and a pre-treatment C-SSRS assessment 
(assessment at Baseline visit).
A frequency distribution at each scheduled time point by treatment will be provided. Shifts from 
the baseline visit to the most severe/maximum score during the double-blind treatment and follow-
up phases will be summarized by treatment group.
The maximum score assigned for each subject will also be summarized into one of three broad 
categories: No suicidal ideation or behavior (0), Suicidal ideation (1-5), Suicidal behavior (6-10). 
Shifts from the baseline visit to the maximum category during the double-blind treatment and 
follow-up phases will be summarized by treatment group.


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6.5.3.
Clinician Administered Dissociative States Scale (CADSS)
The CADSS (Clinician Administered Dissociative States Scale) is an instrument for the 
measurement of present-state dissociative symptoms1, and is administered to assess treatment
emergent dissociative symptoms. The CADSS comprises 23 subjective items and participant’s 
responses are coded on a 5-point scale (0 = “Not at all”, 1 = “Mild”, 2 = “Moderate”, 3 = ‘Severe” 
and 4 = “Extreme”). The CADSS is divided into 3 components using the scoring method shown 
in Table 10.
Table 10:
CADSS Scoring
Component
Questions
Range
Depersonalization
Sum of 3, 4, 5, 6, 7, 20, 23
0-28
Derealization
Sum of 1, 2, 8, 9, 10, 11, 12, 13, 16, 17, 18, 19, 21
0-52
Amnesia
Sum of 14, 15, 22
0-12
Total Score
Sum of 1 through 23
0-92
For the total score and each component, a higher score represents a more severe condition. If any 
response is missing the total score is set to missing.  The CADSS is measured prior to each dose, 
at 40 minutes, and at 1.5 hours postdose.
Descriptive statistics (N, median, minimum, and maximum) of the total scores and component 
scores at each time point and visit, changes from predose and proportion of subjects with an 
increase in CADSS total score from the predose value at any time during the study will be 
summarized. Mean (SD) CADSS values will be presented graphically for each dosing day.
A separate summary will be presented by country.
6.5.4.
Physician Withdrawal Checklist (PWC-20)
The PWC-20 is a 20-item simple and accurate method to assess potential withdrawal symptoms 
following cessation of intranasal esketamine treatment. The PWC-20 will be performed for all 
subjects on Day 25 to establish a baseline prior to discontinuation of esketamine treatment.
The proportion of subjects with withdrawal symptoms at the end of double-blind treatment therapy 
or during the follow-up phase will be presented by treatment group. In addition, symptoms at 
follow-up will be compared to the end of therapy visit and will be summarized using the following 
categories: new or worsened symptoms, symptoms present and unchanged, no symptoms, and 
improved.
A separate summary will be presented for the China population. 
7.
PHARMACOKINETICS
Blood samples for measuring plasma esketamine concentrations will be collected from all subjects 
at the specified visits as shown in the schedule of events of the protocol.


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Data for all subjects who received at least 1 dose of intranasal esketamine and have at least 1 post 
treatment PK sample will be included in the PK analysis. Esketamine concentrations below the 
LLOQ of the assay or missing data will be labeled as such in the concentration data listings. No 
imputation of missing concentration data will be performed, that is, data summaries will be based 
on the observed data. All subjects and samples excluded from the analysis will be clearly 
documented.
Descriptive statistics (N, mean, SD, median, range and CV (%)) will be used to summarize 
esketamine plasma concentrations at each sampling time point by dose.
If feasible, a population PK analysis of plasma concentrations will be performed using nonlinear 
mixed-effects model (NONMEM) approach. Details will be presented in a separate technical 
document. 
8.
BIOMARKER, PHARMACOGENOMIC (DNA), AND EXPRESSION (RNA) 
EVALUATIONS
Details of the analysis plan for both biomarker and pharmacogenomics analyses will be provided 
separately based on the availability of sufficient number of subjects.


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REFERENCES
1.
Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, Mazure CM. Measurement of 
dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress. 
1998;11(1):125-136.
2.
EuroQol Group. About EQ-5D. http://www.euroqol.org/about-eq-5d.html (accessed 18 June 2014).
3.
EuroQol Group. EQ-5D-5L User Guide: basic information on how to use the EQ-5D-5L instrument. 
Version 2.0; October 2013. 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/UserGuide_EQ-
5D5L_v2.0_October_2013.pdf (accessed 6 August 2014).
4.
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. Department of Health, 
Education, and Welfare; 1976.
5.
International Conference on Harmonization (ICH) Tripartite Guideline E14. London: s.n., 2005. pp. The 
clinical evaluation of QT/QTc interval prolongation and proarrhythmic for non-antiarrhythmic drugs.
6.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 
1979;134:382-389.
7.
National Research Council, Panel on Handling Missing Data in Clinical Trials [2010], The prevention and 
treatment of missing data in clinical trials. Available: http://www.nap.edu/catalog/12955.html.
8.
Permutt, T. Sensitivity analysis for missing data in regulatory submissions. Stat Med. 2015; Nov 15 (Epub 
ahead of print).
9.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide 
Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal risk analysis of 
antidepressants. Am J Psychiatry. 2007;164:1035-1043.
10.
Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety disorder: the 
GAD-7. Arch Intern Med. 2006;166(10):1092-1097.
11.
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation 
and Research (CDER), Center for Biologics Evaluation and Research (CBER). [2009] Guidance for industry 
drug induced liver injury: premarketing clinical evaluation. Available: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf.


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ATTACHMENTS
Attachment 1:
Criteria of Markedly Abnormal Laboratory Values
Markedly Abnormal Limits
Laboratory Parameter
Low
High
Albumin [g/L]
24
60
Alkaline phosphatase [U/L]
N/A
250
Alanine transaminase (SGPT) [U/L]
N/A
200
Alanine transaminase (SGPT) [U/L]
N/A
>3X ULN
Aspartate transaminase (SGOT) [U/L]
N/A
250
Bicarbonate [mmol/L]
15.1
34.9
Blood urea nitrogen [mmol/L]
N/A
17.9
Calcium [mmol/L]
1.5
3
Chloride [mmol/L]
94
112
Creatine kinase (Enzyme U/L)
N/A
990
Creatinine [µmol/L]
N/A
265.2
Gamma glutamyl transferase [Enzyme U/L]
N/A
300
Glucose [mmol/L]
2.2
16.7
Phosphate [mmol/L]
0.7
2.6
Potassium [mmol/L]
3.0
5.8
Sodium [mmol/L]
125
155
Bilirubin, total [µmol/L]
N/A
51.3
Protein, total [g/L]
50
N/A 
Urine pH
N/A
8.0
Hematocrit [fraction]
- female
0.28
0.5
- male
0.24
0.55
Hemoglobin [g/L]
80
190
Neutrophils, segmented [fraction of 1]
0.3
0.9
Monocytes [fraction of 1]
N/A
0.2
Eosinophils [fraction of 1]
N/A
0.1
Basophils [fraction of 1]
N/A
0.06
Lymphocytes [fraction of 1]
0.1
0.6
Platelet count [x109/L]
100
600
Red blood cell count [x1012/L] -- female
3.0
5.5
                                                  -- male
3.0
6.4
White blood cell count [x109/L]
2.5
15.0
Hy’s Law criteria:
Alanine transaminase (SGPT) [U/L] or Aspartate 
Aminotransferase (AST)
> 3X ULN
AND
Bilirubin, total [µmol/L]
>2X ULN
Note: The same limits apply to both males and females unless gender is indicated; N/A = Not applicable.