Conditions: Depression
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 202
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of fixed dosed intranasal esketamine compared to intranasal placebo, as an add-on to an oral antidepressant in Japanese participants with treatment-resistant depression (TRD), in improving depressive symptoms.

Detailed description:

Arms:
arm 1: Participant will receive 1 spray of placebo to each nostril at 0 minute, 5 minutes and 10 minutes. arm 2: Participant will receive 1 spray of Esketamine to each nostril at 0 minute and placebo at 5 minutes and 10 minutes. arm 3: Participant will receive 1 spray of Esketamine to each nostril at 0 minute, 5 minutes and placebo at 10 minutes. arm 4: Participant will receive 1 spray of Esketamine to each nostril at 0 minute, 5 minutes and 10 minutes.

Interventions: intervention 1: Placebo intervention 2: Intranasal esketamine (28 mg) intervention 3: Intranasal esketamine (56 mg) intervention 4: Intranasal esketamine (84 mg)
Intervention descriptions: intervention 1: Participant will receive 1 spray of placebo to each nostril at 0 minute, 5 minutes and 10 minutes. intervention 2: Participant will receive 1 spray of Esketamine to each nostril at 0 minute and placebo at 5 minutes and 10 minutes. intervention 3: Participant will receive 1 spray of Esketamine to each nostril at 0 minute, 5 minutes and placebo at 10 minutes. intervention 4: Participant will receive 1 spray of Esketamine to each nostril at 0 minute, 5 minutes and 10 minutes.

Protocol document:
Prot_000.pdf: 
1 
Status: Approved, Date: 21 December 2018  
 
Janssen Pharmaceutical K.K.* 
 
Clinical Protocol 
 
A Randomized, Double-blind, Multicenter, Placebo-controlled Study to Evaluate the 
Efficacy, Safety and Tolerability of Fixed Doses of Intranasal Esketamine in Japanese 
Subjects With Treatment Resistant Depression  
 
 
Protocol 54135419TRD2005; Phase 2b 
AMENDMENT 5 
 
 JNJ-54135419 (esketamine)  
 
*This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used 
throughout the protocol to represent Janssen Pharmaceutical K.K. 
 
 
 
 
 
 
 
 
 
 
 
Status: 
Approved 
Date: 
21 December 2018 
Prepared by: Janssen Pharmaceutical K.K. 
EDMS number: 
EDMS-ERI-122111174, 8.0 
 
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.  
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential. 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
LIST OF ATTACHMENTS ............................................................................................................................ 5 
LIST OF IN-TEXT TABLES AND FIGURES ................................................................................................ 5 
PROTOCOL AMENDMENTS ....................................................................................................................... 6 
SYNOPSIS .................................................................................................................................................. 15 
TIME AND EVENTS SCHEDULE 1 [-SCREENING PHASE, PROSPECTIVE LEAD-IN PHASE 
AND DOUBLE-BLIND INDUCTION PHASE] ................................................................................... 26 
TIME AND EVENTS SCHEDULE 2 [-POSTTREATMENT PHASE AND FOLLOW-UP PHASE] ............ 32 
TIME AND EVENTS SCHEDULE 3 [-OPEN-LABEL INDUCTION PHASE] ............................................. 34 
ABBREVIATIONS ...................................................................................................................................... 36 
1. 
INTRODUCTION ................................................................................................................................ 38 
1.1. 
Background .................................................................................................................................... 39 
1.1.1. 
Nonclinical Studies ..................................................................................................................... 39 
1.1.2. 
Clinical Studies ........................................................................................................................... 42 
1.1.2.1. 
Pharmacokinetics and Product Metabolism ............................................................................ 42 
1.1.2.2. 
Pharmacodynamics and Efficacy ............................................................................................ 44 
1.1.2.3. 
Safety and Tolerability ............................................................................................................. 49 
1.1.3. 
Marketing Experience ................................................................................................................. 53 
1.2. 
Overall Rationale for the Study ...................................................................................................... 53 
2. 
OBJECTIVES AND HYPOTHESIS ................................................................................................... 57 
2.1. 
Objectives ...................................................................................................................................... 57 
2.2. 
Hypothesis ..................................................................................................................................... 58 
3. 
STUDY DESIGN AND RATIONALE ................................................................................................. 58 
3.1. 
Overview of Study Design .............................................................................................................. 58 
3.2. 
Study Design Rationale .................................................................................................................. 64 
3.2.1. 
Study Population ......................................................................................................................... 64 
3.2.2. 
Study Phases .............................................................................................................................. 64 
3.2.3. 
Blinding and Randomization ....................................................................................................... 66 
3.2.4. 
Treatment Groups and Dose Selection ...................................................................................... 66 
3.2.5. 
Selection of Efficacy Scales and Safety Evaluations ................................................................. 68 
3.2.5.1. 
Efficacy Scales ........................................................................................................................ 68 
3.2.6. 
Safety Evaluations ...................................................................................................................... 69 
3.2.7. 
Pharmacokinetic Evaluations ..................................................................................................... 69 
3.2.8. 
Biomarker and Pharmacogenomic (DNA) Evaluations .............................................................. 69 
4. 
SUBJECT POPULATION .................................................................................................................. 70 
4.1. 
Inclusion Criteria ............................................................................................................................ 70 
4.2. 
Exclusion Criteria ........................................................................................................................... 74 
4.3. 
Criteria for Double-blind and Open-label Induction Phases and Posttreatment Phase ................. 78 
4.3.1. 
Criteria to Enter Double-blind Induction Phase .......................................................................... 78 
4.3.2. 
Criteria to Enter Posttreatment Phase ........................................................................................ 79 
4.3.3. 
Criteria to Enter Open-label Induction Phase ............................................................................. 79 
4.4. 
Prohibitions and Restrictions ......................................................................................................... 79 
5. 
TREATMENT ALLOCATION AND BLINDING ................................................................................. 80 
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5.1. 
Treatment Allocation ...................................................................................................................... 80 
5.2. 
Blinding .......................................................................................................................................... 80 
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 81 
6.1. 
Screening Phase ............................................................................................................................ 81 
6.2. 
Prospective Lead-in Phase ............................................................................................................ 81 
6.3. 
Double-blind Induction Phase ........................................................................................................ 82 
6.3.1. 
Guidance on Blood Pressure Monitoring on Intranasal Treatment Session Days ..................... 84 
6.4. 
Posttreatment Phase ...................................................................................................................... 85 
6.4.1. 
Open-label Induction Phase ....................................................................................................... 85 
6.5. 
Follow-up Phase ............................................................................................................................ 85 
7. 
TREATMENT COMPLIANCE ............................................................................................................ 85 
8. 
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 86 
9. 
STUDY EVALUATIONS .................................................................................................................... 87 
9.1. 
Study Procedures ........................................................................................................................... 87 
9.1.1. 
Overview ..................................................................................................................................... 87 
9.1.2. 
Informed Consent Procedure ..................................................................................................... 89 
9.1.3. 
Screening Phase ........................................................................................................................ 90 
9.1.4. 
Prospective Lead-in Phase ......................................................................................................... 91 
9.1.5. 
Double-blind Induction Phase ..................................................................................................... 91 
9.1.6. 
Posttreatment Phase .................................................................................................................. 92 
9.1.7. 
Open-label Induction Phase ....................................................................................................... 93 
9.1.8. 
Follow-up Phase ......................................................................................................................... 94 
9.2. 
Efficacy ........................................................................................................................................... 94 
9.2.1. 
Evaluations ................................................................................................................................. 94 
9.2.1.1. 
Primary Efficacy Evaluation ..................................................................................................... 95 
9.2.1.1.1. 
MADRS (7-day Recall) ......................................................................................................... 95 
9.2.1.2. 
Secondary Efficacy Evaluation (Clinician-completed) ............................................................. 95 
9.2.1.2.1. 
MADRS (24-hour Recall) ..................................................................................................... 95 
9.2.1.2.2. 
CGI-S ................................................................................................................................... 95 
9.2.1.2.3. 
Time to Relapse ................................................................................................................... 96 
9.2.1.3. 
Secondary Efficacy Evaluations (Patient-reported Outcomes) ............................................... 96 
9.2.1.3.1. 
SDS ...................................................................................................................................... 96 
9.2.1.3.2. 
GAD-7 .................................................................................................................................. 96 
9.2.2. 
Endpoints .................................................................................................................................... 96 
9.2.2.1. 
Primary Endpoint ..................................................................................................................... 96 
9.2.2.2. 
Secondary Endpoints .............................................................................................................. 97 
9.3. 
Pharmacokinetics ........................................................................................................................... 97 
9.3.1. 
Evaluations ................................................................................................................................. 97 
9.3.2. 
Analytical Procedures ................................................................................................................. 98 
9.3.3. 
Pharmacokinetic Parameters ..................................................................................................... 98 
9.4. 
Pharmacokinetic/Pharmacodynamic Evaluations .......................................................................... 98 
9.5. 
Biomarker and Pharmacogenomic (DNA) Evaluations .................................................................. 98 
9.6. 
Safety Evaluations ......................................................................................................................... 99 
9.7. 
Other Evaluations ......................................................................................................................... 104 
9.8. 
Sample Collection and Handling .................................................................................................. 105 
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ......................................................................................................................... 105 
10.1. 
Completion ................................................................................................................................... 105 
10.2. 
Withdrawal From the Study .......................................................................................................... 106 
10.3. 
Withdrawal From the Use of Research Samples ......................................................................... 107 
11. 
STATISTICAL METHODS ............................................................................................................... 107 
11.1. 
Subject Information ...................................................................................................................... 107 
11.2. 
Sample Size Determination ......................................................................................................... 108 
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11.3. 
Interim Analysis ............................................................................................................................ 108 
11.4. 
Efficacy Analyses ......................................................................................................................... 108 
11.5. 
Pharmacokinetic Analyses ........................................................................................................... 109 
11.6. 
Biomarker and Pharmacogenomic Analyses ............................................................................... 109 
11.7. 
Pharmacokinetic/Pharmacodynamic Analyses ............................................................................ 109 
11.8. 
Safety Analyses ........................................................................................................................... 110 
12. 
ADVERSE EVENT REPORTING .................................................................................................... 111 
12.1. 
Definitions .................................................................................................................................... 112 
12.1.1. 
Adverse Event Definitions and Classifications ......................................................................... 112 
12.1.2. 
Attribution Definitions ................................................................................................................ 113 
12.1.3. 
Severity Criteria ........................................................................................................................ 113 
12.2. 
Special Reporting Situations ........................................................................................................ 114 
12.3. 
Procedures ................................................................................................................................... 114 
12.3.1. 
All Adverse Events .................................................................................................................... 114 
12.3.2. 
Serious Adverse Events ........................................................................................................... 115 
12.3.3. 
Pregnancy ................................................................................................................................. 116 
12.4. 
Contacting Sponsor Regarding Safety ......................................................................................... 116 
13. 
PRODUCT QUALITY COMPLAINT HANDLING ............................................................................ 116 
13.1. 
Procedures ................................................................................................................................... 117 
13.2. 
Contacting Sponsor Regarding Product Quality .......................................................................... 117 
14. 
STUDY DRUG INFORMATION ....................................................................................................... 117 
14.1. 
Physical Description of Study Drugs ............................................................................................ 117 
14.2. 
Packaging .................................................................................................................................... 117 
14.3. 
Labeling ........................................................................................................................................ 118 
14.4. 
Preparation, Handling, and Storage ............................................................................................. 118 
14.5. 
Drug Accountability ...................................................................................................................... 118 
15. 
STUDY-SPECIFIC MATERIALS ..................................................................................................... 119 
16. 
ETHICAL ASPECTS ....................................................................................................................... 119 
16.1. 
Study-Specific Design Considerations ......................................................................................... 119 
16.2. 
Regulatory Ethics Compliance ..................................................................................................... 122 
16.2.1. 
Investigator Responsibilities ..................................................................................................... 122 
16.2.2. 
Independent Ethics Committee or Institutional Review Board ................................................. 122 
16.2.3. 
Informed Consent ..................................................................................................................... 124 
16.2.4. 
Privacy of Personal Data .......................................................................................................... 124 
16.2.5. 
Long-Term Retention of Samples for Additional Future Research .......................................... 125 
17. 
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 125 
17.1. 
Protocol Amendments .................................................................................................................. 125 
17.2. 
Regulatory Documentation .......................................................................................................... 126 
17.2.1. 
Regulatory Approval/Notification .............................................................................................. 126 
17.2.2. 
Required Prestudy Documentation ........................................................................................... 126 
17.3. 
Subject Identification, Enrollment, and Screening Logs .............................................................. 127 
17.4. 
Source Documentation ................................................................................................................. 127 
17.5. 
Case Report Form Completion .................................................................................................... 128 
17.6. 
Data Quality Assurance/Quality Control ...................................................................................... 128 
17.7. 
Record Retention ......................................................................................................................... 129 
17.8. 
Monitoring .................................................................................................................................... 129 
17.9. 
Study Completion/Termination ..................................................................................................... 130 
17.9.1. 
Study Completion/End of Study ................................................................................................ 130 
17.9.2. 
Study Termination ..................................................................................................................... 130 
17.10. On-Site Audits .............................................................................................................................. 130 
17.11. Use of Information and Publication .............................................................................................. 131 
REFERENCES .......................................................................................................................................... 133 
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JNJ-54135419 (esketamine) 
 
 
 
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Approved, Date: 21 December 2018  
INVESTIGATOR AGREEMENT ............................................................................................................... 142 
 
LIST OF ATTACHMENTS 
Attachment 1: 
Prohibited Concomitant Medications ........................................................................ 137 
Attachment 2: 
New York Heart Association Classification of Cardiac Disease ............................... 140 
Attachment 3: 
Example of the Up-titration Schedule for a New Oral Antidepressant Therapy 
(Physician Determined) in Prospective Lead-in Phase ............................................ 141 
 
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES 
Table 1: 
Adverse Reactions Listed as Very Common, Common, or Frequent Occurrences in 
the Product Information of Anesthetic Ketamine and Esketamine ........................................... 50 
Table 2: 
Intranasal Treatment Administration During the Double-blind Induction Phase ....................... 83 
Table 3: 
Approximate Volume of Blood to be Collected From Each Subject ......................................... 89 
 
FIGURES 
Figure 1: 
Study 54135419TRD2005 Flowchart ........................................................................................ 63 
 
 
 
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PROTOCOL AMENDMENTS 
Protocol Version  
Date 
Original Protocol 
20 June 2016 
Amendment 1 
20 September 2016 
Amendment 2 
17 March 2017 
Amendment 3 
31 August 2017 
Amendment 4 
30 August 2018 
Amendment 5 
21 December 2018 
 
Amendments below are listed beginning with the most recent amendment.  
Amendment 5 (21 December 2018) 
The overall reason for the amendment: The subject exclusion criteria were amended to improve recruitment and 
for clarification. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: Revised the exclusion criterion regarding alanine aminotransferase and aspartate aminotransferase values 
in the screening phase of the study because elevation in liver enzymes were reported at low rates in Phase 1, 2 and 3 
esketamine studies to date. 
4.2 Exclusion Criteria 
A part of exclusion criteria no.13 was revised as follows (bold text revised): 
“Subject has a history of, or symptoms and signs suggestive of, liver cirrhosis (eg, 
esophageal varices, ascites, and increased prothrombin time) OR alanine 
aminotransferase or aspartate aminotransferase values 32× the upper limit of 
normal or total bilirubin >1.5×ULN in the screening phase.” 
Rationale: Revised the exclusion criterion to delete the exclusion for complete right bundle branch block as the 
analyses of PR intervals from subjects in Phase 1, 2, and 3 esketamine studies to date showed no impact of 
esketamine on PR interval. 
4.2 Exclusion Criteria 
A part of exclusion criteria no.11 was revised as follows (bold text revised):  
“Evidence of 2nd and 3rd degree atrioventricular (AV) block, or complete left 
bundle branch block (LBBB), or complete right bundle branch block (RBBB).” 
Rationale: Clarified that any potential subject with cluster A personality disorders will be excluded from the study. 
4.2 Exclusion Criteria 
Exclusion criteria no. 4 was revised as follows (bold text revised): 
“Subject has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD 
with psychotic features bipolar or related disorders (confirmed by the MINI), 
obsessive compulsive disorder (current only), intellectual disability (DSM-5 
diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), autism spectrum 
disorder, borderline personality disorder, antisocial personality disorder, histrionic 
personality disorder, or narcissistic personality disorder, paranoid personality 
disorder, schizoid personality disorder, or schizotypal personality disorder.” 
  
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JNJ-54135419 (esketamine) 
 
 
 
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Approved, Date: 21 December 2018  
Amendment 4 (30 August 2018) 
The overall reason for the amendment: The subject inclusion criteria were amended to improve recruitment. Also, 
the protocol contents were updated and clarified. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: To improve recruitment, inclusion criteria was amended to allow enrollment of subjects who meet the 
diagnostic criteria for single episode major depressive disorder. 
4.1 Inclusion Criteria 
Inclusion criterion no. 3 was revised as follows (bold text revised): 
“At the start of the screening phase, subject must meet the DSM-5 diagnostic 
criteria for single-episode MDD or recurrent MDD, without psychotic features, 
based upon clinical assessment and confirmed by MINI. In the case of single-
episode MDD, the subject must be diagnosed with persistent depressive 
disorder, which meets criteria of major depressive episode for a continuous 
duration of 2 years, and the same physician from the site must be examining 
the subject for 2 years continuously as a primary care physician of the 
subject.” 
Synopsis Overview of Study 
Design;  
To align with the inclusion criterion, the bold text has been revised as follows: 
“Japanese men and women aged 20 to 64 years old (both inclusive), who meet 
Diagnostic and Statistical Manual of Mental Disorders (fifth edition) (DSM-5) 
diagnostic criteria for single-episode major depressive disorder (MDD) or 
recurrent major depressive disorder (MDD) without psychotic features, based 
upon clinical assessment, and confirmed by the MINI will be screened according to 
the inclusion/exclusion criteria. In the case of single-episode MDD, the subject 
must be diagnosed with persistent depressive disorder, which meets criteria of 
major depressive episode for a continuous duration of 2 years, and the same 
physician from the site must be examining the subject for 2 years 
continuously as a primary care physician of the subject.” 
Synopsis Subject Population 
To align with the inclusion criterion, the bold text has been revised as follows: 
“Japanese men or women aged between 20 and 64 years (both inclusive) must meet 
the DSM-5 diagnostic criteria for single-episode MDD or recurrent MDD, without 
psychotic features, based upon clinical assessment and confirmed by the MINI will 
be enrolled. In the case of single-episode MDD, the subject must be diagnosed 
with persistent depressive disorder, which meets criteria of major depressive 
episode for a continuous duration of 2 years, and the same physician from 
the site must be examining the subject for 2 years continuously as a primary 
care physician of the subject.” 
3.1 Overview of Study 
Design 
To align with the inclusion criterion, the bold text has been revised as follows: 
“Japanese men and women aged 20 to 64 years old (both inclusive), who meet 
Diagnostic and Statistical Manual of Mental Disorders (fifth edition) (DSM-5) 
diagnostic criteria for single-episode MDD or recurrent MDD without psychotic 
features, based upon clinical assessment and confirmed by the Mini International 
Neuropsychiatric Interview (mental status questionnaire) (MINI) will be screened 
according to the inclusion/exclusion criteria. In the case of single-episode MDD, 
the subject must be diagnosed with persistent depressive disorder, which 
meets criteria of major depressive episode for a continuous duration of 2 
years, and the same physician from the site must be examining the subject for 
2 years continuously as a primary care physician of the subject. 
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Approved, Date: 21 December 2018  
Applicable Section(s) 
Description of Change(s) 
3.2.1 Study Population 
To align with the inclusion criterion, the bold text has been revised as follows: 
“Subjects will meet DSM 5 diagnostic criteria for single-episode MDD or 
recurrent MDD, without psychotic features, based upon clinical assessment and 
confirmed by the MINI. In the case of single-episode MDD, the subject must be 
diagnosed with persistent depressive disorder, which meets criteria of major 
depressive episode for a continuous duration of 2 years, and the same 
physician from the site must be examining the subject for 2 years 
continuously as a primary care physician of the subject.” 
Rationale: Revised exclusion criteria to exclude subjects with a history (lifetime) of psilocybin and psilocin.  
4.2 Exclusion Criteria 
Exclusion criterion no. 6 was revised as follows (bold text revised): 
“Subject has a history of moderate or severe substance or alcohol use disorder 
according to DSM-5 criteria, except nicotine or caffeine, within 6 months before 
the start of the screening phase.  
A history (lifetime) of ketamine, phencyclidine, lysergic acid diethylamide (LSD), 
or 3, 4-methylenedioxy-methamphetamine (MDMA), or psilocybin/psilocin 
hallucinogen-related use disorder is exclusionary.” 
Rationale: Added definition about going out during hospitalization. 
4.1 Inclusion Criteria 
Inclusion criterion no. 2.1 was revised as follows (bold text revised): 
“In this study, outpatients and inpatients are allowed for enrollment. 
Hospitalization for the study is allowed, subject must remain hospitalized from the 
beginning of the prospective lead-in phase to the end of the double-blind induction 
phase, maintaining the stable environment for 10 weeks. Temporary discharge is 
not permitted basically during the 10-week hospitalization. As a general rule, 
going out from the hospital (leaving the site during hospitalization for reasons 
other than temporary discharge regardless of the attendant’s presence) is to be 
within 6 hours at a time and not to exceed twice in 7 contiguous days.” 
9.1.3 Screening Phase 
To be consistent with the inclusion criteria, the bold text has been added as follows:
“In this study, outpatients and inpatients are allowed for enrollment. 
Hospitalization for the study is allowed, subject must remain hospitalized from the 
beginning of the prospective lead-in phase to the end of the double-blind induction 
phase, maintaining the stable environment for 10 weeks. Temporary discharge is 
not permitted basically during the 10-week hospitalization. As a general rule, 
going out from the hospital (leaving the site during hospitalization for reasons 
other than temporary discharge regardless of the attendant’s presence) is to be 
within 6 hours at a time and not to exceed twice in 7 contiguous days.” 
Rationale: Clarified that intranasal treatment sessions should not take place on consecutive days in the open-label 
induction phase. 
Synopsis Dosage and 
Administration; 
6.4.1 Open-label Induction 
Phase 
The bold statement has been added as follows: 
“Intranasal treatment sessions should not take place on consecutive days.” 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
9 
Approved, Date: 21 December 2018  
Applicable Section(s) 
Description of Change(s) 
Rationale: Clarifications made regarding the usage of antidepressant treatments for indications other than 
depression, and the use of corticosteroids, pseudoephedrine, and dopamine agonists. 
Attachment 1 
Changes were as follows (bold text revised): 
- Antidepressant: “Even if used primarily for sleep, trazodone used is not 
permitted. for indication other than MDD (eg, trazodone or low dose 
tricyclic antidepressants for sleep), the use of any medication listed on 
the ATRQ, is not permitted during the treatment phase.”  
- Corticosteroids: changed from “oral” to “systemic”; episodic use permitted 
(previously prohibited); the following text added: “intermittent IM/IV 
corticosteroids are permitted (chronic use prohibited)”. 
- Pseudoephedrine: clarified that it is an “orally” administered agent (not 
intranasal). 
- Dopamine agonists: “Subjects who were taking these medications at the 
start of the screening phase, can continue them throughout the study; 
however, dose increases or starting new dopamine agonists are not 
permitted. The dopamine agonists must be continued at a stable dose 
for 1 month prior to the beginning of the screening phase.” 
Rationale: Minor errors were noted. 
Time and Events Schedule 1 
The bold text has been deleted from footnote p as follows: 
- Footnote p: “MADRS interview should not be conducted on the same day 
with the MADRS assessment at Visit 3.9.” 
Time and Events Schedule 3 
The bold text has been deleted from footnote j as follows: 
- Footnote j: “MADRS interview should not be conducted on the same day 
with the MADRS assessment at Visit 5.9.” 
 
Amendment 3 (31 August 2017) 
The overall reason for the amendment: The subject entry process is being clarified and revised to improve 
recruitment, based on feedback received from Investigators involved in the study. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: Clarify the informed consent procedure is the independent procedure and obtaining informed consent is 
not required at the same day of the Screening Visit 1.1.  
9.1.2 Informed Consent 
Procedure 
The following text has been added as a new section: 
“Informed consent must be obtained prior to the subject entering the study, 
and before any protocol-directed procedures (eg, washout of prohibited 
medications) are performed. Signing ICF is not required at the same day of 
the Screening Visit 1.1. Investigators can observe the subjects until Screening 
Visit 1.1 after obtaining IC, if clinically indicated (eg, washout of prohibited 
medications). If Screening Visit 1.1 is on more than 28 days after singing ICF, 
investigators must obtain informed consent again, to confirm their 
willingness.” 
Time and Events schedule 1 
“Informed Consent” was added in the Screening/ Administrative row to clarify the 
independence of the procedure. 
The following new footnote o has been added to Informed consent (ICF): 
- Footnote o: “Informed consent must be obtained prior to the initiation of 
any study procedure including washout of prohibited therapies.” 
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JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
10 
Approved, Date: 21 December 2018  
Applicable Section(s) 
Description of Change(s) 
Synopsis Overview of Study 
Design;  
3.1 Overview of Study 
Design; 
To align with the study procedure, the bold text has been deleted as follows: 
“SAFER interview will be conducted as early as feasible during the screening 
period, preferably in the first week after signing of informed consent form 
(ICF) before down-titration of antidepressants to avoid change of depressive 
symptoms because of tapering.” 
8 Prestudy and Concomitant 
Therapy 
To align with the study procedure, the bold text has been revised as follows: 
“Prestudy non-antidepressant therapies administered up to 30 days before 
obtaining IC the start of the screening phase must be recorded at the start of this 
phase. 
All antidepressant treatments, including adjunctive treatment for MDD, taken 
during the current depressive episode (ie, including those taken more than 30 days 
prior to obtaining IC the start of the screening phase) will be recorded at the 
start of the screening phase.” 
Rationale: To improve recruitment, revised the criteria of the hospitalization for the study. 
4.1. Inclusion Criteria 
Inclusion criterion no. 2 was revised as follows (bold text revised): 
“In this study, outpatients and inpatients are allowed for enrollment. However, 
hospitalization Hospitalization for the study is not allowed, subject must remain 
hospitalized from the beginning of the prospective lead-in phase to the end of 
the double-blind induction phase, maintaining the stable environment for 10 
weeks. Temporary discharge is not permitted basically during the 10-week 
hospitalization.which means inpatients who has already hospitalized before 
signing ICF can be enrolled.” 
9.1.3 Screening Phase 
The bold text has been revised as follows: 
“In this study, outpatients and inpatients are allowed for enrollment. However, 
hospitalization Hospitalization for the study is not allowed, subject must remain 
hospitalized from the beginning of the prospective lead-in phase to the end of 
the double-blind induction phase, maintaining the stable environment for 10 
weeks. Temporary discharge is not permitted basically during the 10-week 
hospitalization.which means inpatients who has already hospitalized before 
signing ICF can be enrolled.” 
Rationale: Revise the remote MADRS interview window for Day 28 of the double-blind and Day OL 28 of the 
open-label induction phase to allow more flexibility for conducting the visit 
Time and Events schedule 1;  
Time and Events schedule 3 
For Visit 3.10 during the double-blind induction phase and Visit 5.10 during the 
open-label induction phase, the visit window was revised to -2 days (rather than -1 
day). 
Time and Events schedule 1 
The following text has been added to the remote MADRS interview window at 
Visit 3.10 as Footnote p: 
- Footnote p: “MADRS interview should not be conducted on the same day 
with the MADRS assessment at Visit 3.9.” 
Time and Events schedule 3 
The following text has been added to the remote MADRS interview window at 
Visit 5.10 as Footnote j: 
- Footnote j: “MADRS interview should not be conducted on the same day 
with the MADRS assessment at Visit 5.9.” 
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JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
11 
Approved, Date: 21 December 2018  
Applicable Section(s) 
Description of Change(s) 
Rationale: Revised exclusion criterion no. 11, because ESKETINTRD1013 study, which evaluated the effects of 
esketamine on cardiac repolarization in healthy subjects, showed no impact of esketamine on QT/QTc interval. 
4.2. Exclusion Criteria 
Exclusion criterion no. 11 was revised as follows (bold text revised): 
“Subject has clinically significant ECG abnormalities at the start of the screening 
phase or on Day 1 prior to randomization, defined as: 
- During screening, a QT interval corrected according to Fridericia’s formula 
(QTcF): ≥450 470 msec in males and ≥480 msec in females; if the QTcF 
is prolonged on the initial ECG, the average QTcF of 3 ECGs recorded 4 
minutes apart must not be ≥450 msec. 
- On Day 1 (predose), a QTcF: ≥450 470 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 3 ECGs recorded 4 minutes apart must 
not be ≥450 msec. 
- Evidence of 2nd and 3rd degree atrioventricular (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]).” 
Rationale: Clarify the rule of rescreening. 
4.2. Exclusion Criteria 
The bold text has been added after “NOTE” as follows: 
The sponsor will evaluate and approve/reject requests to rescreen an individual 
subject on a case by-case basis. Rescreening will be allowed only once basically.
Rationale: Minor errors were noted. 
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made. 
 
Amendment 2 (17 March 2017) 
The overall reason for the amendment: To add a new inflammatory biomarker assessment and to update and/or 
clarify protocol content based on ongoing feedback received from Investigators during study initiation activities. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: Add IL-17A as a new biomarker to assess the potential relationship with inflammation more clearly. 
9.1 Study Procedures,  
Table 3 
IL-17A has been added: 
- Footnote f: “This sample will provide serum for all of the following assays: 
IL-10, IL-1b, IL-6, TNFa, Adiponectin, Cortisol, hs-CRP (non-cardiac),  
IL-6R, BDNF, IGF-1, and Leptin and IL-17A.” 
Rationale: Clarification of intranasal esketamine dose adjustments which are permitted on Day OL8 and OL11 in 
the open-label induction phase. 
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JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
12 
Approved, Date: 21 December 2018  
Applicable Section(s) 
Description of Change(s) 
Synopsis Overview of Study 
Design, Dosage and 
Administration;  
3.1 Overview of Study 
Design; 
6.4.1 Open-label Induction 
Phase;  
9.1.6 Open-label Induction 
Phase 
The bold text has been revised as follows: 
“On Day OL8 and OL11, the dose may could be maintained, remain the same as 
84 mg or increased or could be reduced by 28 mg as determined by the investigator 
based on efficacy and tolerability.” 
Rationale: Revise the visit window for Day 32 of the post treatment phase to prevent overlapping the visit window 
of Day 28. 
Time and Events schedule 2 
For Visit 4.1 during the post treatment phase, the visit window was revised to +3 day 
(rather than ±3 days). 
Rationale: Clarify the restrictions of benzodiazepines. 
3.1 Overview of Study 
Design; 
8. Prestudy and 
Concomitant Therapy 
The bold text has been revised as follows: 
“Subjects receiving benzodiazepines (at dosages equal to or less than the equivalent 
of 6 mg/day of lorazepam) or permitted non-benzodiazepine sleep medications (eg, 
zolpidem, eszopiclone, and zopiclone) or both during the screening phase can 
continue these medications throughout the study, provided the doses of these 
medications remain unchanged or no new benzodiazepine medications or both 
are initiated during the study; however, dose increases or starting new 
benzodiazepine medications are not permitted.” 
Rationale: Clarify protocol text, where required. 
Time and Events schedule 1 
Footnote “e” has been added to the PWC-20 and POMS-2 to align with the study 
procedure in the double-blind induction phase. 
Time and Events schedule 1 
For the following items, footnote “e” has been added and deleted footnote “c” to 
align with the study procedure in the double-blind induction phase:  
CGI-S, SDS, GAD-7, Hematology, Chemistry, Urinalysis, Urine drug screen, Urine 
pregnancy test, Blood sample collection (Protein) and Blood sample collection 
(DNA) 
4.3 Criteria for Double-
blind and Open-label 
Induction Phases and 
Posttreatment Phase 
The following has been delated to align with the study procedure: 
“Subjects who do not meet the predetermined criteria as defined below will be 
discontinued from the study, undergo EOS/EW Withdrawal Visit procedures, and 
treated according to an accepted standard-of-care. ” 
9.1 Study Procedures 
The order of administration has been revised and clarified: 
“PRO: GAD-7, SDS, POMS-2 
Clinician-administered: CGI-S, C-SSRS, PWC-20, BPRS+, CADSS, MOAA/S, 
CGADR, PWC-20 
Attachment 1 
A new row was added for dopamine agonists. 
Rationale: Minor errors were noted. 
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made. 
Time and Events schedule 1 
Day P14, P28 and P42 were corrected to Day P15, P29 and P43, respectively.  
 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
13 
Approved, Date: 21 December 2018  
Amendment 1 (20 September 2016) 
The overall reason for the amendment: Based on the feedback received from Investigators from the study, 
recording of remote MADRS interview is clarified from the perspective of protecting subject privacy. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: Provide clarification in the recording of the remote MADRS interview from the perspective of 
protecting subject privacy. 
Synopsis Overview of Study 
Design;  
9.2.1. Evaluations 
The following text has been added: 
“The remote MADRS interviews will be recorded to assess accuracy and 
thoroughness of the interviews and measure overall quality assurance.” 
Rationale: Provide clarification of antidepressants which should be washed out in the screening phase. 
Synopsis Overview of Study 
Design, Dosage and 
Administration;  
3.1 Overview of Study 
Design; 
6.1 Screening Phase;  
9.1.2 Screening Phase 
The bold text has been added as follows : 
“Subject’s current antidepressant treatment(s), including adjunctive treatment for 
MDD, should be tapered and discontinued in this phase per the local prescribing 
information.” 
Rationale: Clarify the handling of exacerbation of primary disease. 
12.1.1. Adverse Event 
Definitions and 
Classifications 
The following text has been added: 
“Exacerbation of primary disease is not defined as AE.” 
Rationale: Clarify protocol text, where required. 
Time and Events schedule 1 
The following text has been added to Visit 3.10 as Footnote m: 
- Footnote m: “Visit 3.10 will be identical to the start day of the posttreatment 
phase.” 
Time and Events schedule 1 
The “xn” at Visit 2.1 and 3.1 was added to the MOAA/S and pulse oximetry row to 
align with the exclusion criteria 10 and the following was added. 
- Footnote n: “Pulse oximetry only.” 
Time and Events schedule 3 
The following text has been added to Day OL 1 as Footnote i: 
- Footnote i: “If the assessment on Day OL 1 is conducted on the same day as a 
scheduled visit in the posttreatment phase, duplicate assessments are not 
required.” 
Synopsis Overview of Study 
Design, Dosage and 
Administration;  
3.1 Overview of Study 
Design;  
6.4.1 Open-label Induction 
Phase;  
9.1.6 Open-label Induction 
Phase 
The period between the double-blind induction phase and the open-label induction 
phase has been clarified by calendar day: 
“The beginning of the OL induction phase should be at least 2 weeks (14 calendar 
days) after the last dose in the double-blind induction phase.” 
4.2 Exclusion Criteria 
Transcranial magnetic stimulation has been clarified in Exclusion Criteria 3: 
“Subject has received vagal nerve stimulation, has received transcranial magnetic 
stimulation or has received deep brain stimulation in the current episode of 
depression.” 
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JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
14 
Approved, Date: 21 December 2018  
Applicable Section(s) 
Description of Change(s) 
9.1 Study Procedures,  
Table 3 
IGF-1 has been added and C reactive protein has been deleted: 
- Footnote f: “This sample will provide serum for all of the following assays: 
IL-10, IL-1b, IL-6, TNFa, Adiponectin, Cortisol, hs-CRP (non-cardiac),  
IL-6R, BDNF, IGF-1 and Leptin and C-reactive protein.” 
9.1 Study Procedures 
The order of administration has been revised and clarified: 
“PRO: GAD-7, SDS, POMS-2 
Clinician-administered: MADRS, CGI-S, C-SSRS, BPRS+, CADSS, MOAA/S, 
CGADR, PWC-20 
Remote MADRS interview should be conducted at predose on intranasal dosing 
days during the double blind induction phase and the open label induction 
phase.” 
9.6 Safety Evaluations 
The recall period of POMS-2 has been clarified:  
“The recall period for this study is 7 days.” 
Rationale: Minor errors were noted. 
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made. 
Time and Events schedule 3 
An “x” has been deleted from Drug Accountability at EW Visit. 
17.4 Source Documentation
The following has been delated because each source data will be recorded in 
separate documents: 
“• Blood pressure and heart rate  
 • Height and weight  
 • Details of physical examination 
 • Some subject- and clinician- reported scales and assessments designated by the 
sponsor” 
9.1 Study Procedures,  
Table 3 
An “h” has been added to the Approximate total blood volume for the study row to 
align with the footnote.  
Attachment 1 
Corrected the number of predefined oral antidepressant treatment options: 
“Only 1 of the 6 predefined oral antidepressant treatment options are permitted” 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
15 
Approved, Date: 21 December 2018  
SYNOPSIS 
A Randomized, Double-blind, Multicenter, Placebo-controlled Study to Evaluate the Efficacy, 
Safety and Tolerability of Fixed Doses of Intranasal Esketamine in Japanese Subjects With 
Treatment Resistant Depression  
Ketamine and esketamine (S-ketamine, the S enantiomer of ketamine) are approved medications and 
widely used for the induction and maintenance of anesthesia via intramuscular (IM) or intravenous (IV) 
administration. The desired analgesic-anesthetic effects of ketamine and esketamine are attributed to the 
blockade of ionotropic N-methyl-D-aspartate (NMDA) glutamate receptors. The antidepressive 
mechanism of action of ketamine and esketamine is distinct from conventional monoaminergic treatments. 
Ketamine profoundly affects fast excitatory glutamate transmission, increases brain-derived neurotrophic 
factor (BDNF) release, and stimulates synaptogenesis. 
Due to the higher NMDA receptor affinity of esketamine over arketamine (R-ketamine), Janssen 
Research & Development (JRD) is developing esketamine for antidepressant therapy, thereby requiring a 
lower volume which can be administered via a non-invasive and rapidly absorbed route. 
The study 54135419TRD2005 is a randomized, double-blind, placebo-controlled, multicenter study 
designed to evaluate the efficacy, safety and tolerability of fixed dosed intranasal esketamine (28 mg, 
56 mg or 84 mg) as an add-on therapy to an oral antidepressant in Japanese subjects with 
treatment-resistant depression (TRD). 
OBJECTIVES 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of fixed dosed intranasal esketamine 
compared to intranasal placebo, as an add-on to an oral antidepressant in Japanese subjects with TRD, in 
improving depressive symptoms. 
Secondary Objectives 
 
To assess the effect of intranasal esketamine compared with intranasal placebo as an add-on to an 
oral antidepressant in Japanese subjects with TRD, including the following parameters: 
 
Dose response; 
 
Depression response rates; 
 
Depression remission rates; 
 
Onset of clinical response; 
 
Overall severity of depressive illness; 
 
Anxiety symptoms;  
 
Functioning and associated disability. 
 
To investigate the safety and tolerability of intranasal esketamine compared with intranasal placebo 
as an add-on to an oral antidepressant in Japanese subjects with TRD, including the following 
parameters: 
 
Treatment-emergent adverse events (TEAEs), including adverse events (AEs) of special 
interest; 
 
Potential withdrawal or rebound symptoms or both following cessation of intranasal esketamine 
treatment; 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
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Approved, Date: 21 December 2018  
 
Perceptual changes (dissociative symptoms); 
 
Effects on alertness and sedation; 
 
Effects on heart rate, blood pressure, respiratory rate, and blood oxygen saturation; 
 
Potential effects on suicidal ideation/behavior; 
 
Potential abuse-liability; 
 
Potential psychosislike effects. 
 
To evaluate the durability of intranasal esketamine as an add-on to an oral antidepressant in Japanese 
subjects with TRD, with attention to: 
 
Time to relapse in the posttreatment phase for subjects in remission and for subjects who 
respond but are not in remission, at the end of the double-blind induction phase. 
 
To evaluate the pharmacokinetics (PK) of intranasally administered esketamine in Japanese subjects 
with TRD. 
Exploratory Objectives 
 
To assess the comparability of the efficacy and safety of intranasal esketamine as an add-on to an 
oral antidepressant between the double-blind and open-label (OL) intranasal esketamine induction 
treatment courses; 
 
To evaluate the PK/pharmacodynamic (PD) relationship of intranasal esketamine and 
Montgomery-Asberg Depression Rating Scale (MADRS) total score (and possibly selected AEs as 
additional PD parameters) in Japanese subjects with TRD; 
 
To examine the relationship between deoxyribonucleic acid (DNA) single nucleotide polymorphism 
(SNPs) (including, but not limited to BDNF) with clinical outcome to intranasal esketamine in 
Japanese subjects with TRD; 
 
To assess the potential relationship of biomarkers with response, maintenance, relapse, and 
nonresponse to intranasal esketamine in Japanese subjects with TRD. 
Hypothesis 
The hypothesis for this study is that, at least one dose of intranasal esketamine (28, 56, and 84 mg) is 
superior to intranasal placebo in improving depressive symptoms in Japanese subjects with TRD, as 
assessed by the change from baseline in the MADRS total score at the end of the double-blind induction 
phase. 
OVERVIEW OF STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the 
efficacy, safety and tolerability of fixed dose of intranasal esketamine (28 mg, 56 mg, or 84 mg) as an 
add-on therapy to an oral antidepressant in Japanese subjects with TRD. A total of 183 subjects are 
planned to be enrolled in this study.  
The study consists of the following phases: a screening phase (up to 4 weeks); a 6-week prospective oral 
antidepressant lead-in phase; a 4-week double-blind induction phase; a posttreatment phase (up to 24 
weeks comprising of only oral antidepressant therapy), including an optional 4-week OL induction phase; 
and a 4-week follow-up phase. The 4-week OL induction phase will be applicable for subjects who 
relapse during the posttreatment phase.  
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JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
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Approved, Date: 21 December 2018  
Thus, the duration of a subject’s participation will be a maximum of 42 weeks, depending on whether 
they meet phase-specific criteria for response or relapse. The end-of-study (EOS) will occur when the last 
subject in the study completes his/her last study assessment (ie, last follow-up Visit). 
Screening Phase 
Japanese men and women aged 20 to 64 years old (both inclusive), who meet Diagnostic and Statistical 
Manual of Mental Disorders (fifth edition) (DSM-5) diagnostic criteria for single-episode major 
depressive disorder (MDD) or recurrent MDD without psychotic features, based upon clinical assessment, 
and confirmed by the MINI will be screened according to the inclusion/exclusion criteria. In the case of 
single-episode MDD, the subject must be diagnosed with persistent depressive disorder, which meets 
criteria of major depressive episode for a continuous duration of 2 years, and the same physician from 
the site must be examining the subject for 2 years continuously as a primary care physician of the 
subject. 
To confirm eligibility for participation in the prospective lead-in phase, subjects will have a review of the 
inclusion/exclusion criteria in the screening phase. Subjects must not have responded to ≥1 but <5 
different oral antidepressants taken at adequate dosage and for adequate duration, as assessed on the 
Massachusetts General Hospital – Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and 
documented by medical history/prescription records, for the current episode of depression. The subject’s 
current major depressive episode, depression symptom severity (MADRS total score ≥28 required), and 
treatment response to antidepressant medication used in the current episode (retrospectively assessed) 
must be deemed valid for participation in the clinical study based on the SAFER interview, which is 
administered by a remote, independent rater. At the screening visit, subjects who continue to fulfill all 
inclusion criteria and none of the exclusion criteria will be enrolled. 
SAFER interview will be conducted as early as feasible during the screening period, before down-titration 
of antidepressants to avoid change of depressive symptoms because of tapering. 
Subject’s current antidepressant treatment(s), including adjunctive treatment for MDD, should be tapered 
and discontinued in this phase per the local prescribing information. Down-titration of antidepressants 
will be started after SAFER interview and will be completed in the screening phase basically. However, if 
clinically indicated, cross-tapering is allowed. Cross-tapering is defined as discontinuation of previous 
antidepressant treatment(s) by lowering the dose(s) per the local prescribing information and 
simultaneously increasing the dose of single new antidepressant treatment within the first 2 weeks of the 
prospective lead-in phase.  
The subject’s current antidepressant treatment(s) will not be discontinued for the sole purpose of 
participating in the study.  
Prospective Lead-in Phase 
After enrollment, eligible subjects will enter the 6-week OL prospective lead-in phase (Visits 2.1 to 3.1 
[prerandomization]) during which, subjects will receive a new antidepressant therapy (physician 
determined) daily for the duration of this phase.  
The oral antidepressant will be 1 of the following: selective serotonin re-uptake inhibitors or serotonin-
specific reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), or 
mirtazapine (ie, escitalopram, paroxetine controlled-release [CR], sertraline, duloxetine, venlafaxine 
extended-release [XR], or mirtazapine), which the subject has not previously had a nonresponse to in the 
current depressive episode or has not been previously intolerant to (lifetime).  
In the last 4 weeks during the prospective lead-in phase, 'oral antidepressant' must be single treatment of 
switched new oral antidepressant. New oral antidepressant treatment should be titrated to the approved 
maximum dose, to optimize the potential for response. The up-titration schedule should be per prescribing 
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JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
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Approved, Date: 21 December 2018  
information. The dose, which is above the minimum therapeutic dose defined in MGH-ATRQ should be 
kept at last 4 weeks during the prospective lead-in phase, in case they start at lower doses. 
The criteria of TRD is defined as nonresponse (≤25% improvement) to at least 1 antidepressant treatment 
determined retrospectively and 1 antidepressant prospectively in the current episode of depression. After 
6 weeks, subjects who are nonresponders to the new oral antidepressant treatment at the end of the 
prospective lead-in phase can be eligible to proceed to the double-blind induction phase. Nonresponse at 
the end of the prospective lead-in phase is defined as ≤25% improvement in the MADRS total score from 
Visits 2.1 to each of Visit 2.3 and 3.1 (prerandomization) respectively, and a MADRS total score of ≥28 
on each of the Visits 2.1, 2.3, and 3.1 (prerandomization). Assessment of antidepressant treatment 
response at the end of the prospective lead-in phase will be performed by investigators. All other subjects 
who do not proceed to the double-blind induction phase will end study participation at this time. No 
follow-up or further study visits will be performed for these subjects. All subjects who are discontinued 
must be treated with an oral antidepressant after completion of the study, unless it is clinically 
inappropriate. 
MADRS assessment throughout the study will be performed by an independent, remote, blinded rater. 
The remote MADRS interviews will be recorded to assess accuracy and thoroughness of the interviews 
and measure overall quality assurance. 
Double-blind Induction Phase 
The 4-week fixed dose double-blind induction phase will start on Day 1 (Visit 3.1) and end at Day 28 
(Visit 3.10). A total of 183 subjects will be randomly assigned in a 2:1:1:1 ratio to receive double-blind 
intranasal treatment with either placebo, esketamine 28 mg, esketamine 56 mg, or esketamine 84 mg add-
on to the continued stable oral antidepressant initiated in the prospective lead-in phase. The intranasal 
treatment sessions (esketamine or placebo) will occur twice weekly. Subjects will self-administer the 
intranasal study drug (esketamine 28 mg, 56 mg, 84 mg, or placebo) at treatment sessions occurring twice 
a week for 4 weeks at the clinical site under clinical supervision. The first treatment session will be on 
Day 1. Responders (subjects who have 50% reduction from baseline in MADRS total score) at the end 
of the double-blind induction phase will be eligible to proceed to the posttreatment phase; those who do 
not (ie, nonresponders) will proceed to the 4-week follow-up phase. Given the potential for treatment-
emergent transient elevation in SBP and DBP, the guidance on Blood Pressure Monitoring should be 
followed on intranasal dosing days during the double-blind induction phase. 
Posttreatment Phase 
Responders who completed the double-blind induction phase will enter the 24-week posttreatment phase 
to evaluate durability of efficacy after cessation of add-on intranasal esketamine or placebo treatment 
while continuing the oral antidepressant treatment regimen, as assessed by the time to relapse and 
proportion of responders and remitters at each visit in this phase. All subjects who are discontinued must 
be treated with an oral antidepressant after completion of the study, unless it is clinically inappropriate. 
Open-label Induction Phase 
Subjects who relapsed in the posttreatment phase will receive a 4-week open-label induction treatment 
course of intranasal esketamine. The beginning of the OL induction phase should be at least 2 weeks (14 
calendar days) after the last dose in the double-blind induction phase. Subjects who meet the relapse 
criteria before 2 weeks after the last dose in the double-blind induction phase will not have an option for 
joining open label induction phase. They will withdraw from the posttreatment phase and move forward 
to the follow up phase. 
Subjects who enter the OL induction phase will start treatment sessions with 56 mg of intranasal 
esketamine on the first day of OL induction phase (Day OL1). On the fourth day (Day OL4), the dose will 
be increased to 84 mg. On Day OL8 and OL11, the dose could be maintained, increased or reduced by 
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Clinical Protocol 54135419TRD2005 Amendment 5 
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Approved, Date: 21 December 2018  
28 mg as determined by the investigator based on efficacy and tolerability. On Day OL15, a dose 
reduction is permitted if required for tolerability; no dose increase is permitted on Day OL15. After Day 
OL15, the dose should be stable (unchanged). If needed for tolerability, a dose reduction is permitted 
from Day OL15 until Day OL25. 
The oral antidepressant medication initiated from the prospective lead-in phase, which will continue in 
the posttreatment phase will also be maintained throughout this phase. 
Follow-up Phase 
Following subjects will have follow-up Visits; subjects who withdraw from double blind induction phase, 
nonresponders after double-blind induction phase, responders who withdraw within 4 weeks after the last 
dose of double blind intranasal drug and all subjects who receive open label intranasal drug. During this 
phase, further clinical/standard-of-care treatment will be provided by the study investigator however, in 
order to better assess potential withdrawal symptoms from intranasal study drug, the oral antidepressant 
medication must be continued for the follow-up phase unless determined as not clinically appropriate. 
SUBJECT POPULATION 
Main Criteria for Inclusion 
Japanese men or women aged between 20 and 64 years (both inclusive) must meet the DSM-5 diagnostic 
criteria for single-episode MDD or recurrent MDD, without psychotic features, based upon clinical 
assessment and confirmed by the MINI will be enrolled. In the case of single-episode MDD, the subject 
must be diagnosed with persistent depressive disorder, which meets criteria of major depressive episode 
for a continuous duration of 2 years, and the same physician from the site must be examining the subject 
for 2 years continuously as a primary care physician of the subject. At the start of the screening phase, 
subject must have had nonresponse (≤25% improvement) to 1 but <5 oral antidepressant treatments in 
the current episode of depression, assessed using the MGH-ATRQ and confirmed by documented 
medical/pharmacy/prescription records, letter from treating physician etc. The subject’s current major 
depressive episode, depression symptom severity (MADRS total score ≥28 required), and antidepressant 
treatment response in the current depressive episode, must be confirmed using the SAFER interview. 
DOSAGE AND ADMINISTRATION 
Intranasal esketamine will be made available as an aqueous solution of esketamine hydrochloride 
(16.14% 
weight/volume 
[w/v]; 
equivalent 
to 
14% 
w/v 
of 
esketamine 
base) 
containing 
ethylenediaminetetraacetic acid (EDTA) and citric acid. The solution will consist of 161.4 mg/mL 
esketamine hydrochloride (equivalent to 140 mg of esketamine base) in water for injection. It will be 
provided in a nasal spray pump, which delivers 16.14 mg esketamine hydrochloride (14 mg esketamine 
base) per 100-μL spray. Each device contains sufficient volume for 2 sprays. 
The placebo solution will be provided as a clear, colorless intranasal solution of water for injection, with a 
bittering agent (denatonium benzoate [Bitrex®] at a final concentration of 0.001mg/mL) added to 
simulate the taste of the intranasal solution with active drug. 
Screening Phase 
Benzodiazepines or permitted non-benzodiazepine sleep medications or both, which have been taken and 
are ongoing before the start of screening phase will be continued throughout the study. Subject’s current 
antidepressant treatment(s), including adjunctive treatment for MDD, should be tapered and discontinued 
in this phase per the local prescribing information. 
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Clinical Protocol 54135419TRD2005 Amendment 5 
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Approved, Date: 21 December 2018  
Prospective Lead-in Phase 
All subjects will initiate a physician determined new OL oral antidepressant daily for the duration of this 
phase. The oral antidepressant will be 1 oral antidepressant medication of SSRIs, SNRIs or Mirtazapine 
(eg, escitalopram, paroxetine controlled-release [CR], sertraline, duloxetine, venlafaxine extended-release 
[XR], or mirtazapine), that the subject has not previously had a nonresponse to in the current depressive 
episode has not been previously intolerant to (lifetime).  If clinically indicated, cross-tapering is allowed 
in the first 2 weeks during the prospective lead-in phase. In the last 4 weeks during the prospective lead-in 
phase, 'oral antidepressant' must be single treatment of switched new oral antidepressant. New oral 
antidepressant treatment should be titrated to the approved maximum dose, to optimize the potential for 
response. Up-titration of the antidepressant may be performed per investigator’s discretion based on 
prescribing information in the prospective lead-in phase. The dose, which is above the minimum 
therapeutic dose defined in MGH ATRQ, should be kept at last 4 weeks during the prospective lead-in 
phase, in case they start at lower doses. 
Double-blind Induction Phase 
Eligible and randomized TRD subjects will self-administer double-blind intranasal treatment either 
placebo, esketamine 28 mg, esketamine 56 mg, or esketamine 84 mg add-on to continued stable oral 
antidepressant. 
Prior to the first intranasal dose on Day 1, subjects will practice spraying (into the air, not intranasally) 
with a demonstration intranasal device that is filled with placebo solution. 
The following table describes how each intranasal treatment session will be administered in the 
double-blind induction phase. 
Intranasal Treatment 
Time of Intranasal Device Administrationa 
0 minuteb 
5 minutes
10 minutes
Intranasal device c 
1st
2nd 
3rd 
Placebo 
1 spray of placebo to 
each nostril 
1 spray of placebo to 
each nostril 
1 spray of placebo to 
each nostril 
Esketamine 28 mg 
1 spray of esketamine to 
each nostril 
1 spray of placebo to 
each nostril 
1 spray of placebo to 
each nostril 
Esketamine 56 mg  
1 spray of esketamine to 
each nostril 
1 spray of esketamine to 
each nostril 
1 spray of placebo to 
each nostril 
Esketamine 84 mg 
1 spray of esketamine to 
each nostril 
1 spray of esketamine to 
each nostril 
1 spray of esketamine to 
each nostril 
a. The 3 intranasal devices for each intranasal treatment session should be administered in the medication kit order 
provided by the interactive web response system (IWRS) 
b. Time 0 is defined as the time of administration of the first intranasal spray to 1 nostril from the first intranasal 
device.  
c. 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) 
 
The first treatment session will be on Day 1. Intranasal treatment sessions should not take place on 
consecutive days. To improve tolerability, subjects who will be randomly assigned to esketamine 84 mg 
will start at 56 mg on Day 1 and then the dose will increase to 84 mg on Day 4 as a forced titration and 
stay at 84 mg for all subsequent intranasal treatment sessions. Starting with a lower dose may therefore 
reduce the number of subjects discontinuing the study treatment because of intolerability in the 84 mg 
dose group. Subjects who are randomly assigned to 28 mg or 56 mg will remain on that dose for all 
subsequent intranasal treatment sessions. No adjustment to the intranasal esketamine dose is permitted for 
the duration of the double-blind induction phase. 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
21 
Approved, Date: 21 December 2018  
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 new oral antidepressant 
treatment which is ongoing and stable from the prospective lead-in phase will also be maintained 
throughout the study. 
Posttreatment Phase 
Subjects who relapse within 20 weeks after the start of the posttreatment phase will transit to an OL 
induction phase and receive 4 weeks of OL treatment course with intranasal esketamine. Subjects who 
relapse more than 20 weeks after the start of the posttreatment phase will withdraw from the study and 
clinical/standard-of-care treatment will be arranged by the study investigator after relapse. Subjects who 
have no relapse throughout this 24-week posttreatment phase will complete this study without 4-week 
follow-up phase. The oral antidepressant must be continued at a stable dose during post treatment phase. 
Open-label Induction Phase 
Subjects who relapsed in the posttreatment phase will receive a 4-week OL induction treatment course of 
intranasal esketamine. During this phase, subjects will continue to receive their switched oral 
antidepressant medication. The beginning of the OL induction phase should be at least 2 weeks (14 
calendar days) after the last dose in the double-blind induction phase.  
Eligible TRD subjects will start treatment sessions with 56 mg of intranasal esketamine on the first day of 
OL induction phase (Day OL1). On Day OL4, the dose must be increased to 84 mg. On Day OL8 and 
OL11, the dose could be maintained, increased or reduced by 28 mg as determined by the investigator 
based on efficacy and tolerability. On Day OL15, a dose reduction is permitted, if required for 
tolerability; no dose increase is permitted on Day OL15. After Day OL15, the dose should be stable 
(unchanged). If needed for tolerability, a dose reduction is permitted from Day OL15 until Day OL25. 
Intranasal treatment sessions should not take place on consecutive days. 
Follow-up Phase 
During this phase, further clinical/standard-of-care treatment will be arranged by the study investigator 
however, in order to better assess potential withdrawal symptoms from intranasal study drug, the oral 
antidepressant medication must be continued for the follow-up phase unless determined as not clinically 
appropriate. 
EFFICACY EVALUATIONS/ENDPOINTS 
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, using the Structured Interview Guide for the MADRS. The 
MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to 
antidepressant treatment. 
The primary efficacy endpoint is the change in the MADRS total score as measured by the change from 
baseline (prior to randomization) to the end of the 4-week double-blind induction phase.  
Secondary Efficacy Evaluations and Endpoints 
1. 
Proportion of responders (50% reduction from baseline in MADRS total score) in the double-blind 
induction phase. 
2. 
Proportion of remitters (MADRS total score 12) in the double-blind induction phase. 
3. 
Proportion of subjects showing onset of clinical response in the double-blind induction phase.  
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
22 
Approved, Date: 21 December 2018  
4. 
Severity of depressive illness, using the Clinical Global Impression – Severity (CGI-S). Endpoint: 
Change from baseline in CGI-S in the double-blind induction phase. 
5. 
The 7-item subject-reported Generalized Anxiety Disorder 7-item scale (GAD-7) will be used to 
measure the secondary objective of symptoms of anxiety. Endpoint: Change from baseline in GAD-7 
in the double-blind induction phase.  
6. 
Sheehan Disability Scale (SDS): The SDS is a subject-reported outcome measure that will be used to 
assess functional impairment and associated disability. Endpoint: Change from baseline in SDS total 
score in the double-blind induction phase. 
7. 
Time to relapse: 
a. 
In subjects who remit (MADRS total score 12) at the end of the double-blind induction phase.  
b. 
In subjects with response (≥50% reduction from baseline in MADRS total score) but who are 
not in remission at the end of the double-blind induction phase. 
Relapse is defined as any of the following: 
1) 
MADRS total score 22 for 2 consecutive assessments. The date of the second MADRS 
assessment will be used for the date of relapse. 
2) 
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. 
3) 
In case both relapse criteria are met, the earlier date will be defined as the date of relapse 
for this subject. 
8. 
Change from baseline in SDS total score in the posttreatment phase.  
9. 
Change from baseline (prior to the first dose of OL induction phase) in MADRS total score in the 
OL induction phase. 
10. Proportion of responders (50% reduction from baseline in MADRS total score) in the OL induction 
phase. 
11. Proportion of remitters (MADRS total score 12) in the OL induction phase. 
12. Change from baseline (prior to the first dose of OL induction phase) in CGI-S in the OL induction 
phase. 
Pharmacokinetic Evaluations 
Whole blood samples will be used to evaluate the PK of esketamine (and noresketamine or additional 
metabolites, if warranted). The plasma concentration-time data of esketamine (and noresketamine or 
additional metabolites, if warranted) will be analyzed using population PK modeling. Typical population 
values of basic PK parameters (eg, esketamine clearance, distribution volume) 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. 
Pharmacokinetic/Pharmacodynamic Evaluations 
The PK/PD relationship of intranasal esketamine and MADRS total score (and possibly selected AEs as 
additional PD parameters) may be evaluated. If there is any visual trend in graphical analysis, suitable 
models will be applied to describe the exposure-effect relationships. The results of the PK/PD evaluations 
will be presented in a separate report. 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
23 
Approved, Date: 21 December 2018  
Biomarker Evaluations 
During the study, blood will be collected for the assessment of biomarkers at the time points indicated in 
the TIME AND EVENTS SCHEDULE 1. The biomarker blood samples should be collected prior to 
dosing.  
Pharmacogenomic (DNA) Evaluations 
A pharmacogenomic blood sample will be collected to allow for pharmacogenomic research, as necessary.  
A pharmacogenomic blood sample will be collected to allow for the assessment of genetic and epigenetic 
variation in genes in pathways relevant to the effect of esketamine. 
SAFETY EVALUATIONS 
Physical examination, height, and body weight, vital signs (including temperature, heart rate, blood 
pressure measurements, and respiratory rate), 12-lead electrocardiogram (ECG), pulse oximetry, clinical 
laboratory tests, evaluation of concomitant therapies, and TEAEs including TEAEs of special interest will 
be performed throughout the study to monitor subject safety.  
The Columbia Suicide Severity Rating Scale (C-SSRS) will be performed to assess suicidal ideation and 
behavior, the Clinician-Administered Dissociative States Scale (CADSS) will be administered to assess 
treatment-emergent dissociative symptoms, the four-item Positive Symptom Subscale of the Brief 
Psychiatric Rating Scale (BPRS+) will be administered to assess treatment-emergent psychotic symptoms, 
the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S will) be used to measure 
treatment-emergent sedation, the Clinical Global Assessment of Discharge Readiness (CGADR) will be 
used to measure the subject’s readiness for discharge based on parameters including sedation, blood 
pressure and AEs, and the 20-item Physician Withdrawal Checklist (PWC-20) will be administered to 
assess potential withdrawal symptoms after cessation of esketamine treatment, and Profile of Mood States 
2nd edition (POMS-2) will be used to evaluate the abuse-liability of intranasal esketamine treatment.  
On all intranasal dosing days, subjects will remain at the site until study procedures have been completed 
and the subject is ready for discharge. Subjects should be accompanied by a responsible adult when 
released from the clinical site. Subjects must not drive a car or work with machines for 24 hours after 
receiving the intranasal study drug.  
STATISTICAL METHODS 
Subject Information 
The primary efficacy (full analysis set [FAS]) and safety analysis sets are defined below. 
 
Full Analysis Set: All randomized subjects who receive at least 1 dose of intranasal study drug in 
the double-blind induction phase.  
 
Open-label Analysis Set: All subjects who receive at least 1 dose of intranasal study drug in the OL 
induction phase.  
 
Safety Analysis Set: All randomized subjects who receive at least 1 dose of intranasal study drug in 
the double-blind induction phase. 
Sample Size Determination 
The sample size for this study was calculated assuming a treatment difference for the double-blind 
induction phase of 4, 4.5, 5 points in MADRS total score between each dose (28 mg, 56 mg, 84 mg) of 
esketamine and the placebo respectively, a SD of 10 for each treatment group, a 1-sided significance level 
of 0.05 and a drop-out rate of 12.5%. A total of 183 subjects will need to be randomized to treatment in a 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
24 
Approved, Date: 21 December 2018  
2:1:1:1 ratio (72 subjects on placebo group and 37 subjects per intranasal esketamine dose group) to 
achieve 80% power to detect difference for at least one dose group of intranasal esketamine to placebo 
using a Dunnett adjustment. The treatment difference and SD used in this calculation were assumed based 
on results of Panel B of the ESKETINTRD2003 study with clinical consideration. 
Efficacy Analyses 
Efficacy analysis will be performed on the FAS, which will include all randomized subjects who receive 
at least 1 dose of intranasal study drug in the double-blind induction phase. Unless otherwise specified, a 
1-sided significance level of 0.05 will be used. For the primary efficacy analysis, change from baseline in 
MADRS total score at Week 4 in the double-blind induction phase will be analyzed using a mixed-effects 
model for repeated measures. The model will include baseline MADRS total score as a covariate, and 
treatment, day, and day-by-treatment interaction as fixed effects. An unstructured variance-covariance 
matrix will be used. Comparison of each esketamine dose groups with the placebo group will be 
performed with the appropriate contrast using a Dunnett adjustment. 
The impact of the missing data on the efficacy results will be assessed using sensitivity analyses. The 
follow-up data from subjects who discontinued the double-blind induction phase will be incorporated in 
the sensitivity analyses. Methods of sensitivity analyses will be specified in the statistical analysis plan 
(SAP). 
For the secondary efficacy analysis, the dose-response relationship will be investigated using the 
MCP-Mod procedure. Details will be provided in the SAP. 
The other secondary efficacy endpoints, the endpoints with continuous values will be analyzed by using 
mixed-effects model for repeated measures similar to the primary endpoint. Comparison of each 
esketamine group versus placebo group will be performed using the appropriate contrast. Binary 
endpoints will be analyzed using Fisher’s exact test with 90% confidence intervals (CIs) for the 
proportion provided for each treatment group. 
Time to relapse will be defined as the time between the end of the double-blind induction phase and the 
first documentation of a relapse event during the posttreatment phase. This will be analyzed separately 
either remitters or responders (but who are not remitters) at the end of the double-blind induction phase. 
Summary statistics (eg, number of relapses, number of censored subjects, median 25th and 75th 
percentile) will be provided from the Kaplan-Meier method. 
Additionally, scores and the changes from baseline of all efficacy endpoints will be summarized for all 
visits in the each induction phase. Data from the OL induction phase will be summarized based on 
subjects who received treatment during the OL induction phase. 
Pharmacokinetic Analyses 
Plasma esketamine (and noresketamine, if needed) concentrations will be listed for all subjects. 
Descriptive statistics of plasma esketamine (and noresketamine, if needed) concentration at each PK 
assessment time points will be calculated by dose. All concentrations below the lowest quantifiable 
sample concentration of the assay (BQL) or missing data will be labeled as such in the concentration data 
listing. 
Population PK analysis of plasma concentration-time data of esketamine (and noresketamine, if needed) 
will be performed with non-linear mixed-effects modeling (NONMEM) approach. 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
25 
Approved, Date: 21 December 2018  
Biomarker and Pharmacogenomic (DNA) Analyses 
Baseline biomarker values and changes from baseline biomarker values to the time points specified in the 
TIME AND EVENTS SCHEDULE 1 will be assessed. Biomarker values will be tabulated by treatment 
group over time points and summary statistics will be calculated. Associations between biomarkers and 
clinical endpoints will be explored. Correlations between baseline values and change in baseline values 
with efficacy and other clinical evaluations will be assessed, including the relation with response, 
maintenance of response, illness relapse, and nonresponse.  
Pharmacogenomic analyses may include candidate gene analyses or genome-wide association analyses in 
relation to treatment response, maintenance/stabilization of response, relapse, and nonresponse.  
Details of the analysis plan and summary of results from both biomarker and pharmacogenomics analyses 
will be provided in a separate report. 
Pharmacokinetic/Pharmacodynamic Analyses 
The PK/PD relationship of intranasal esketamine and MADRS total score (and possibly selected AEs as 
additional PD parameters) may be evaluated. If there is any visual trend in graphical analysis, suitable 
models will be applied to describe the exposure-effect relationships. The results of the PK/PD evaluation 
will be presented in a separate report. 
Safety Analyses 
Safety analysis set will consist of all randomized subjects who receive at least 1 dose of intranasal study 
drug in the double-blind induction phase. Safety data for the double-blind period will be analyzed for this 
population. For the analysis of safety data in the OL induction phase, all subjects who received at least 
1 dose of intranasal study drug in this period will be analyzed. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 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 discontinue treatment due to an AE and serious adverse 
events (SAEs) will be summarized separately.  
The TEAEs of special interest will be examined separately grouped in the following categories: Drug 
abuse, dependence and withdrawal (standardized MedDRA queries [SMQ]), increased blood pressure, 
increased heart rate, transient dizziness/vertigo, impaired cognition, anxiety, and cystitis. AEs of special 
interest will be further listed in the SAP. 
Body weight, vital signs, 12-lead ECG, pulse oximetry, and clinical laboratory test results, and changes 
from baseline will be presented over time by treatment group, using descriptive statistics. Any 
treatment-emergent abnormalities will be presented. 
PWC-20 rating scale, dissociative data from the CADSS, alertness data from the CGADR, sedation data 
from the MOAA/S, suicide-related thoughts and behaviors based on C-SSRS, Abuse-liability data from 
POMS-2, and psychosislike effect data from the BPRS+ will be summarized descriptively at each 
scheduled visit by treatment group. 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
26 
Approved, Date: 21 December 2018  
TIME AND EVENTS SCHEDULE 1 [-SCREENING PHASE, PROSPECTIVE LEAD-IN PHASE AND DOUBLE-BLIND 
INDUCTION PHASE] 
 
Screening 
Phase Prospective Lead-in Phase
Double-blind Induction Phase 
Visit number 
1.1 b 
2.1 b 
2.2 
2.3 
3.1 a 
3.2 
3.3 
3.4 
3.5 
3.6 
3.7 
3.8 
3.9 
3.10 m
EW c
Study Week 
Within 
4 weeks 
of Day P1 
-6 
-4 
-2 
1 
2 
3 
4 
— 
Study day 
-70 
(P-28 to 
P-1) 
-42 
(P1) 
-28 
(P15)
-14 
(P29)
1 
(P43) 
2 
4 
8 
11 
15 
18 
22 
25 
28 
EW
Prerand
omizati
on 
Postrand
omizatio
n 
Clinic visit window (days) 
 
-3 
±3 
±3 
— 
— 
— 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
— 
Remote MADRS 
interview window (in 
days; relative to Study 
day [not including visit 
window]) 
 
-3 
±3 
±3 
— 
— 
— 
— 
-2d 
— 
-2d 
— 
-2d 
— 
-2d, p
— 
Clinic visit (C) or remote 
MADRS interview only 
(RM) 
 
C 
C 
C 
C 
RM
C 
C 
C 
C 
C 
C 
C 
C 
C 
Informed Consent/Screening/Administrative
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent (ICF) 
X o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, psychiatric 
history, demographics, 
employment status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MGH-ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAFER interview 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
Study Drug and Oral Antidepressants (Base Therapy) 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispensing of new oral 
antidepressant  
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Practice session for use of 
intranasal device 
 
 
 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
27 
Approved, Date: 21 December 2018  
 
Screening 
Phase Prospective Lead-in Phase
Double-blind Induction Phase 
Visit number 
1.1 b 
2.1 b 
2.2 
2.3 
3.1 a 
3.2 
3.3 
3.4 
3.5 
3.6 
3.7 
3.8 
3.9 
3.10 m
EW c
Study Week 
Within 
4 weeks 
of Day P1 
-6 
-4 
-2 
1 
2 
3 
4 
— 
Study day 
-70 
(P-28 to 
P-1) 
-42 
(P1) 
-28 
(P15)
-14 
(P29)
1 
(P43) 
2 
4 
8 
11 
15 
18 
22 
25 
28 
EW
Prerand
omizati
on 
Postrand
omizatio
n 
Clinic visit window (days) 
 
-3 
±3 
±3 
— 
— 
— 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
— 
Remote MADRS 
interview window (in 
days; relative to Study 
day [not including visit 
window]) 
 
-3 
±3 
±3 
— 
— 
— 
— 
-2d 
— 
-2d 
— 
-2d 
— 
-2d, p
— 
Clinic visit (C) or remote 
MADRS interview only 
(RM) 
 
C 
C 
C 
C 
RM
C 
C 
C 
C 
C 
C 
C 
C 
C 
Intranasal esketamine or 
placebo  
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Drug accountability 
(intranasal study drug) 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Oral antidepressant 
compliance check 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments (Clinician) 
Physical examination 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X
X 
X 
Vital signs: blood pressure, 
pulse, respiratory rate, 
temperature e 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs (postdose): 
blood pressure, pulse, 
respiratory rate f 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight 
X 
 
 
 
X
 
 
 
 
X 
 
 
 
X 
X 
12-lead ECG g 
X 
 
 
 
X
X
 
X 
X
X
X 
C-SSRS: 
Baseline/Screening version 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
28 
Approved, Date: 21 December 2018  
 
Screening 
Phase Prospective Lead-in Phase
Double-blind Induction Phase 
Visit number 
1.1 b 
2.1 b 
2.2 
2.3 
3.1 a 
3.2 
3.3 
3.4 
3.5 
3.6 
3.7 
3.8 
3.9 
3.10 m
EW c
Study Week 
Within 
4 weeks 
of Day P1 
-6 
-4 
-2 
1 
2 
3 
4 
— 
Study day 
-70 
(P-28 to 
P-1) 
-42 
(P1) 
-28 
(P15)
-14 
(P29)
1 
(P43) 
2 
4 
8 
11 
15 
18 
22 
25 
28 
EW
Prerand
omizati
on 
Postrand
omizatio
n 
Clinic visit window (days) 
 
-3 
±3 
±3 
— 
— 
— 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
— 
Remote MADRS 
interview window (in 
days; relative to Study 
day [not including visit 
window]) 
 
-3 
±3 
±3 
— 
— 
— 
— 
-2d 
— 
-2d 
— 
-2d 
— 
-2d, p
— 
Clinic visit (C) or remote 
MADRS interview only 
(RM) 
 
C 
C 
C 
C 
RM
C 
C 
C 
C 
C 
C 
C 
C 
C 
C-SSRS: Since last visit 
version 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MOAA/S and pulse 
oximetry h 
 
X n 
 
 
X n 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
BPRS+ i 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
CADSS i 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
CGADR j 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PWC-20 e 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
X 
Subject-completed Assessments (Safety) 
POMS-2 e 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Efficacy Assessments (Clinician) 
MADRS (7-day recall; 
performed by independent, 
remote raters) 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
MADRS (24-hr recall; 
performed by independent, 
remote raters) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
CGI-S e 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
29 
Approved, Date: 21 December 2018  
 
Screening 
Phase Prospective Lead-in Phase
Double-blind Induction Phase 
Visit number 
1.1 b 
2.1 b 
2.2 
2.3 
3.1 a 
3.2 
3.3 
3.4 
3.5 
3.6 
3.7 
3.8 
3.9 
3.10 m
EW c
Study Week 
Within 
4 weeks 
of Day P1 
-6 
-4 
-2 
1 
2 
3 
4 
— 
Study day 
-70 
(P-28 to 
P-1) 
-42 
(P1) 
-28 
(P15)
-14 
(P29)
1 
(P43) 
2 
4 
8 
11 
15 
18 
22 
25 
28 
EW
Prerand
omizati
on 
Postrand
omizatio
n 
Clinic visit window (days) 
 
-3 
±3 
±3 
— 
— 
— 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
— 
Remote MADRS 
interview window (in 
days; relative to Study 
day [not including visit 
window]) 
 
-3 
±3 
±3 
— 
— 
— 
— 
-2d 
— 
-2d 
— 
-2d 
— 
-2d, p
— 
Clinic visit (C) or remote 
MADRS interview only 
(RM) 
 
C 
C 
C 
C 
RM
C 
C 
C 
C 
C 
C 
C 
C 
C 
Subject-completed Assessments 
SDS e 
 
 
 
 
X
 
 
 
 
 
 
 
X 
X 
GAD-7 e 
 
 
 
 
X
 
 
 
 
X
 
 
X 
X 
Clinical Laboratory Assessments 
TSH, HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid panel (fasting) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, chemistry e  
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Urinalysis e  
X 
 
 
 
X
 
 
 
 
X
 
 
 
X 
X 
Urine drug screen  e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urine pregnancy test e 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collectionk 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Biomarker and Pharmacogenomic (DNA) Evaluations 
 
 
 
 
 
 
 
 
 
 
 
Blood sample collection  
(Protein) e, l 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
Blood sample collection 
(DNA) e, l 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
30 
Approved, Date: 21 December 2018  
 
Screening 
Phase Prospective Lead-in Phase
Double-blind Induction Phase 
Visit number 
1.1 b 
2.1 b 
2.2 
2.3 
3.1 a 
3.2 
3.3 
3.4 
3.5 
3.6 
3.7 
3.8 
3.9 
3.10 m
EW c
Study Week 
Within 
4 weeks 
of Day P1 
-6 
-4 
-2 
1 
2 
3 
4 
— 
Study day 
-70 
(P-28 to 
P-1) 
-42 
(P1) 
-28 
(P15)
-14 
(P29)
1 
(P43) 
2 
4 
8 
11 
15 
18 
22 
25 
28 
EW
Prerand
omizati
on 
Postrand
omizatio
n 
Clinic visit window (days) 
 
-3 
±3 
±3 
— 
— 
— 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
— 
Remote MADRS 
interview window (in 
days; relative to Study 
day [not including visit 
window]) 
 
-3 
±3 
±3 
— 
— 
— 
— 
-2d 
— 
-2d 
— 
-2d 
— 
-2d, p
— 
Clinic visit (C) or remote 
MADRS interview only 
(RM) 
 
C 
C 
C 
C 
RM
C 
C 
C 
C 
C 
C 
C 
C 
C 
Ongoing Subject Review  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Footnotes:  
Note: On intranasal dosing days, time 0 is defined as the time of the first intranasal spray. Therefore, postdose time points are referenced from this. 
a. 
Visit 3.1 Prerandomization must coincide exactly on the same day as Visit 3.1 Postrandomization. All subjects who will be randomized and enrolled in the double-
blind induction phase must meet all of the inclusion criteria and none of the exclusion criteria at Visit 3.1 Prerandomization. After randomization, all subjects will 
proceed to Visit 3.1 Postrandomization.  
b. 
If clinically indicated, cross tapering is allowed. 
c. 
If a subject withdraws before the end of the double-blind induction phase (ie, before completing Visit 3.10/Day 28) for reasons other than withdrawal of consent, 
an EW Visit should be conducted within 1 week of the date of discontinuation, followed by the follow-up phase. If the EW Visit is conducted on the same day as a 
scheduled visit, duplicate assessments are not required. 
d. 
MADRS assessment should be conducted at predose. 
e. 
Predose (if/when performed on intranasal dosing days). With the exception of postdose assessments, subject-reported outcome assessments should be administered 
before all other study-related procedures during a clinic visit. 
f. 
Postdose vital signs will be performed at 40 minutes, 1 hour, and 1.5 hours postdose. Please refer to Section 6.3.1 for guidance for blood pressure monitoring on 
intranasal dosing days. 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
31 
Approved, Date: 21 December 2018  
g. 
Twelve-lead ECG will be performed at t=1 hour postdose at Visit 3.1 Postrandomization. Twelve-lead ECG will be performed at t=1 hour postdose at Visits 3.4 to 
3.9 (only at the time points indicated), but no predose ECGs are required at Visits 3.4 to 3.9. A time window of ±15 minutes is permitted. 
h. 
The MOAA/S will be performed every 15 minutes from predose to t=+1.5 hours postdose. Pulse oximetry will be performed every 15 minutes from predose to 
t=1.5 hours postdose. 
i. 
The BPRS+ and CADSS to be performed predose and at 40 minutes and 1.5 hours postdose.  
j. 
CGADR to be performed at 1 hour and 1.5 hour postdose; if the response is not “Yes” at 1.5 hour postdose, the assessment will be repeated every 15 minutes until 
a “Yes” response is achieved or until the subject is referred for appropriate medical care if clinically indicated. A subject should not be discharged prior to the 1.5 
hour time point. 
k. 
PK blood collection will be performed at t=40 minutes, t=1 hour and t=2 hours postdose (where time=0 is defined as the time of the first intranasal spray on PK 
blood collection Day).  
l. 
Blood samples should be collected prior to dosing. It is preferred that subjects adhere to a low fat diet on the day of sample collection. Subjects also should refrain 
from strenuous exercise for 24 hours prior to sample collection. 
m. 
Visit 3.10 will be identical to the start day of the posttreatment phase. 
n. 
Pulse oximetry only. 
o. 
Informed consent must be obtained prior to the initiation of any study procedure including washout of prohibited therapies.  
p. 
MADRS interview should not be conducted on the same day with the assessment at Visit 3.9. 
 
 
 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
32 
Approved, Date: 21 December 2018  
TIME AND EVENTS SCHEDULE 2 [-POSTTREATMENT PHASE AND FOLLOW-UP PHASE] 
 
Posttreatment Phase 
Follow-up 
Phase a 
Visit number 
4.1 
4.2 
4.3 
4.4 
4.5 
4.6
4.7 
4.8 
4.9, 4.10, 4.11,
4.13, 4.14, 4.15, 
4.17, 4.18, 4.19,
4.21, 4.22, 4.23
4.12 
4.16 
4.20 
4.24 
EW
6.1 
6.2 
6. 3
Study week 
5 
6 
7 
8 
9 
10 
11 
12 
13, 14, 15,  
17, 18, 19, 
21, 22, 23, 
25, 26, 27 
16 
20 
24 
28 
- 
F1 
F2 
F4 
Study day 
32 
39 
46 
53 
60 
67 
74 
81 
88, 95, 102, 
116, 123, 130, 
144, 151, 158, 
172, 179, 186 
109 
137 
165 
193 
- 
F7 
F14
F28
Clinic visit or remote MADRS window 
(days) 
+3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±3 
±3 
Clinic (C) or remote MADRS interview 
only (RM) 
C 
C 
C 
C 
RM
C 
RM 
C 
RM 
C 
C 
C 
C 
Safety Assessments (Clinician-completed) 
C-SSRS: Since last visit version  
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
PWC-20 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
Safety Assessments (Subject-completed) 
POMS-2 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Efficacy Assessments (Clinician-completed) 
MADRS (7-day recall) 
Performed weekly b, c 
X 
X 
CGI-S  
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Efficacy Assessments (Subject-completed) 
SDS 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Clinical Laboratory Assessments 
Urine pregnancy test 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
Oral antidepressant 
Oral antidepressant compliance check 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Dispensing of oral antidepressant  
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
33 
Approved, Date: 21 December 2018  
 
Posttreatment Phase 
Follow-up 
Phase a 
Visit number 
4.1 
4.2 
4.3 
4.4 
4.5 
4.6
4.7 
4.8 
4.9, 4.10, 4.11,
4.13, 4.14, 4.15, 
4.17, 4.18, 4.19,
4.21, 4.22, 4.23
4.12 
4.16 
4.20 
4.24 
EW
6.1 
6.2 
6. 3
Study week 
5 
6 
7 
8 
9 
10 
11 
12 
13, 14, 15,  
17, 18, 19, 
21, 22, 23, 
25, 26, 27 
16 
20 
24 
28 
- 
F1 
F2 
F4 
Study day 
32 
39 
46 
53 
60 
67 
74 
81 
88, 95, 102, 
116, 123, 130, 
144, 151, 158, 
172, 179, 186 
109 
137 
165 
193 
- 
F7 
F14
F28
Clinic visit or remote MADRS window 
(days) 
+3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±3 
±3 
Clinic (C) or remote MADRS interview 
only (RM) 
C 
C 
C 
C 
RM
C 
RM 
C 
RM 
C 
C 
C 
C 
Ongoing Subject Review 
Concomitant therapy 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Footnotes: 
a. 
All subjects who are discontinued must be treated with an oral antidepressant after completion of the study, unless it is clinically inappropriate. 
b. 
MADRS assessments will be performed weekly through Week 24 or relapse, whichever occurs first. In the posttreatment phase, subjects who relapse within 20 
weeks after the start of the posttreatment phase will receive an open-label treatment course of esketamine. The beginning of the open-label induction phase should 
be at least 2 weeks after the last dose in the double-blind induction phase. 
c. 
Relapse based on MADRS assessment is defined as MADRS total score ≥22 for 2 consecutive visits.  
 
 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
34 
Approved, Date: 21 December 2018  
TIME AND EVENTS SCHEDULE 3 [-OPEN-LABEL INDUCTION PHASE] 
 
Open-label Induction Phase (Visit number; 5.1-5.10, Study week; OL1-OL4, Study day; OL1-OL28) 
Visit number 
5.1 
5.3 
5.4 
5.5 
5.6 
5.7 
5.8 
5.9 
5.10 
EW a
Study Week 
OL 1 
OL 2 
OL 3 
OL 4 
— 
Study day 
OL 1 i 
OL 4 
OL 8 
OL 11 
OL 15 
OL 18 
OL 22 
OL 25 
OL 28 
EW 
Clinic visit window (days) 
— 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
— 
Remote MADRS interview 
window (in days; relative to Study 
day [not including visit window]) 
— 
— 
-2 
— 
-2 
— 
-2 
— 
-2 j 
— 
Clinic visit (C) or remote MADRS 
interview only (RM) 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
Study Drug and Oral Antidepressants (Base Therapy) 
Dispensing of new oral antidepressant  
X 
 
X 
 
 
 
X 
 
 
 
Intranasal esketamine  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Drug accountability 
(intranasal study drug) 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Oral antidepressant compliance check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments (Clinician) 
Physical examination b 
X 
 
X 
 
X 
 
 
X
X 
X 
Vital signs: blood pressure, pulse, 
respiratory rate, temperature b  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs (postdose): blood pressure, 
pulse, respiratory rate c 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight b 
X 
 
 
 
X 
 
 
 
X 
X 
12-lead ECG d 
X 
 
 
X
X
X 
C-SSRS: Since last visit version b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MOAA/S and pulse oximetrye  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
BPRS+ f 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CADSS f 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CGADR g 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PWC-20 b 
 
 
 
 
 
 
 
X
X 
Efficacy Assessments (Clinician) 
MADRS (7-day recall; performed by 
independent, remote raters) 
X 
 
X 
 
X 
 
X 
 
X 
X 
CGI-S b 
X 
 
X 
 
X 
X 
 
X 
X 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
35 
Approved, Date: 21 December 2018  
 
Open-label Induction Phase (Visit number; 5.1-5.10, Study week; OL1-OL4, Study day; OL1-OL28) 
Visit number 
5.1 
5.3 
5.4 
5.5 
5.6 
5.7 
5.8 
5.9 
5.10 
EW a
Study Week 
OL 1 
OL 2 
OL 3 
OL 4 
— 
Study day 
OL 1 i 
OL 4 
OL 8 
OL 11 
OL 15 
OL 18 
OL 22 
OL 25 
OL 28 
EW 
Clinic visit window (days) 
— 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
— 
Clinical Laboratory Assessments 
Hematology, chemistry b  
X 
 
 
 
 
 
 
X 
X 
Urinalysis b  
X 
 
 
 
X
 
 
 
X 
X 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
X 
X 
Urine pregnancy test b  
 
 
 
 
X 
 
 
 
 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
Blood collection h 
 
 
 
 
 
 
 
X 
 
 
Ongoing Subject Review 
 
 
 
 
 
 
 
 
 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes: 
Note: On intranasal dosing days, time 0 is defined as the time of the first intranasal spray. Therefore, postdose time points are referenced from this. 
a. 
If a subject withdraws before the end of the open-label induction phase (ie, before completing Visit 5.10/Day OL28) for reasons other than withdrawal of consent, 
an EW Visit should be conducted within 1 week of the date of discontinuation, followed by the follow-up phase. If the EW Visit is conducted on the same day as a 
scheduled visit, duplicate assessments are not required. 
b. 
Predose (if/when performed on intranasal dosing days).  
c. 
Postdose vital signs will be performed at 40 minutes, 1 hour, and 1.5 hours postdose. Please refer to Section 6.3.1 for guidance for blood pressure monitoring on 
intranasal dosing days. 
d. 
Twelve-lead ECG will be performed at t=1 hour postdose at Visit 5.1 to 5.10 (only at the time points indicated), but no predose ECGs are required at Visits 5.1 to 
5.10. A time window of ±15 minutes is permitted. 
e. 
The MOAA/S will be performed every 15 minutes from predose to t=+1.5 hours postdose. Pulse oximetry will be performed every 15 minutes from predose to 
t=1.5 hours postdose. 
f. 
The BPRS+ and CADSS to be performed predose and at 40 minutes and 1.5 hours postdose.  
g. 
CGADR to be performed at 1 hour and 1.5 hour postdose; if the response is not “Yes” at 1.5 hour postdose, the assessment will be repeated every 15 minutes until 
a “Yes” response is achieved or until the subject is referred for appropriate medical care if clinically indicated. A subject should not be discharged prior to the 1.5 
hour time point.  
h. 
PK blood collection will be performed at t=40 minutes, t=1 hour and t=2 hours postdose (where time=0 is defined as the time of the first intranasal spray on PK 
blood collection Day). 
i. 
If the assessment on Day OL 1 is conducted on the same day as a scheduled visit in the posttreatment phase, duplicate assessments are not required. 
j. 
MADRS interview should not be conducted on the same day with the assessment at Visit 5.9. 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
36 
Approved, Date: 21 December 2018  
ABBREVIATIONS 
 
AE 
adverse event 
ASA 
American Society of Anesthesiologists 
AUC 
area under curve 
BDNF 
brain-derived neurotrophic factor 
BPRS+ 
four-item positive symptom subscale of the Brief Psychiatric Rating Scale 
CADSS 
Clinician-Administered Dissociative Symptom Scale 
CGADR 
Clinical Global Assessment of Discharge Readiness 
CGI-S 
Clinical Global Impression – Severity 
Cmax 
maximum plasma concentration 
CI 
confidence interval 
CR 
controlled-release 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
hepatic cytochrome P450 
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 
EOS 
end-of-study 
EW 
early withdrawal 
FAS 
full analysis set 
FT4 
free thyroxine 
GAD-7 
Generalized Anxiety Disorder 7-item scale 
GCP 
good clinical practice 
HbA1c 
glycated hemoglobin  
HPA 
hypothalamic pituitary-adrenal 
HRUQ 
Healthcare Resource Use Questionnaire 
HVLT-R 
Hopkins Verbal Learning Test-Revised 
IC 
informed consent 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IM 
intramuscular 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous 
IWRS 
interactive web response system 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MDD 
major depressive disorder 
MGH-ATRQ 
Massachusetts General Hospital – Antidepressant Treatment Response Questionnaire 
MINI 
Mini International Neuropsychiatric Interview 
MOAA/S 
Modified Observer’s Assessment of Alertness/Sedation 
MMRM 
mixed-effects model for repeated measures 
NMDA 
N-methyl-D-aspartate 
OL 
open-label 
PD 
pharmacodynamics 
PK 
pharmacokinetic 
POMS-2 
Profile of Mood States 2nd edition 
PQC 
product quality complaint 
PWC-20 
Physician Withdrawal Checklist; 20-item 
QTc 
corrected QT 
QTcF 
QT interval corrected according to Fridericia’s formula 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
37 
Approved, Date: 21 December 2018  
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SDS 
Sheehan Disability Scale 
SE 
standard error 
SNPs 
single nucleotide polymorphisms 
SSRI 
selective serotonin re-uptake inhibitor 
SNRI 
serotonin–norepinephrine reuptake inhibitor 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TRD 
treatment-resistant depression 
TSH 
thyroid-stimulating hormone 
XR 
extended-release 
 
 
 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
38 
Approved, Date: 21 December 2018  
1. 
INTRODUCTION 
Major depressive disorder (MDD) is a serious, recurrent, and disabling psychiatric illness.67 It is 
the second leading cause of years lost to disability worldwide and is associated with excess 
mortality; and the estimated median years of potential life lost is 10 years.68,71 About 30% of 
subjects fail to achieve remission despite treatment with multiple antidepressant medications, and 
are considered to have treatment-resistant MDD (TRD).26,58 In subjects who respond to 
antidepressant treatments, the time to onset of effect is typically 4 to 7 weeks, during which time 
subjects continue to suffer from their symptoms and continue to be at risk of self-harm, as well 
as being impacted by the associated harm to their personal and professional lives.58,61 Therefore, 
there is a significant need to develop novel treatments based upon relevant pathophysiologic 
pathways underlying MDD for the rapid relief of depressive symptoms, especially in subjects 
with TRD.22,23 
Ketamine and esketamine (S-ketamine, the S-enantiomer of ketamine) are approved and widely 
used for the induction and maintenance of anesthesia via intramuscular (IM) or intravenous (IV) 
administration. The desired analgesic-anesthetic effects of ketamine and esketamine are 
attributed to the blockade of ionotropic N-methyl-D-aspartate (NMDA) glutamate receptors. The 
mechanism of action of ketamine and esketamine are distinct from conventional monoaminergic 
antidepressant treatments, in that they profoundly affect fast excitatory glutamate transmission, 
increases in brain-derived neurotrophic factor (BDNF) release, and stimulate synaptogenesis. 
Monoamines (serotonin, norepinephrine, or dopamine) are only modulatory transmitters; 
therefore, conventional monoaminergic antidepressant treatments would not be expected to 
robustly affect synaptic transmission, activity-dependent release of BDNF, or synaptogenesis.23 
In contrast, the mechanism of action of ketamine is distinct from conventional antidepressant 
treatments by profoundly affecting fast excitatory glutamate transmission, increasing BDNF 
release, and stimulating synaptogenesis.23 
Most literature reports of the antidepressant effects of ketamine describe studies using IV 
administration of the racemate, with a few exceptions.20,45 Janssen Research & Development is 
developing intranasal esketamine because of the higher NMDA receptor affinity of esketamine in 
contrast to its racemate arketamine (R-ketamine), which would require administration of a lower 
volume of medication via the intranasal route.38,46,51 
For the most comprehensive nonclinical and clinical information regarding esketamine, refer to 
the latest version of the Investigator's Brochure32 for esketamine. 
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document. 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
39 
Approved, Date: 21 December 2018  
1.1. 
Background 
1.1.1. 
Nonclinical Studies 
Safety Pharmacology 
The following text, quoted from the United States (US) prescribing information for anesthetic 
Ketalar® (ketamine hydrochloride [HCl] injection)33: Intravenous Ketalar produces a fall in 
arterial blood pressure in the Rhesus monkey and a rise in arterial blood pressure in the dog. In 
this respect, the dog mimics the cardiovascular effect observed in man. The pressor response to 
Ketalar injected into intact, unanesthetized dogs is accompanied by a tachycardia, rise in cardiac 
output, and a fall in total peripheral resistance. The pressor response to Ketalar is reduced or 
blocked by chlorpromazine (central depressant and peripheral α-adrenergic blockade), by 
β-adrenergic blockade, and by ganglionic blockade. 
Findings from animal studies suggest that the increase in blood pressure produced by 
ketamine/esketamine is due to selective activation of central cardiac stimulating mechanisms 
leading to an increase in cardiac output. 
In a 3-month repeat-dose toxicity study with intranasally administered esketamine in dogs, no 
relevant electrocardiogram (ECG) changes were noted up to the highest dose tested, ie, 
72 mg/day. Heart rate was slightly increased. The cardiovascular safety of racemic ketamine and 
esketamine in humans and animals is summarized in the Investigator's Brochure.32 
Toxicology 
Repeat-dose Toxicity Studies 
In repeat-dose toxicity studies with intranasally administered esketamine in rats up to 9 mg/day 
for 6 months, and dogs up to 72 mg/day for 3 months of duration, the clinical observations 
mainly related to the central nervous system (eg, changes in activity and gait). No adverse effects 
were noted up to the highest dose tested, ie, 9 mg/day in rats and 72 mg/day in dogs. These 
observations reflected the (exaggerated) pharmacology of the test compound. Minor histologic 
findings were noted in the nasal cavity. These tissue changes were not considered adverse. 
In 3- and 9-month repeat-dose toxicity studies with intranasally administered esketamine in dogs, 
no relevant electroencephalographic changes were noted up 72 mg/day. Heart rate was slightly 
increased.32 
Genetic Toxicity 
A series of in vitro and in vivo genotoxicity studies was conducted with ketamine and 
esketamine. The weight of evidence indicates that esketamine poses no genotoxic risk to 
humans.32 
Neurotoxicity 
Racemic ketamine has been reported to induce neurotoxicity in animal fetuses, and in juvenile, 
adolescent, and adult animals, as evidenced by histopathologic brain lesions and functional 
NCT02918318


JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
40 
Approved, Date: 21 December 2018  
sequelae. The precise thresholds for dose and duration of exposure causing neurotoxicity in 
animals remain to be established. The relevance to humans of ketamine’s neurotoxic action in 
animals is unknown. 
In studies exploring neurotoxic effects of ketamine on juvenile and prenatal monkeys, 
neuroapoptosis was observed to be more widespread in fetal brains than in neonatal brains, after 
administration of ketamine anesthesia IV for 5 hours. In fetal brains, the cerebellum, caudate 
nucleus, putamen, and nucleus accumbens were most severely affected. In neonatal brains, the 
cerebellum was not affected; the strongest neuroapoptotic response was noted in the basal 
ganglia and several thalamic areas. 
In juvenile rodents, ketamine-induced apoptotic neurodegeneration was observed that was more 
widespread than in adult rodents, with the developing brain affected in several major regions. 
Neuronal cell death was induced in the dorsolateral thalamus at blood levels of ketamine of 
14 µg/mL (7 times the human anesthetic blood level of approximately 2 µg/mL). 
No significant neurotoxic effects occurred in juvenile Rhesus monkeys if the anesthesia was 
administered as IM induction followed by IV maintenance. 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 elderly 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 postnatal 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 subjects is 
considered low.32 
Abuse Potential 
Animal studies with ketamine suggest that it would have abuse potential in humans. These 
studies included self-administration and withdrawal experiments in several species.32 
NCT02918318


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Clinical Protocol 54135419TRD2005 Amendment 5 
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Reproductive Toxicity 
In a rat fertility and early embryonic developmental toxicity study with intranasally administered 
esketamine, no adverse effects on fertility or reproductive capacity or performance were found. 
Rat and rabbit embryo-fetal developmental toxicity studies with intranasally administered 
racemic ketamine did not reveal evidence of reproductive toxicity. However, when monkey 
fetuses were exposed in utero to high dose levels of racemic ketamine, neurotoxicity was 
observed.  
Intranasally administered esketamine did not affect pre- and postnatal development in rats. 
However, high dose levels of racemic ketamine-induced neurotoxicity in early postnatal rat 
pups.32 
Considering the neurotoxic potential of ketamine and esketamine; and the fact that no threshold 
for these effects has been demonstrated, female subjects of childbearing potential should be 
adequately protected from becoming pregnant and pregnant women should not be enrolled. 
Cardiovascular Toxicity 
In guinea pig tissues, ketamine-induced negative inotropic effects and shortening of action 
potential duration at the 0-mV level was observed, likely as a result of the suppression of inward 
calcium current whereas in rat left atria and ketamine-induced positive inotropic effects and 
prolongation of action potential duration at the 0-mV level was observed, likely as a result of a 
decrease in calcium-insensitive transient outward current.25 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.33 
These observations support the hypothesis that the hypertension produced by Ketalar is due to 
selective activation of central cardiac stimulating mechanisms leading to an increase in cardiac 
output.  
The dog would be considered the most predictive species in terms of ketamine’s cardiovascular 
effects in humans, but the antidepressant effects of ketamine were studied only in rodent models. 
The myocardial contractility effects and blood pressure responses to ketamine vary between 
species.32 Consequently, a margin of safety could not be reliably derived from the available 
animal data. 
Overall Conclusion 
The currently available nonclinical safety studies support chronic intranasal administration of 
esketamine in human subjects up to a dosage of 84 mg/day. 
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1.1.2. 
Clinical Studies 
1.1.2.1. 
Pharmacokinetics and Product 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.70 Like ketamine, norketamine is a noncompetitive antagonist at 
the NMDA receptor. Norketamine has a half-life in plasma of approximately 5 hours.24,31 The 
major human hepatic CYPs that catalyze ketamine N-demethylation in vitro are CYP2B6 and 
CYP3A4.52 The CYP enzymes responsible for the formation of norketamine metabolites include 
CYP2A6 and CYP2B6.52 Published results of a clinical pharmacokinetic (PK) study indicate that 
esketamine does not invert to the R-enantiomer.28 
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.3 Less than 3% of an 
administered dose was excreted in urine as parent drug.69 
A PK summary 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 ESKTIVTRD2001.17 Maximum concentrations of esketamine were observed at the 
end of the infusion. Mean maximum plasma concentration (Cmax) and area under the plasma 
concentration-time curve (AUC) values 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. 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, ESKTINTRD1002, 
ESKETINTRD1003, ESKETINTRD1012, and ESKETINTRD2003 are described below.12, 13, 14, 
15, 16 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.12 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 from 28 to 112 mg. The regimens were self-administered by subjects in the upright 
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position. No instructions were given with regards to sniffing after administration. The reported 
median Tmax 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 AUC∞ 
values ranged from 164 to 565 ng*h/mL. Mean Cmax and AUC values of esketamine increased in 
a less than dose-proportional manner across the dose regimens. Furthermore, there was 
substantial overlap in the range of individual Cmax and AUC values among the 3 doses. The mean 
terminal half-life of esketamine ranged from 5.86 to 9.83 hours across all treatments. 
Subjects in Cohort 2 received 84 mg in a semi-reclined position and were instructed to sniff after 
each spray. Higher mean Cmax and AUC∞ values were observed in this cohort (174 ng/mL and 
437 ng*h/mL, respectively) compared with the same esketamine dose self-administered by 
subjects in Cohort 1 (107 ng/mL and 363 ng*h/mL, respectively). The semi-reclined position of 
the head and the instruction to subjects to sniff gently 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, 15 healthy Japanese and 14 healthy Caucasian 
subjects received single intranasal doses of esketamine 28 mg, 56 mg, and 84 mg in a crossover 
manner.13 The mean body mass index (BMI) were 21.98 kg/m2 and 23.49 kg/m2 in Japanese and 
Caucasian subjects, respectively. On average, plasma esketamine Cmax and AUC values were up 
to 48% higher in Japanese subjects compared with Caucasian subjects. The incidence of the 
treatment-emergent adverse events (TEAEs) was higher in Japanese subjects (80% [12/15]) as 
compared to Caucasian subjects (50% [7/14]). The most commonly reported TEAEs by preferred 
term (>10%) in Japanese subjects were headache (26.7% [4/15] of subjects), vertigo (46.7% 
[7/15] of subjects), vomiting (26.7% [4/15] of subjects), derealization (20.0% [3/15] of subjects), 
nausea (20.0% [3/15] of subjects), depressed level of consciousness (13.3% [2/15] of subjects), 
somnolence (13.3% [2/15] of subjects), and confusional state (13.3% [2/15] of subjects). Though 
TEAEs were seen in majority of subjects, they were transient, mild or moderate in severity and 
were consistent with previously reported TEAEs for esketamine. Hence, a single intranasal dose 
of esketamine (28 mg, 56 mg, and 84 mg) was observed to be safe and well tolerated in Japanese 
subjects with no new safety findings of clinical concern. 
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, both inclusive).14 Subjects received a single intranasal treatment of esketamine 28 mg. 
Median time to reach the maximum plasma concentration (tmax) of esketamine was 
approximately 30 minutes for both age groups. The geometric means of the Cmax and area under 
the plasma concentration-time curve from time 0 to infinite time, AUC∞, for esketamine were 
approximately 21% and 17% higher, respectively, in the elderly compared with younger adult 
subjects.14  
Another Study, ESKETINTRD1012, compared the PK, safety, and tolerability of intranasally 
administered esketamine in elderly subjects (≥75 years of age) and healthy younger adult 
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subjects (18 to 55 years of age, both inclusive). On average, the plasma Cmax, AUClast, and AUC∞ 
of esketamine produced by a single, 84 mg intranasal dose were approximately 67%, 34%, and 
38% higher, respectively, in subjects who are ≥75 years of age, relative to younger adult subjects. 
A small difference was observed in the mean half-life of esketamine in plasma between elderly 
subjects (8.8 hours) and younger adults (7.5 hours).15 
Study ESKETINTRD2003 is a 2-panel, doubly randomized, double-blind, placebo-controlled, 
multicenter study.16 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. A limited PK sampling strategy was 
included in Study ESKETINTRD2003.16 The esketamine concentrations in plasma samples 
collected at 40 minutes postdose on Days 1 and 11 (Panels A and B) were compared. For each 
panel, a dose-dependent increase in esketamine concentrations was evident. Plasma esketamine 
concentrations in subjects from Panel B who received 56 mg of esketamine were higher relative 
to the corresponding concentrations produced by the same esketamine dose administered in 
Panel A, consistent with results from Phase 1 Study ESKETINTRD1002.13 
1.1.2.2. 
Pharmacodynamics and Efficacy 
The efficacy of subanesthetic doses (0.5 mg/kg IV administered over 40 minutes) of IV ketamine 
has been evaluated in approximately 192 subjects with MDD (cases and controls), and 2 studies 
in bipolar depressed subjects (meta-analysis).27 This recently published meta-analysis of studies 
suggests that ketamine has a rapid onset (within 1 day) of antidepressant efficacy, including in 
those who have not benefitted from other antidepressant treatments, used as monotherapy or in 
combination with oral antidepressant treatments. 
Esketamine (0.2 and 0.4 mg/kg administered IV over 40 minutes) has similar, rapid, and robust 
antidepressant effect as that seen with IV ketamine. A double-blind, double-randomization, 
placebo-controlled study (ESKETIVTRD2001) enrolled 30 adult subjects with TRD: 10 in the 
IV placebo group, 9 in the IV esketamine 0.20-mg/kg group, and 11 in the IV esketamine 
0.40-mg/kg group (based on Day 1 randomization).17 The full analysis set (FAS) of the primary 
efficacy variable (change in Montgomery-Asberg Depression Rating Scale [MADRS] total score 
from baseline Day 1 to Day 2) indicated that the improvement in both esketamine dose groups 
was statistically significant (1-sided p=0.001 in both dose groups) compared with the placebo 
group. The mean (standard deviation [SD]) change from baseline Day 1 to Day 2 in MADRS 
total score was -4.9 (4.72) in the placebo group, -16.8 (10.12) in the esketamine 0.20 mg/kg 
group, and -17.8 (9.45) in the esketamine 0.40 mg/kg group. 
The studies listed above assessed the efficacy of ketamine or esketamine after a single dose as 
the primary endpoint. The average duration of response to a single-dose of ketamine (0.5 mg/kg) 
was approximately 5 days. An open-label (OL) 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 
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Study KETIVTRD2002 assessed whether multiple doses of ketamine given twice a week would 
also maintain the antidepressant response; the data from this study suggest that ketamine 
(0.50 mg/kg IV over 40 minutes) administered twice a week was sufficient for maintaining the 
initial effect over a 4-week treatment period.18 
As noted above, Study ESKETINTRD2003 is a 2-panel, doubly-randomized, double-blind, 
placebo-controlled, multicenter study.16 Panel A was conducted in the US 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 is 
designed to assess the efficacy and safety of 14-mg and 56-mg dose strengths. In Panel A, 
subjects in Period 1 (1-week duration) were randomly assigned in a 3:1:1:1 ratio to placebo 
(33 subjects), esketamine 28 mg (11 subjects), esketamine 56 mg (11 subjects), or esketamine 
84 mg (12 subjects). An initial analysis of the data from the double-blind phase of Panel A 
indicates that of the 67 subjects randomized in Period 1, 63 entered Period 2 (1-week duration), 
in which 28 placebo subjects who were eligible for re-randomization at the end of Period 1, were 
randomly assigned in a 1:1:1:1 ratio to placebo (n=6), esketamine 28 mg (n=8), esketamine 
56 mg (n=9), or esketamine 84 mg (n=5). Subjects eligible for re-randomization had to have a 
Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR16) total score of >11 at 
the end of Period 1.16 
In Panel A, the improvement (with respect to change in MADRS total score from baseline 
[Day 1] to Day 8) in all 3 esketamine dose groups reached statistical significance (p=0.021, 
p=0.001, and p<0.001 for esketamine 28, 56, 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 (standard error [SE] 2.09); 
 Esketamine 56 mg:  
-6.3 (SE 2.07); 
 Esketamine 84 mg: 
-9.0 (SE 2.13). 
The effect sizes (confidence interval [CI]) in Period 1 for esketamine, compared with placebo, 
were: 
 
Esketamine 28 mg: 0.43 (-0.259-1.118); 
 
Esketamine 56 mg: 0.92 (0.201-1.621); 
 
Esketamine 84 mg: 1.19 (0.473-1.883). 
The duration of effect with the 28-mg dose appears to be shorter, with the MADRS total score 
higher on Day 8 than on Day 2. The duration of effect for the 56- and 84-mg doses appears to 
support twice-a-week dosing.16 
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-blinded data in Panel A, and the point 
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estimates and CIs suggest a high effect size (Cohen’s D) with the 56-mg and 84-mg dose groups, 
supporting further development.16 
In Panel B, 41 Japanese subjects entered Period 1 and were randomly assigned in a 2:1:1 ratio to 
placebo (21 subjects), esketamine 14 mg (11 subjects) or esketamine 56 mg (9 subjects). All 41 
subjects in Period 1 entered Period 2, where 13 subjects initially randomized to placebo were 
eligible for re-randomization at the end of Period 1 and were randomized to receive placebo, 
esketamine 14 mg, or esketamine 56 mg in Period 2 in a 1:1:1 ratio. The remaining placebo 
subjects of Period 1 who were not eligible for re-randomization at the end of Period 1 (8 
subjects) and subjects who were randomized to esketamine 14 mg (11 subjects), or esketamine 
56 mg (9 subjects) continued to receive the same treatment in Period 2. Subjects eligible for 
re-randomization had to have a QIDS-SR16 total score ≥11 at the end of Period 1.16  
In Period 1, greater improvements in MADRS total score were observed in the esketamine 56 mg 
group compared with the placebo group (least squares mean treatment difference 
[SE]:  -3.7 [2.81]; p=0.096). Smaller improvements in MADRS total score were observed in the 
esketamine 14 mg group compared with the placebo group (least squares mean treatment 
difference [SE]: +1.8 [2.62]). Although there was a statistically significant difference at the 
one-sided 0.10 level between the esketamine 56 mg and placebo groups in Period 1, this result 
should be interpreted with caution because there was a significant treatment by baseline MADRS 
total score interaction (p=0.052), where results favored the placebo group for subjects with 
higher baseline MADRS total scores and the esketamine groups for subjects with lower baseline 
MADRS total scores. In addition, there was a high placebo response rate for subjects in Panel B 
in Period 1. In Period 2, greater improvements in MADRS score were observed in both 
esketamine groups compared with the placebo group (least squares mean treatment differences 
[SE]: -5.9 [5.58] for esketamine 14 mg and -0.5 [6.25] for esketamine 56 mg). However, the 
results for Period 2 must be interpreted with caution due to the small number of subjects in each 
treatment group. A consistency test showed that the results for Period 1 were not consistent with 
Period 2 in Panel B; therefore, the data from each period were not combined to assess the 
treatment differences using the weighted combination test.16 
A dose response was detected in Period 1 (p=0.097); however this should be interpreted with 
caution given the significant treatment by baseline MADRS total score interaction that was 
observed in Period 1 (see above). No dose response was detected in Period 2, which may be due 
to the small number of subjects included in the analysis in Period 2 (n=13). Because of the 
observed inconsistency between the two periods, the combination test was not performed.16  
In Panel B, the decrease in MADRS total score was greater in the esketamine 56-mg treatment 
group compared with the placebo group at the double-blind endpoint (Study Day 15). Adjusted 
treatment differences between the esketamine groups and the placebo group (estimate for 
placebo group adjusted to account for subjects who received placebo in Period 1 and esketamine 
in Period 2) after 2 weeks of treatment for subjects who received the same treatment for both 
periods and completed the double-blind phase were -1.0 for esketamine 14 mg and -7.4 for 
esketamine 56 mg.16 
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MADRS total score decreased from OL baseline (Study Day 15) to Study Day 25; mean (SE) 
change from OL baseline was -2.4 (1.33) for all subjects. Mean (SE) change from OL baseline 
was -4.5 (2.30) in the placebo/placebo/OL esketamine group, -1.3 (4.67) in the 
placebo/esketamine/OL esketamine group, and -1.4 (1.48) in the esketamine/esketamine/OL 
esketamine group.16 
The results from subjects in Panel B who received the same treatment during both periods 
suggested that after 2 weeks of treatment, subjects who received esketamine 56-mg in both 
periods had greater improvements in mean MADRS score, response rates, and remission rates 
compared with those who received placebo. Furthermore, evaluation of response rates and 
remission rates in Panel B over time during the double-blind and OL phases suggested that 
improvements in symptoms of depression resulting from esketamine treatment could be 
sustained over 25 days with repeated dosing.16  
At the time of protocol writing, there are 6 ongoing Phase 3 studies of intranasal esketamine 
formulation: 
ESKETINTRD3001, 
ESKETINTRD3002, 
ESKETINTRD3003, 
ESKETINTRD3004, ESKETINTRD3005, and ESKETINTRD3008.32, 5 
ESKETINTRD3001 is a randomized, double-blind, multicenter, active-controlled study to 
evaluate the efficacy, safety, and tolerability of fixed doses of intranasal esketamine plus an oral 
antidepressant in adult subjects with TRD (TRANSFORM-1).7 Subjects will be randomly 
assigned at a 1:1:1 ratio to receive double-blind intranasal treatment with either esketamine 
56 mg, esketamine 84 mg, or placebo twice weekly. Subjects will self-administer the drug at 0-, 
5-, and 10 minutes. In addition, all subjects will initiate a new OL oral antidepressant on Day 1 
that will be taken daily until 4 weeks. Subjects assigned to 84 mg will receive 56 mg on Day 1; 
thereafter 84 mg on subsequent dosing days. Responders (subjects with ≥50% reduction in the 
MADRS total score) may be eligible to participate in the subsequent study ESKETINTRD3003.9 
ESKETINTRD3002 is a randomized, double-blind, multicenter, active-controlled study to 
evaluate the efficacy, safety, and tolerability of flexible doses of intranasal esketamine plus an 
oral antidepressant in adult subjects with TRD (TRANSFORM-2).8 Subjects will be randomly 
assigned in a 1:1 ratio to receive intranasal esketamine (flexible dose, 56 mg or 84 mg) or 
placebo twice weekly. Subjects will self-administer the drug at 0-, 5-, and 10 minutes. In 
addition, all subjects will be initiated on a new OL oral antidepressant on Day 1 that will be 
taken daily until 4 weeks. Responders (subjects with ≥50% reduction in the MADRS total score) 
may be eligible to participate in the subsequent Study ESKETINTRD3003.9 
ESKETINTRD3003 is a randomized, double-blind, multicenter, active-controlled study of 
intranasal esketamine plus an oral antidepressant for relapse prevention in TRD (SUSTAIN-1).9 
This study includes following phases: 4 weeks OL Induction Phase, Optimization Phase, 
Maintenance Phase and Follow-up Phase. During OL Induction Phase, eligible direct-entry 
subjects will receive intranasal esketamine, flexible dose: 56 mg or 84 mg, twice weekly. In 
addition, all subjects will initiate a new OL oral antidepressant on Day 1 daily until 4 weeks. 
Responders (≥50% reduction in the MADRS total score) may be eligible to proceed to the 
optimization phase. During the 12-week optimization phase, eligible direct-entry subjects from 
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the OL induction phase and transferred-entry subjects will receive intranasal esketamine dose 
weekly for first 4 weeks followed by either once weekly or once every other week (based on 
total MADRS score) and same oral antidepressant treatment initiated during the induction phase. 
Subjects in stable remission and those with stable response at the end of optimization phase may 
be eligible to continue into the maintenance phase. Maintenance Phase has a variable duration, 
until 84 relapses occur in subjects with stable remission, or earlier based on interim analysis 
results. Approximately 211 subjects in stable remission with stable response will be randomized 
in a 1:1 ratio (each using a separate randomization list) to either continue with intranasal 
esketamine (same dose) and the same oral antidepressant or to continue with the same oral 
antidepressant (active comparator) but switch to intranasal placebo. Transferred-entry subjects 
who achieve stable remission or stable response at the end of optimization phase after treatment 
with an oral antidepressant plus intranasal placebo will continue to receive the same treatment. 
The frequency of intranasal treatment sessions will be further individualized once weekly or 
once every other week (based on MADRS score) during the maintenance phase.9 
Study ESKETINTRD3005 is a randomized, double-blind, multicenter, active-controlled study to 
evaluate the efficacy, safety, and tolerability of intranasal esketamine plus an oral antidepressant 
in elderly subjects with TRD (TRANSFORM-3).11 During the double-blind induction phase 
(4 weeks), approximately 148 eligible subjects will be randomly assigned at a 1:1 ratio to receive 
double-blind intranasal treatment with either esketamine (flexible dose 28 mg, 56 mg, or 84 mg), 
or placebo, starting with an initial dose of 28 mg on Day 1 to be taken twice weekly. In addition, 
all subjects will initiate a new, OL oral antidepressant on Day 1 to be taken daily until 4 weeks. 
After completing the double-blind induction phase, subjects may be eligible to participate in the 
subsequent Study ESKETINTRD3004 if they meet all other study entry criteria or else will be 
followed by 2-week follow-up phase. 
Study ESKETINTRD3004 is an OL, long-term, safety and efficacy study of intranasal 
esketamine in TRD (SUSTAIN-2).10 Approximately, 750 direct-entry subjects will be enrolled in 
this study, plus transferred-entry subjects from Study ESKETINTRD3005.11 A total of at least 
100 subjects who are 65 years or older (who are either direct-entry subjects or transferred-entry 
subjects from the Study ESKETINTRD3005) will be enrolled. During an OL induction phase 
(4 weeks), direct-entry subjects will receive intranasal esketamine (flexible dose: 28 mg [dose 
option for elderly subjects only], 56 mg, or 84 mg twice weekly) with dose adjusted based on the 
age and efficacy and tolerability. In addition, all subjects will initiate a new OL oral 
antidepressant on Day 1 daily until 4 weeks. Transferred-entry nonresponder subjects will start 
intranasal esketamine with an initial dose of 28 mg on Day 1, with the dose adjusted based on 
efficacy and tolerability (28, 56, or 84 mg) and continue to take the same oral antidepressant at 
same dose as taken in the last week of double-blind induction phase of Study 
ESKETINTRD3005. Responders (subjects with ≥50% reduction in the MADRS total score) may 
be eligible to proceed to the optimization phase of 12 weeks.  
Study ESKETINTRD3008 is an OL, long-term, extension safety study of intranasal esketamine 
in TRD (SUSTAIN-3).5 This study provides an opportunity for subjects who have participated in 
select Phase 3 studies (ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, 
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ESKETINTRD3004, and ESKETINTRD3005) to receive open label intranasal esketamine until: 
it is commercially available or a preapproval access program is made available to the subject in 
the subject’s respective country; the subject does not benefit from further treatment (based on the 
investigator’s clinical judgment), or withdraws consent; or the company terminates clinical 
development of intranasal esketamine for TRD.7, 8, 9, 10, 11 
In addition, 2 Phase 1 studies related to Japanese, Study 54135419TRD10086 and 
54135419TRD10184, are ongoing. Study 54135419TRD1008 is a single-dose study to assess the 
PK, safety, and tolerability of intranasally administered esketamine in healthy Han Chinese, 
Korean, Japanese, and Caucasian Subjects. Study 54135419TRD1018 is a single-ascending dose 
study to compare the PK, safety, and tolerability of intranasally administered esketamine in 
elderly Japanese subjects and healthy younger adult Japanese subjects.4 
1.1.2.3. 
Safety and Tolerability 
Ketamine is a rapidly acting general anesthetic that is approved and widely used IV or IM 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.30,34,64,54  
In the US prescribing information for ketamine HCl for injection and the Summary of Product 
Characteristics (SmPC) for esketamine HCl for injection, the following adverse reactions are 
listed as very common, common, or frequent occurrences: Emergence or recovery reactions, 
elevated blood pressure and heart rate, stimulation of respiration, nausea, and vomiting.33 See 
Table 1 for details. 
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Table 1: 
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 USPI33,a 
"Very Common" or "Common" Reactions 
Per Anesthetic Esketamine SmPC34,b 
Psychiatric 
disorders 
Frequency: Emergence reactions occurred in 
approximately 12% of subjects. 
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 subjects recalled as an unpleasant 
experience. 
 
Frequency: Recovery reactions were common. 
When esketamine was the sole anesthetic, up to 
30% of subjects displayed dose-dependent 
recovery reactions. 
Characteristics: Reactions included vivid dreams 
(including nightmares), nausea and vomiting, 
increased salivation, blurred vision, dizziness, and 
motor restlessnessc. 
 
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. 
 
Gastrointestinal 
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. 
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).32 
Adverse Events Associated with Short-term Use of Intranasal Esketamine in Subjects With 
MDD 
Administration of esketamine is associated with a number of adverse events (AEs), which are 
transient in nature and typically resolve in 2 hours or less from the start of drug administration. 
The phase 1 study ESKETINTRD1003 evaluated the PK and safety of a single intranasal 
esketamine 28 mg in 14 healthy elderly subjects (65 years of age, with 3 subjects 75 years of 
age) and 20 healthy younger adult subjects (18 to 55 years of age, inclusive). The incidences of 
the TEAEs were slightly higher in young subjects (100% [20 subjects]) as compared with elderly 
subjects (85.7% [12 subjects]). The most commonly reported TEAEs by preferred term (>20%) 
in elderly subjects were dysgeusia and vertigo (9 [64%] of 14 subjects each).14 
No deaths were reported in the double-blind or OL phases of Study ESKETINTRD2003 in 
Panel A. One subject experienced a serious adverse event (SAE) of esophagitis in Panel A 
(double-blind phase, placebo/placebo treatment group). A total of 3 subjects withdrew during the 
double blind phase because of AEs. One subject in esketamine 28 mg group experienced a TEAE 
of syncope of severe intensity on Day 2 of Period 1, 1 day after receiving the first dose of study 
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medication. The subject was discontinued from the study and the study drug was permanently 
withdrawn due to this event, which resolved on the same day. The investigator considered the 
event to be possibly related to the study drug. Another subject in the placebo/esketamine 56 mg 
group experienced a TEAE of headache of moderate intensity on Day 11 of Period 2 and the 
study drug was permanently withdrawn due to this event, which resolved on the same day. The 
investigator considered the event to be very likely related to the study drug. A third subject in the 
esketamine group (84 mg/esketamine 84 mg) experienced a TEAE of dissociative disorder 
(verbatim term: Dissociative syndrome) of moderate intensity on Day 8 of Period 2 (day of the 
third esketamine 84 mg dose in the study). The subject was discontinued from the study and the 
study drug was permanently withdrawn due to the event of dissociative disorder, which resolved 
on the same day. The investigator considered the event to be very likely related to the study 
drug.59  
Dissociative symptoms measured on the Clinician-Administered Dissociative States Scale 
(CADSS) were dose-dependent and were observed to reduce significantly with multiple doses 
over 2 weeks. No psychotic symptoms were seen. Transient increases in mean blood pressure 
(systolic and diastolic) were observed post dose following the intranasal esketamine 
administration.59 
The mean (SD) peak systolic blood pressure (SBP) after the first administration in each dose 
group was: 
 
Placebo: 124.2 (11.51) mm Hg (mean [SD] increase of 5.4 [7.84] mm Hg); 
 
28 mg: 131.8 (15.49) mm Hg (mean [SD] increase of 10.4 [10.44] mm Hg); 
 
56 mg: 130.4 (18.64 mm Hg (mean [SD] increase of 11.2 [15.01] mm Hg); 
 
84 mg: 146.1 (19.9) mm Hg (mean [SD] increase of 17.1 [15.5] mm Hg). 
Mean (SD) peak diastolic blood pressure (DBP) after the first administration in each dose group 
was: 
 
Placebo: 81.2 (8.36) mm Hg (mean [SD] increase of 3.8 [7.99] mm Hg); 
 
28 mg: 85.7 (9.16) mm Hg (mean [SD] increase of 6.5 [7.00] mm Hg); 
 
56 mg: 86.5 (11.34) mm Hg (mean [SD] increase of 7.2 [9.67] mm Hg); 
 
84 mg: 87.8 (10.62) mm Hg (mean [SD] increase of 8.1 [9.12] mm Hg). 
The blood pressure increase typically resolved within 2 hours. Unlike dissociative symptoms, the 
blood pressure changes observed do not appear to attenuate over time with multiple doses. 
Transient increases in heart rate were also observed in parallel with blood pressure change. There 
was no clinically meaningful change in blood oxygen level.59 
In Panel B of Study ESKETINTRD2003 the most common TEAEs during the double-blind 
phase (≥10% of subjects in any treatment group) were somnolence, hypoesthesia, dizziness, 
headache, dysgeusia, feeling abnormal, nausea, dissociation, dizziness postural, and 
hyperhidrosis.59 
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There were no deaths or other SAEs during the double-blind or OL phase of the study. However, 
there was one death by completed suicide in the follow-up phase of the study. The investigator 
considered the event to be not related to study medication.  
The dissociative and perceptual change symptoms measured by the CADSS, suggest these 
symptoms had an onset shortly after the start of the dose, with a peak by 40 minutes and resolved 
by 2 hours post dose.59 
The mean (SD) peak SBP after the first administration in each dose group was: 
 
Placebo: 116.4 (14.84) mm Hg (mean [SD] increase of 1.7 [1.74] mm Hg); 
 
14 mg: 124.9 (13.46) mm Hg (mean [SD] increase of 6.5 [3.33] mm Hg); 
 
56 mg: 125.4 (10.11) mm Hg (mean [SD] increase of 7.2 [3.04] mm Hg). 
The mean (SD) peak DBP after the first administration in each dose group was: 
 
Placebo: 75.3 (11.30) mm Hg (mean [SD] increase of 3.6 [1.81] mm Hg); 
 
14 mg: 80.6 (14.42) mm Hg (mean [SD] increase of 5.4 [3.02] mm Hg); 
 
56 mg: 82.6 (9.33) mm Hg (mean [SD] increase of 8.3 [3.13] mm Hg). 
Adverse Events Associated With Chronic Use of Ketamine 
There are no controlled studies of long-term use with esketamine/ketamine in subjects 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.43 Eighty percent of the participants were retested at the end of 1 year. Cognitive deficits 
(including impairment in spatial working memory, pattern recognition memory and category 
fluency) were mainly observed in frequent users and not with the infrequent users. Short-lasting, 
dose-dependent effects of psychosis were associated with ketamine users. There was no increase 
in symptoms over time, and symptoms were completely reversible upon stopping use of 
ketamine. As noted, these data should be interpreted with caution, as baseline data predating 
drug use were not available. Furthermore, in their recent review, Morgan and Curran report that 
there is little evidence of any link between chronic, heavy use of ketamine and diagnosis of a 
psychotic disorder.42  
The principal action of ketamine is at the NMDA receptor, and the consequences of ketamine use 
on cognition have been fairly widely investigated. Several studies have examined cognitive 
function in infrequent and frequent ketamine users.42,43 Overall, infrequent or recreational ketamine 
use does not appear to be associated with long-term cognitive impairment.43 The most robust 
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findings are that frequent ketamine users (more than 5 times a week) exhibit impairments in both 
short- and long-term memory.41 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. 42, 43  
Ketamine-induced ulcerative cystitis is a recently identified complication.42 The most common 
symptoms are frequency and urgency of urination, dysuria, urge incontinence, and occasionally 
painful hematuria (blood in urine). Computerized tomography scans of these subjects revealed a 
marked thickening of the bladder wall, a small bladder capacity, and perivesicular stranding 
consistent with severe inflammation. At cystoscopy, all subjects had severe ulcerative cystitis. 
Biopsies in 4 of these cases found denuded urothelial mucosa with thin layers of reactive and 
regenerating epithelial cells, and ulcerations with vascular granulation tissue and scattered 
inflammatory cells. Cessation of ketamine use provided some relief of symptoms. Most of the 
described cases are in near-daily users of ketamine for recreational purposes. The prevalence is 
difficult to determine, as it is seen in recreational users who often do not seek help.  
The majority of cases resolve after stopping ketamine use, one-third remaining static. 
Abuse-liability, Dependence, and Withdrawal 
There are a number of reports of ketamine dependence in the literature but no large-scale studies, 
and so the incidence of ketamine dependence is largely unknown.43,49 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.44 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.63 There is conflicting evidence 
of the existence of a "withdrawal syndrome" after cessation of ketamine use. 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.43 The 
same study found that 12 of the 30 daily users reported withdrawal symptoms characterized by 
anxiety, shaking, sweating, and palpitations when they stopped using. A few published case 
studies also show craving and somatic and psychologic aspects of anxiety as withdrawal 
symptoms.19 However, a specific ketamine withdrawal syndrome has not yet been described.  
1.1.3. 
Marketing Experience 
No intranasal formulation of esketamine is currently marketed. 
1.2. 
Overall Rationale for the Study 
Converging lines of evidence suggest that the glutamatergic system may play a role in the 
pathophysiology and treatment of depression, and that drugs modulating glutamatergic 
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neurotransmission, and therefore synaptic plasticity, may represent a novel class of 
antidepressants. Esketamine/ketamine is an antagonist of the NMDA receptor (a subtype of 
glutamatergic ion channel receptor), for which there is both preclinical and clinical data 
supporting its potential for the treatment of depression. Preclinical studies demonstrate that the 
rapid antidepressant actions of ketamine are mediated by the induction of synaptic proteins and 
increased number and function of new spine synapses in the prefrontal cortex.23  
A range of pilot studies with esketamine/ketamine suggests that it is a paradigm-shifting 
breakthrough for the treatment of MDD and TRD. The sponsor has completed clinical conduct of 
a Phase 2 study with IV esketamine (Clinical Study Report ESKETIVTRD2001)17 in Europe, 
which demonstrated the efficacy of 0.2 mg/kg and 0.4 mg/kg (both as 40-minute IV infusions) of 
esketamine in a TRD population. The efficacy of esketamine appears similar to the efficacy seen 
in studies with ketamine. A second Phase 2 study with IV ketamine in the US (Clinical Study 
Report KETIVTRD2002)18 was done to demonstrate the minimal dosing frequency necessary for 
the short-term induction phase. This study demonstrated that ketamine (0.5 mg/kg IV over 
40 minutes) administered twice a week is sufficient for maintaining the initial effect over a 
4-week treatment period. In parallel to the studies done with IV esketamine and ketamine, a 
Phase 1 study in healthy subjects with intranasal esketamine (Clinical Study Report 
ESKETINTRD1001)12 has demonstrated that plasma levels equivalent to those achieved after 0.2 
to 0.4 mg/kg IV administration can be achieved after intranasal administration of doses of 28 to 
84 mg esketamine.  
A 2-panel Phase 2, ESKETINTRD2003,16 in which the primary objective was to assess the 
efficacy and dose-response of intranasal esketamine (Panel A: 28 mg, 56 mg, 84 mg; Panel B: 
14 mg and 56 mg) compared with placebo in improving depressive symptoms in subjects with 
TRD, as assessed by a change from baseline in the MADRS total score for the combined periods 
in the double-blind induction phase. Non-Japanese subjects in Panel A demonstrated the 
statistically significant efficacy of 56-mg and 84-mg doses of intranasal esketamine, as measured 
by a change in MADRS total score after 1 week of treatment. The 28-mg dose, which was 
administered in Panel A only, showed also statistically significant efficacy compared to placebo, 
however did not demonstrate sufficient clinically meaningful efficacy. Japanese subjects in 
Panel B showed a statistically significant improvement in symptoms of depression in the 56-mg 
dose of intranasal esketamine, however there was no statistically significant difference at 1 week 
postdose between the esketamine 14 mg group and the placebo group in Period 1. The 
distribution of plasma esketamine concentrations in Japanese subjects treated at 14 mg was 
comparable with that in non-Japanese subjects treated at 28 mg. Overall, Panel B showed higher 
response to placebo than Panel A, with smaller changes from baseline and smaller differences 
from placebo. In addition, the distribution of plasma esketamine concentrations in Japanese 
subjects treated at 56 mg was comparable with that in non-Japanese subjects treated at 84 mg. In 
this study, the PK/pharmacodynamic (PD) analysis suggested the efficacy of esketamine 28 mg 
in Japanese Panel. Meanwhile, from the pooled dose-response analyses of non-Japanese Panel 
and Japanese Panel, the efficacy of esketamine 28 mg was considered low. But as this analysis 
only included 28 mg from non-Japanese Panel, the efficacy of esketamine 28 mg could not 
clearly be excluded in Japanese subjects with TRD. On the other hand, esketamine 84 mg has not 
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been evaluated in the Japanese subjects with TRD in Phase 2 studies. It was well tolerated in 
Japanese subjects in the Phase 1 study, however, considering the PK results of this study and no 
treatment experience at 84 mg in Japanese subjects with TRD, safety and tolerability of 84 mg 
with fixed dose for 4 weeks in Japanese subjects with TRD needs to be carefully assessed. Hence, 
this Phase 2 study will be conducted to investigate the appropriate doses from esketamine 28 mg 
to esketamine 84 mg in Japanese subjects with TRD, to proceed to the confirmatory Phase 3 
study. 
The randomized, double-blind, multicenter, 54135419TRD2005 study is being conducted to 
evaluate the efficacy, safety, and tolerability of 28 mg, 56 mg and 84 mg fixed doses of 
intranasal esketamine add-on to an oral antidepressant in Japanese subjects with TRD. 
The study consists of the following phases: a screening phase (up to 4 weeks); a 6-week 
prospective oral antidepressant lead-in phase; a 4-week double-blind induction phase; a 
posttreatment phase (up to 24 weeks comprising of only oral antidepressant therapy), including 
an optional 4-week OL induction phase; and a 4-week follow-up phase. The primary objective of 
the study will be achieved in the double-blind induction phase. 
Screening Phase 
A screening phase of up to 4 weeks was chosen to allow adequate time for completion of all 
screening procedures with results available to the investigator before the first dose of the new 
antidepressant in the prospective lead-in phase, and to allow sufficient time for tapering and 
washout of prohibited medications to occur.  
Prospective Lead-in Phase 
Implementation of a prospective lead-in phase before randomization and active treatment will 
allow the use of a new antidepressant treatment which will contribute to standardize the base 
therapy in the population and the 6-week duration will allow for a prospective confirmation of 
nonresponse to the new antidepressant treatment that is continued for the duration of this phase.  
Double-blind Induction Phase 
Subjects must meet the predefined criteria of nonresponse to antidepressant therapy at the end of 
the prospective lead-in phase for eligibility to enter the randomized, double-blind induction 
phase. The determination of nonresponse in prospective manner is necessary to enroll qualified 
TRD patients. 
Subjects who fulfill all inclusion criteria and none of the exclusion criteria will be randomized to 
4-week double-blind intranasal treatment with either placebo, esketamine 28 mg, esketamine 
56 mg, or esketamine 84 mg.  
The primary endpoint will be assessed in the 4-week double blind induction phase, as the change 
from baseline in the MADRS total score at Week 4. 
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At the end of the 4-week double-blind induction phase, responders will be eligible to proceed to 
the posttreatment phase; those who do not (ie, nonresponders) will proceed to the 4-week 
follow-up phase.  
Posttreatment Phase 
Responders who completed the double-blind induction phase will enter the 24-week 
posttreatment phase. The 24-week duration of the posttreatment phase will allow sufficient time 
to evaluate sustained efficacy after cessation of add-on intranasal esketamine treatment while 
continuing the oral antidepressant medication regimen, as assessed by the following efficacy 
endpoints: 1) the time to relapse; and 2) proportion of responders and remitters at each visit in 
this phase. In the first 4 weeks of the posttreatment phase, withdrawal or rebound symptoms or 
both and potential abuse-liability will be evaluated. Subjects who relapse within 20 weeks after 
the start of the posttreatment phase will transit to an open-label induction phase and receive 4 
weeks of open-label treatment with intranasal esketamine (28, 56, or 84 mg). 
Subjects who relapse more than 20 weeks after the start of the posttreatment phase will withdraw 
from the study and clinical/standard-of-care treatment will be arranged by the study investigator 
after relapse.  
Subjects who do not experience relapse throughout this 24-week posttreatment phase will 
complete study without the 4-week follow-up phase. 
Open-label Induction Phase 
The 4-week OL induction phase will be conducted for subjects who relapse in the posttreatment 
phase. This will evaluate if subjects will respond again to a second induction treatment course 
without any new safety signal compared to the double-blind induction treatment course. The 
beginning of the open-label induction phase should be at least 2 weeks after the last dose in the 
double-blind induction phase. 
Subjects who meet the relapse criteria before 2 weeks after the last dose in the double-blind 
induction phase will not have an option for joining open label induction phase. They will 
withdraw from the posttreatment phase and move forward to the follow up phase. 
Follow-up Phase 
Following subjects will have follow-up Visits; subjects who withdraw from double blind 
induction phase, nonresponders after double-blind induction phase, responders who withdraw 
within 4 weeks after the last dose of double blind intranasal drug and all subjects who receive 
open label intranasal drug. During this phase, further clinical/standard-of-care treatment will be 
arranged by the study investigator. 
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2. 
OBJECTIVES AND HYPOTHESIS 
2.1. 
Objectives 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of fixed dosed intranasal 
esketamine compared to intranasal placebo, as an add-on to an oral antidepressant in Japanese 
subjects with TRD, in improving depressive symptoms. 
Secondary Objectives 
 
To assess the effect of intranasal esketamine compared with intranasal placebo as an add-on 
to an oral antidepressant in Japanese subjects with TRD, including the following parameters: 
 
Dose response; 
 
Depression response rates; 
 
Depression remission rates; 
 
Onset of clinical response; 
 
Overall severity of depressive illness; 
 
Anxiety symptoms;  
 
Functioning and associated disability. 
 
To investigate the safety and tolerability of intranasal esketamine compared with intranasal 
placebo as an add-on to an oral antidepressant in Japanese subjects with TRD, including the 
following parameters: 
 
TEAEs, including AEs of special interest; 
 
Potential withdrawal or rebound symptoms or both following cessation of intranasal 
esketamine treatment; 
 
Perceptual changes (dissociative symptoms); 
 
Effects on alertness and sedation; 
 
Effects on heart rate, blood pressure, respiratory rate, and blood oxygen saturation; 
 
Potential effects on suicidal ideation/behavior; 
 
Potential abuse-liability; 
 
Potential psychosislike effects. 
 
To evaluate the durability of intranasal esketamine as an add-on to an oral antidepressant in 
Japanese subjects with TRD, with attention to: 
 
Time to relapse in the posttreatment phase for subjects in remission and for subjects 
who respond but are not in remission, at the end of the double-blind induction phase. 
 
To evaluate the PK of intranasally administered esketamine in Japanese subjects with TRD. 
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Exploratory Objectives 
 
To assess the comparability of the efficacy and safety of intranasal esketamine as an add-on 
to an oral antidepressant between the double-blind and OL intranasal esketamine induction 
treatment courses; 
 
To evaluate the PK/PD relationship of intranasal esketamine and MADRS total score (and 
possibly selected AEs as additional PD parameters) in Japanese subjects with TRD; 
 
To examine the relationship between deoxyribonucleic acid (DNA) single nucleotide 
polymorphisms (SNPs) (including, but not limited to BDNF) with clinical outcome to 
intranasal esketamine in Japanese subjects with TRD; 
 
To assess the potential relationship of biomarkers with response, maintenance, relapse, and 
nonresponse to intranasal esketamine in Japanese subjects with TRD. 
2.2. 
Hypothesis 
The hypothesis for this study is that, at least one dose of intranasal esketamine (28, 56, and 
84 mg) is superior to intranasal placebo in improving depressive symptoms in Japanese subjects 
with TRD, as assessed by the change from baseline in the MADRS total score at the end of the 
double-blind induction phase. 
3. 
STUDY DESIGN AND RATIONALE 
3.1. 
Overview of Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter study designed to evaluate 
the efficacy, safety and tolerability of fixed dose of intranasal esketamine (28 mg, 56 mg, or 
84 mg) as an add-on therapy to an oral antidepressant in Japanese subjects with TRD. A total of 
183 subjects are planned to be enrolled in this study.  
The study consists of the following phases: a screening phase (up to 4 weeks); a 6-week 
prospective oral antidepressant lead-in phase; a 4-week double-blind induction phase; a 
posttreatment phase (up to 24 weeks comprising of only oral antidepressant therapy), including 
an optional 4-week OL induction phase; and a 4-week follow-up phase.  
Thus, the duration of a subject’s participation will be a maximum of 42 weeks, depending on 
whether they meet phase-specific criteria for response or relapse. The end-of-study (EOS) will 
occur when the last subject in the study completes his/her last study assessment (ie, last 
follow-up Visit). 
Screening Phase 
Japanese men and women aged 20 to 64 years old (both inclusive), who meet Diagnostic and 
Statistical Manual of Mental Disorders (fifth edition) (DSM-5) diagnostic criteria for single-
episode MDD or recurrent MDD without psychotic features, based upon clinical assessment and 
confirmed by the Mini-International Neuropsychiatric Interview (mental status questionnaire) 
(MINI) will be screened according to the inclusion/exclusion criteria. In the case of single-
episode MDD, the subject must be diagnosed with persistent depressive disorder, which meets 
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criteria of major depressive episode for a continuous duration of 2 years, and the same 
physician from the site must be examining the subject for 2 years continuously as a primary 
care physician of the subject. Subjects receiving benzodiazepines (at dosages equal to or less 
than the equivalent of 6 mg/day of lorazepam) or permitted non-benzodiazepine sleep 
medications (eg, zolpidem, eszopiclone and zopiclone) or both during the screening phase can 
continue these medications throughout the study; however, dose increases or starting new 
benzodiazepine medications are not permitted.  
To confirm eligibility for participation in the prospective lead-in phase, subjects will have a 
review of the inclusion/exclusion criteria in the screening phase. Subjects must not have 
responded to ≥1 but <5 different oral antidepressants taken at adequate dosage and for adequate 
duration, as assessed on the Massachusetts General Hospital – Antidepressant Treatment 
Response Questionnaire (MGH-ATRQ) and documented by medical history/prescription records, 
for the current episode of depression. The subject’s current major depressive episode, depression 
symptom severity (MADRS total score ≥28 required), and treatment response to antidepressant 
medication used in the current episode (retrospectively assessed) must be deemed valid for 
participation in the clinical study based on the SAFER interview, which is administered by a 
remote, independent rater. At the screening visit, subjects who continue to fulfill all inclusion 
criteria and none of the exclusion criteria will be enrolled. 
SAFER interview will be conducted as early as feasible during the screening period, before 
down-titration of antidepressants to avoid change of depressive symptoms because of tapering. 
Subject’s current antidepressant treatment(s), including adjunctive treatment for MDD, should be 
tapered and discontinued in this phase per the local prescribing information. Down-titration of 
antidepressants will be started after SAFER interview and will be completed in the screening 
phase basically. However, if clinically indicated, cross-tapering is allowed. Cross-tapering is 
defined as discontinuation of previous antidepressant treatment(s) by lowering the dose(s) per the 
local prescribing information and simultaneously increasing the dose of single new 
antidepressant treatment within the first 2 weeks of the prospective lead-in phase. 
Prospective Lead-in Phase 
After enrollment, eligible subjects will enter the 6-week OL prospective lead-in phase (Visits 2.1 
to 3.1 [prerandomization]) during which, subjects will receive a new antidepressant therapy 
(physician determined) daily for the duration of this phase.  
All subjects will initiate a physician-determined new OL oral antidepressant daily for the 
duration of this phase. The oral antidepressant will be 1 of the following: selective serotonin 
re-uptake inhibitors or serotonin-specific reuptake inhibitors (SSRIs), serotonin–norepinephrine 
reuptake inhibitors (SNRIs), or mirtazapine (ie, escitalopram, paroxetine controlled-release [CR], 
sertraline, duloxetine, venlafaxine extended-release [XR], or mirtazapine), which the subject has 
not previously had a nonresponse to in the current depressive episode or has not been previously 
intolerant to (lifetime). If clinically indicated, cross-tapering is allowed in the first 2 weeks 
during the prospective lead-in phase. In the last 4 weeks during the prospective lead-in phase, 
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'oral antidepressant' must be single treatment of switched new oral antidepressant. New oral 
antidepressant treatment should be titrated to the approved maximum dose, to optimize the 
potential for response. The up-titration schedule should be per prescribing information. The dose, 
which is above the minimum therapeutic dose defined in MGH-ATRQ should be kept at last 4 
weeks during the prospective lead-in phase, in case they start at lower doses. Refer Attachment 3 
(Example of the Up-titration Schedule for a New Oral Antidepressant Therapy (Physician 
Determined) in Prospective Lead-in Phase) for further information on up-titration. 
The criteria of TRD is defined as nonresponse (≤25% improvement) to at least 1 antidepressant 
treatment determined retrospectively and 1 antidepressant prospectively in the current episode of 
depression. After 6 weeks, subjects who are nonresponders to the new oral antidepressant 
treatment at the end of the prospective lead-in phase can be eligible to proceed to the double-
blind induction phase. Nonresponse at the end of the prospective lead-in phase is defined as 
≤25% improvement in the MADRS total score from Visits 2.1 to each of Visit 2.3 and 3.1 
(prerandomization) respectively, and a MADRS total score of ≥28 on each of the Visits 2.1, 2.3, 
and 3.1 (prerandomization). Assessment of antidepressant treatment response at the end of the 
prospective lead-in phase will be performed by investigators. All other subjects who do not 
proceed to the double-blind induction phase will end study participation at this time. No 
follow-up or further study visits will be performed for these subjects. All subjects who are 
discontinued must be treated with an oral antidepressant after completion of the study, unless it is 
clinically inappropriate. 
MADRS assessment throughout the study will be performed by an independent, remote, blinded 
rater. 
Double-blind Induction Phase 
The 4-week fixed dose double-blind induction phase will start on Day 1 (Visit 3.1) and end at 
Day 28 (Visit 3.10). A total of 183 subjects will be randomly assigned in a 2:1:1:1 ratio to 
receive double-blind intranasal treatment with either placebo, esketamine 28 mg, esketamine 
56 mg, or esketamine 84 mg add-on to the continued stable oral antidepressant initiated in the 
prospective lead-in phase. The intranasal treatment sessions (esketamine or placebo) will occur 
twice weekly. Subjects will self-administer the intranasal study drug (esketamine 28 mg, 56 mg, 
84 mg, or placebo) at treatment sessions occurring twice a week for 4 weeks at the clinical site 
under clinical supervision. The first treatment session will be on Day 1. 
Subjects assigned to esketamine 84 mg dosing will start treatment sessions with 56 mg of 
intranasal esketamine on Day 1 to improve tolerability. On Day 4 (Visit 3.3), the dose will be 
increased to 84 mg as a forced titration and remain at 84 mg for all subsequent intranasal 
treatment sessions. Subjects who are randomly assigned to 28 mg and 56 mg on Day 1 will 
remain on that dose for all subsequent intranasal treatment sessions. No adjustment to the 
intranasal esketamine dose is permitted during the double-blind induction phase. 
Use of benzodiazepines and non-benzodiazepine sleeping medications (eg, zolpidem, 
eszopiclone, and zopiclone) is prohibited within 12 hours prior to the start of each intranasal 
treatment session. 
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Responders (subjects who have 50% reduction from baseline in MADRS total score) at the end 
of the double-blind induction phase will be eligible to proceed to the posttreatment phase; those 
who do not (ie, nonresponders) will proceed to the 4-week follow-up phase.  
If a subject withdraws before the end of the double-blind induction phase for reasons other than 
withdrawal of consent, the Early Withdrawal (EW) Visit should be conducted within 1 week of 
the date of discontinuation, followed by a 4-week follow-up phase. MADRS information will be 
collected during the 4 week follow-up phase. If the EW Visit occurs on the same day as a 
scheduled visit, the EW Visit can be performed on the same day; duplicate assessments are not 
required. 
Given the potential for treatment-emergent transient elevation in SBP and DBP, the guidance on 
Blood Pressure Monitoring (see Section 6.3.1) should be followed on intranasal dosing days 
during the double-blind induction phase. 
Posttreatment Phase 
Responders who completed the double-blind induction phase will enter the 24-week 
posttreatment phase to evaluate durability of efficacy after cessation of add-on intranasal 
esketamine or placebo treatment while continuing the oral antidepressant treatment regimen, as 
assessed by the time to relapse and proportion of responders and remitters at each visit in this 
phase. All subjects who are discontinued must be treated with an oral antidepressant after 
completion of the study, unless it is clinically inappropriate. 
Relapse is defined as any of the following: 
 
MADRS total score 22 for 2 consecutive assessments. The date of the second MADRS 
assessment will be used for the date of relapse. 
 
Hospitalization for worsening depression or any other clinically relevant event determined 
per clinical judgment to be suggestive of a relapse of depressive illness such as suicide 
attempt, completed suicide, or hospitalization for suicide prevention. If hospitalized for any 
of these events, the start date of hospitalization will be used for the date of relapse. 
Otherwise the date of the event will be used if the subject is not hospitalized. 
In case both relapse criteria are met, the earlier date will be defined as the date of relapse for this 
subject. 
Subjects who relapse within 20 weeks after the start of the posttreatment phase will transit to an 
OL induction phase and receive 4 weeks of OL treatment with intranasal esketamine (28, 56, or 
84 mg). Subjects who relapse more than 20 weeks after the start of the posttreatment phase will 
withdraw from the study and clinical/standard-of-care treatment will be arranged by the study 
investigator after relapse. Subjects who do not experience relapse throughout this 24-week 
posttreatment phase will complete study without the 4-week follow-up phase (see 
Section 9.2.1.2.3). 
Subjects who meet the criteria of relapse, they need to join OL induction phase before next 
remote MADRS assessment.  
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In the first 4 weeks of the posttreatment phase, withdrawal or rebound symptoms or both and 
potential abuse-liability will be evaluated using Physician’s Withdrawal Checklist, 20-item 
(PWC-20) and Profile of Mood States, 2nd Edition (POMS-2). 
The oral antidepressant medication initiated from the prospective lead-in phase, which will 
continue to be ongoing and stable during the double-blind induction phase will also be 
maintained throughout this phase. 
Open-label Induction Phase 
Subjects who relapsed in the posttreatment phase will receive a 4-week OL induction treatment 
course of intranasal esketamine. The beginning of the OL induction phase should be at least 
2 weeks (14 calendar days) after the last dose in the double-blind induction phase. Subjects who 
meet the relapse criteria before 2 weeks after the last dose in the double-blind induction phase 
will not have an option for joining open label induction phase. They will withdraw from the 
posttreatment phase and move forward to the follow up phase.  
Subjects who enter the OL induction phase will start treatment sessions with 56 mg of intranasal 
esketamine on the first day of OL induction phase (Day OL1). On the fourth day (Day OL4), the 
dose will be increased to 84 mg. On Day OL8 and OL11, the dose could be maintained, 
increased or reduced by 28 mg as determined by the investigator based on efficacy and 
tolerability. On Day OL15, a dose reduction is permitted if required for tolerability; no dose 
increase is permitted on Day OL15. After Day OL15, the dose should be stable (unchanged). If 
needed for tolerability, a dose reduction is permitted from Day OL15 until Day OL25. 
The oral antidepressant medication initiated from the prospective lead-in phase, which will 
continue in the posttreatment phase will also be maintained throughout this phase. 
Guidance on Blood Pressure Monitoring (Section 6.3.1) as indicated for intranasal treatment 
sessions during the double-blind induction phase should also be followed on intranasal dosing 
days in the OL induction phase. 
Follow-up Phase 
Following subjects will have follow-up Visits; subjects who withdraw from double blind 
induction phase, nonresponders after double-blind induction phase, responders who withdraw 
within 4 weeks after the last dose of double blind intranasal drug and all subjects who receive 
open label intranasal drug. During this phase, further clinical/standard-of-care treatment will be 
provided by the study investigator however, in order to better assess potential withdrawal 
symptoms from intranasal study drug, the oral antidepressant medication must be continued for 
the follow-up phase unless determined as not clinically appropriate. 
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A schematic representation of the study design is provided in Figure 1. 
Figure 1: 
Study 54135419TRD2005 Flowchart 
 
Esk: esketamine; IN: intranasal; AD: Antidepressant Day 1: The first day in the double-blind induction phase.  
* Only responders after completion of the double-blind induction phase are eligible to join the posttreatment phase. 
In the posttreatment phase, subjects who relapse within 20 weeks after the start of the posttreatment phase will 
receive an open-label treatment course of esketamine. Subjects who relapse more than 20 weeks after the start of 
the posttreatment phase will withdraw from the study and clinical/standard-of-care treatment will be arranged by 
the study investigator after relapse. The beginning of the open-label induction phase should be at least 2 weeks 
after the last dose in the double-blind induction phase. 
** Following subjects will have follow-up Visits; subjects who withdraw from double blind induction phase, 
nonresponders after double-blind induction phase, responders who withdraw within 4 weeks after the last dose of 
double blind intranasal drug and all subjects who receive open label intranasal drug. 
 
Blood samples will be collected from all subjects to further explore the PK of esketamine. The 
total volume of blood to be drawn for laboratory evaluations, pharmacogenomics, biomarker 
analyses, and PK sampling throughout this study is approximately 112.5 mL for each subject. 
Pharmacogenomic blood samples will be collected to allow for genetic and/or epigenetic 
research related to esketamine. 
The study assessments will be performed at timepoints shown in the Time and Events Schedules 
for the respective study phases (see Section 9). 
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3.2. 
Study Design Rationale 
3.2.1. 
Study Population 
The study will include Japanese men and women 20 to 64 years old (both inclusive). This age 
range is selected because it includes the adults in the conventional age range of 20 to 64 years, 
thereby facilitating the evaluation of safety and tolerability of add-on esketamine in adults with 
TRD. 
Subjects will meet DSM-5 diagnostic criteria for single-episode MDD or recurrent MDD, 
without psychotic features, based upon clinical assessment and confirmed by the MINI. In the 
case of single-episode MDD, the subject must be diagnosed with persistent depressive disorder, 
which meets criteria of major depressive episode for a continuous duration of 2 years, and the 
same physician from the site must be examining the subject for 2 years continuously as a 
primary care physician of the subject. 
Treatment-resistant depression is defined as a lack of clinically meaningful improvement after 
treatment with at least 2 different antidepressant agents prescribed in adequate dosages for 
adequate duration. At the start of the prospective lead-in phase, subjects must not have responded 
to 1 but <5 different oral antidepressants taken at adequate dosage and for adequate duration, as 
assessed on the MGH-ATRQ and documented by medical history/prescription records, for the 
current episode of depression. The use of historical data to define nonresponse 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. Additionally, in the prospective lead-in phase, all 
subjects will start a new switched antidepressant to confirm nonresponse to ≥2 antidepressants in 
their current episode.  
Nonresponders to the new oral antidepressant treatment can be eligible to proceed to the 
double-blind induction phase. Nonresponse at the end of the prospective lead-in phase is defined 
as ≤25% improvement in the MADRS total score from Visits 2.1 (beginning of the prospective 
lead-in phase) to each of Visit 2.3 (Week 4 of the prospective lead-in phase) and Visit 3.1 
(prerandomization [Week 6 of the prospective lead-in phase]) respectively, and a MADRS total 
score of ≥28 on each of the Visits 2.1, 2.3 and 3.1 (prerandomization). 
The subject’s current major depressive episode and antidepressant nonresponse in the current 
depressive episode will be confirmed using the SAFER criteria interview, which will be 
administered by remote, independent raters. SAFER criteria interview 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. 
3.2.2. 
Study Phases  
Screening Phase 
A screening phase of up to 4 weeks was chosen to allow adequate time for completion of all 
screening procedures with results available to the investigator before the first dose of the new 
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antidepressant in the prospective lead-in phase, and to allow sufficient time for tapering and 
washout of prohibited medications to occur.  
Prospective Lead-in Phase 
Implementation of a 6-week prospective lead-in phase before randomization and active treatment 
will allow the following: 
 
Use of a new antidepressant therapy will contribute to standardize the base therapy in the 
population. 
 
Use of an antidepressant prior to randomization and active treatment will be used to enrich 
the population in the treatment phase and minimize the impact of the expectation bias on the 
part of subjects and investigators on treatment effect. Because the add-on effects of 
esketamine are yet to be established, the prospective lead-in phase will assist in determining 
an ideal antidepressant medication, which would be combined with esketamine as an add-on 
treatment. 
 
The 6-week duration of the prospective lead-in phase will allow for a prospective 
confirmation of nonresponse to the new antidepressant treatment that is continued for the 
duration of this phase.  
Double-blind Induction Phase 
Subjects must meet the predefined criteria of nonresponse to antidepressant therapy at the end of 
the prospective lead-in phase for eligibility to enter the double-blind induction phase. The 
determination of nonresponse in prospective manner is necessary to enroll qualified TRD 
patients.  
Randomization and blinding is necessary only in the double-blind induction phase of this study. 
The randomized design will allow the comparison of intranasal esketamine (3 doses to be 
evaluated) and placebo and provides a method of unambiguous assignment to study groups. 
As described in Section 1.1.2, the duration of the 4 week double-blind induction phase was 
selected based upon the onset of effect of typical antidepressant treatments and the duration is 
considered to be sufficiently long to show the antidepressant effects of the oral antidepressants. 
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.36,72 Similarly, it has been demonstrated that improvement of 25% on the 
Hamilton Depression 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.47 All together, these results suggest that a 4 week 
duration should be adequate to assess antidepressant response. 
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Posttreatment Phase 
The 24-week duration of the posttreatment phase will allow sufficient time to evaluate sustained 
efficacy after cessation of add-on intranasal esketamine treatment while continuing the oral 
antidepressant medication regimen, as assessed by the following efficacy endpoints: 1) the time 
to relapse; and 2) proportion of responders and remitters at each visit in this phase. In the first 
4 weeks of the posttreatment phase, withdrawal or rebound symptoms or both and potential 
abuse-liability will be evaluated.  
Open-label Induction Phase 
The 4-week OL induction phase will be conducted for subjects who relapse in the posttreatment 
phase. This will evaluate if subjects will respond again to a second induction treatment course 
without any new safety signal compared to the double-blind induction treatment course. 
Follow-up Phase 
Following subjects will have follow-up Visits; subjects who withdraw from double blind 
induction phase, nonresponders after double-blind induction phase, responders who withdraw 
within 4 weeks after the last dose of double blind intranasal drug and all subjects who receive 
open label intranasal drug. During this phase, further clinical/standard-of-care treatment will be 
arranged by the study investigator.  
3.2.3. 
Blinding and Randomization 
Randomization will be with an allocation ratio of 2:1:1:1 to intranasal placebo, intranasal 
esketamine 28 mg, intranasal esketamine 56 mg, or intranasal esketamine 84 mg. Randomization 
will be used in the double-blind induction phase to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg, 
demographics and baseline characteristics) are evenly balanced across treatment groups, and to 
enhance the validity of statistical comparisons across treatment groups. Blinded treatment will be 
used to reduce potential bias during data collection and evaluation of clinical endpoints in this 
phase. Measures will be taken to ensure that the study subjects and study staff are not unblinded.  
The placebo group is included in this design to maintain blinding in the double-blind phase of the 
study. A placebo group is necessary to allow an accurate assessment of the safety and efficacy of 
the study drug. 
3.2.4. 
Treatment Groups and Dose Selection 
The 4 treatment groups in the double-blind induction phase are: 
 
Intranasal placebo; 
 
Intranasal esketamine (28 mg); 
 
Intranasal esketamine (56 mg); 
 
Intranasal esketamine (84 mg). 
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In all treatment groups, subjects must have been switched to a new, oral antidepressant, initiated 
during prospective lead-in phase, which will continue throughout the study, except follow-up 
phase. 
The treatment groups will allow for an evaluation of the efficacy, safety and tolerability of 
3 fixed doses of intranasal esketamine in addition to an oral antidepressant compared with 
intranasal placebo in addition to an oral antidepressant medication in adult subjects with TRD.  
Intranasal Study Drug (Esketamine) 
The dose selection (28, 56, and 84 mg) and administration interval (2 treatment sessions per 
week for 4 weeks) for this study were based on the results from Studies ESKETIVTRD2001, 
KETIVTRD2002, 
ESKETINTRD1001, 
and 
ESKETINTRD2003, 
described 
above 
in 
Section 1.1.2. 17, 18, 12, 16 
The data from PK/PD analysis of study ESKETINTRD2003 suggested the efficacy of 
esketamine 28 mg in Japanese subjects with TRD.16 Results of the pooled dose-response 
analyses of non-Japanese Panel (Panel A) and Japanese Panel (Panel B) of the Study 
ESKETINTRD2003 showed the efficacy of esketamine 28 mg to be low. However, as this 
analysis included only the 28-mg esketamine dose from the non-Japanese panel, the efficacy of 
esketamine 28 mg could not clearly be excluded in Japanese subjects with TRD. 
The data from Study ESKETINTRD2003 Panel A support the hypothesis that both 56 mg and 
84 mg doses of esketamine are effective in 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 induction phase. In addition, the 56 mg and 
84 mg doses were generally well-tolerated by subjects. The exposure is expected to be higher at 
each esketamine dose in Japanese subjects compared with non-Japanese subjects.16 
To improve tolerability, subjects who will be randomly assigned to esketamine 84 mg will start 
at 56 mg on Day 1 and then, in a blinded manner, the dose will be increased to 84 mg on Day 4. 
By the lower dose (56 mg) initially and then increasing to 84 mg, may allow subjects to adjust to 
the effects of the lower dose before going to the higher dose (84 mg). Thereafter, no dose 
adjustments will be permitted. For example, internal data from the CADSS suggest a 
dose-response, with the greatest effect seen initially on the 84 mg dose (Study 
ESKETINTRD2003).16 However, on subsequent repeated dosing, dissociative symptoms lessen. 
Starting with a lower dose may therefore limit the number of subjects discontinuing the study 
treatment because of intolerability in the 84-mg dose group. 
Oral Antidepressant 
A new, OL oral antidepressant medication will be initiated for all subjects in the prospective 
lead-in phase. Each subject will be assigned to receive 1 oral antidepressant medication of SSRIs, 
SNRIs, or mirtazapine (ie, escitalopram, paroxetine CR, sertraline, duloxetine, venlafaxine XR, 
or mirtazapine), that the subject has not previously had a nonresponse to in the current depressive 
episode, has not been previously intolerant to (lifetime). 
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The antidepressant medication will be assigned by the investigator based on review of the 
MGH-ATRQ and relevant prior antidepressant medication information. 
The SSRIs and SNRIs were selected because they are the most commonly prescribed 
antidepressant classes in this population and are generally well tolerated. Mirtazapine was 
selected 
because 
>50% 
of 
Japanese 
subjects 
used 
mirtazapine 
in 
the 
Study 
ESKETINTRD2003.16 If clinically indicated, subjects can join the prospective lead-in phase and 
initiate a new oral antidepressant before discontinuation of current oral antidepressants; therefore, 
cross-tapering is allowed. Dosing of the oral antidepressant will begin from prospective lead-in 
phase. New oral antidepressant treatment should be titrated to the approved maximum dose, to 
optimize the potential for response. The up-titration schedule should be per prescribing 
information. The dose, which is above the minimum therapeutic dose defined in MGH-ATRQ 
should be kept at last 4 weeks during the prospective lead-in phase, in case they start at lower 
doses. 
The new oral antidepressant medication initiated during the prospective lead-in phase will be 
ongoing and at a stable dose during the double-blind induction phase. The treatment will be 
maintained at the same dose throughout the posttreatment phase. 
3.2.5. 
Selection of Efficacy Scales and Safety Evaluations 
The full lists of efficacy and safety assessments for this study are described in Sections 9.2 and 
9.6, respectively.  
3.2.5.1. 
Efficacy Scales 
The 10-item clinician-administered MADRS is designed to be used in subjects with MDD to 
measure the overall severity of depressive symptoms.40 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 Clinical Global Impression – Severity (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.29  
The Sheehan Disability Scale (SDS) is a subject-reported outcome measure and is included as an 
assessment of functional impairment and associated disability.37,62  
Generalized Anxiety Disorder 7-item scale (GAD-7) is included as a brief and validated measure 
of overall anxiety.65  
The relapse criteria used in this study (see Section 9.2.1.2.3) are identical to the criteria that have 
been used in the previous and ongoing esketamine clinical studies. 
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3.2.6. 
Safety Evaluations 
Physical examination, body weight, vital signs (including blood pressure measurements), 12-lead 
ECG, pulse oximetry, clinical laboratory tests, and evaluation of TEAEs and concomitant 
therapies will be performed throughout the study to monitor subject safety. 
The TEAEs of special interest will be examined separately grouped in the following categories: 
Drug abuse, dependence and withdrawal (standardized Medical Dictionary for Regulatory 
Activities [MedDRA] queries [SMQ]), increased blood pressure, increased heart rate, transient 
dizziness/vertigo, impaired cognition, anxiety, and cystitis. 
Given the potential for treatment-emergent transient elevation in SBP and DBP, increased 
oxygen consumption, laryngospasms, and temporary respiratory depression following will be 
monitored throughout the study and at multiple time points on dosing days: heart rate, blood 
pressure, respiratory rate, and SpO2. Specific guidance to be followed on intranasal dosing days 
is provided in Section 6.3.1. 
Safety scales will include the Columbia Suicide Severity Rating Scale (C-SSRS) for assessing 
suicidal ideation and behavior, CADSS for assessing treatment-emergent dissociative symptoms, 
four-item positive symptom subscale of the brief psychiatric rating scale (BPRS+) for assessing 
treatment-emergent psychotic symptoms, Modified Observer’s Assessment of Alertness/Sedation 
(MOAA/S) for measuring treatment-emergent sedation, Clinical Global Assessment of 
Discharge Readiness (CGADR) for measuring the subject’s readiness for discharge based on 
parameters including sedation, blood pressure, and AEs, PWC-20 for assessing potential 
withdrawal symptoms after cessation of esketamine treatment, and POMS-2 to evaluate the 
abuse-liability of intranasal esketamine treatment. These safety scales are widely accepted scales 
for the rating of extrapyramidal side effects. 
3.2.7. 
Pharmacokinetic Evaluations 
Pharmacokinetic samples will be obtained during the study for measurement of the plasma 
concentrations of esketamine and if warranted, noresketamine or additional metabolites. 
The purpose of PK/PD modeling is to evaluate relationship of intranasal esketamine and 
MADRS total score (and possibly selected AEs as additional PD parameters) in Japanese 
subjects with TRD. 
3.2.8. 
Biomarker and Pharmacogenomic (DNA) Evaluations 
Assessment of biomarkers (protein) and their potential relationship to the different treatment 
groups and to maintenance/stabilization of response, nonresponse, 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. 
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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. 
Protein 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 biomarker analyses is to evaluate 
the PD of the different treatment groups, and aid in evaluating the drug-clinical response 
relationship. 
For the 24 hour period prior to sample collection, participants should refrain from strenuous 
exercise as this increases levels of inflammatory biomarkers. On the day of biomarker sample 
collection, it is preferred that subjects adhere to low fat diet (as an alternative to fasting) to 
reduce the level of postprandial lipemia in blood samples because moderately or grossly lipemic 
specimens may interfere with assay results. 
4. 
SUBJECT POPULATION 
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 considerations 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. 
Subject must be a Japanese man or woman aged between 20 and 64 years (both 
inclusive) at the time of signing the ICF. 
2. 
Criterion modified per amendment 3 
2.1 Criterion modified per amendment 4 
2.2 In this study, outpatients and inpatients are allowed for enrollment. Hospitalization 
for the study is allowed, subject must remain hospitalized from the beginning of the 
prospective lead-in phase to the end of the double-blind induction phase, maintaining 
the stable environment for 10 weeks. Temporary discharge is not permitted basically 
during the 10-week hospitalization. As a general rule, going out from the hospital 
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(leaving the site during hospitalization for reasons other than temporary discharge 
regardless of the attendant’s presence) is to be within 6 hours at a time and not to exceed 
twice in 7 contiguous days. 
3. 
Criterion modified per amendment 4 
3.1 At the start of the screening phase, subject must meet the DSM-5 diagnostic criteria 
for single-episode MDD or recurrent MDD, without psychotic features, based upon 
clinical assessment and confirmed by the MINI. In the case of single-episode MDD, the 
subject must be diagnosed with persistent depressive disorder, which meets criteria of 
major depressive episode for a continuous duration of 2 years, and the same physician 
from the site must be examining the subject for 2 years continuously as a primary care 
physician of the subject. 
4. 
The subject’s current major depressive episode, depression symptom severity (MADRS 
total score ≥28 required), and antidepressant treatment response in the current 
depressive episode, must be confirmed using the SAFER interview. 
5. 
The reported duration of the current major depressive episode is at least 12 weeks at 
Day 1 of the double-blind induction phase. 
6. 
At the start of the screening phase, subject must have had a nonresponse (≤25% 
improvement) to 1 but <5 oral antidepressant treatments in the current episode of 
depression, assessed using the MGH-ATRQ and confirmed by documented 
medical/pharmacy/prescription records or letter from treating physician. For specific 
tricyclic antidepressants, which are being taken at a dose below the MGH-ATRQ 
minimum therapeutic dose, a blood level that is within the therapeutic (antidepressant) 
range, is acceptable to establish the adequacy of the antidepressant treatment.  
Subjects who are nonresponders to a new oral antidepressant medication from the 
prospective lead-in phase (as assessed by independent, remote raters) may be eligible 
for randomization if all other entry criteria are met. Nonresponse at the end of the 
prospective lead-in phase is defined as ≤25% improvement in the MADRS total score 
from Visits 2.1 to each of Visit 2.3 and 3.1 (prerandomization) respectively, and a 
MADRS total score of ≥28 on each of the Visits 2.1, 2.3 and 3.1 (prerandomization).  
7. 
Subject must be medically stable on the basis of clinical laboratory tests performed at 
screening. If the results of the serum chemistry panel hematology, or urinalysis are 
outside the normal reference ranges, the subject may be included only if the investigator 
judges the abnormalities or deviations from normal to be not clinically significant or to 
be appropriate and reasonable for the population under study. This determination must 
be recorded in the subject's source documents and initialed by the investigator. 
o 
Subjects with a preexisting-history of thyroid disease/disorder who are 
treated with thyroid hormones must be on a stable dosage for 3 months 
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prior to the start of the screening phase. 
o 
For any subject (regardless of thyroid history), if the thyroid-stimulating 
hormone (TSH) value is out of range, a free thyroxine (FT4) will be 
conducted. If the FT4 value is abnormal and considered to be clinically 
significant (after discussion with the medical monitor), the subject is not 
eligible. 
8. 
Subject must be 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 phase. If there are any abnormalities that are not specified in the inclusion 
and exclusion criteria, the determination of their clinical significance must be 
determined by the investigator and recorded in the subject's source documents and 
initialed by the investigator. 
9. 
Subject must be comfortable with self-administration of intranasal medication and be 
able to follow the intranasal administration instruction. 
10. 
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. 
11. 
A woman of childbearing potential must have a negative highly sensitive serum 
β-human chorionic gonadotropin [β-hCG] test at the start of the screening phase and a 
negative urine pregnancy test must be obtained before the first dose of study drug on 
Day 1 of the double-blind induction phase prior to randomization. 
12. 
Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for subject participating in clinical studies. 
Before randomization, a woman must be either: 
a. 
Not of childbearing potential defined as:  
o 
Postmenopausal  
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level 
(>40 IU/L or mIU/mL) in the postmenopausal range 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 follicle stimulating hormone 
measurement is insufficient. 
o 
Permanently sterile 
 
Permanent 
sterilization 
methods 
include 
hysterectomy, 
bilateral 
salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral 
oophorectomy. 
b. Of childbearing potential and 
o 
practicing a highly effective method of contraception (failure rate of <1% 
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per year when used consistently and correctly)  
Examples of highly effective contraceptives include 
- user-independent methods: 
implantable progestogen-only hormone contraception associated with 
inhibition of ovulation; intrauterine device (IUD); intrauterine 
hormone-releasing system (IUS); vasectomized partner; sexual 
abstinence (sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study drug. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of 
the study and the preferred and usual lifestyle of the subject); 
- user-dependent methods: 
combined (estrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation: oral, 
intravaginal, and transdermal; progestogen-only hormone 
contraception associated with inhibition of ovulation: oral and 
injectable; 
 
Typical use failure rates may differ from those when used consistently and 
correctly. Use should be consistent with local regulations regarding the 
use of contraceptive methods for subjects participating in clinical studies. 
Hormonal contraception may be susceptible to interaction with the study 
drug, which may reduce the efficacy of the contraceptive method. 
 
o 
agrees to remain on a highly effective method throughout the study and for 
at least 6 weeks after the last dose of study drug. 
13. 
During the study and for a minimum of 1 spermatogenesis cycle (defined as 
approximately 90 days) after receiving the last dose of study drug, in addition to the 
highly effective method of contraception, a man 
 
who is sexually active with a woman of childbearing potential must be practicing a 
highly effective method of contraception with his female partner from those listed 
above (see examples of highly effective methods of contraception provided for 
female subjects); 
 
who is sexually active with a woman who is pregnant must use a condom; 
 
must agree not to donate sperm. 
14. 
Subject must be willing and able to adhere to the prohibitions and restrictions specified 
in this protocol (see Section 4.3). 
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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 nonresponse to: 
o 
All of the oral antidepressant treatment options available in the prospective 
lead-in phase (ie, escitalopram, paroxetine CR, sertraline, duloxetine, 
venlafaxine XR or, mirtazapine) in the current major depressive episode 
(based on MGH-ATRQ); or 
o 
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 previously received esketamine or ketamine as treatment for their MDD. 
3. 
Subject has received vagal nerve stimulation, has received transcranial magnetic 
stimulation or has received deep brain stimulation in the current episode of 
depression. 
4. 
Criterion modified per amendment 5 
4.1 Subject has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD 
with psychotic features bipolar or related disorders (confirmed by the MINI), 
obsessive compulsive disorder (current only), intellectual disability (DSM-5 
diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, 
borderline personality disorder, antisocial personality disorder, histrionic personality 
disorder, narcissistic personality disorder, paranoid personality disorder, schizoid 
personality disorder, or schizotypal personality disorder. 
5. 
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 phase, per the investigator’s clinical judgment or based on the C-SSRS, 
corresponding to a response of “Yes” on Item 4 (active suicidal ideation with some 
intent to act, without specific plan) or Item 5 (active suicidal ideation with specific 
plan and intent) for suicidal ideation on the C-SSRS, or a history of suicidal behavior 
within the past year prior to the start of the screening phase. Subjects reporting 
suicidal ideation with intent to act or suicidal behavior prior to the start of the double-
blind induction phase should be excluded. 
6. 
Criterion modified per amendment 4 
6.1 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 
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start of the screening phase.  
A history (lifetime) of ketamine, phencyclidine, lysergic acid diethylamide (LSD), 3, 
4-methylenedioxy-methamphetamine (MDMA), or psilocybin/psilocin hallucinogen-
related use disorder is exclusionary. 
7. 
Subject has a current or past history of seizure disorder (uncomplicated childhood 
febrile seizures with no sequelae are not exclusionary). 
8. 
Subject has 1 of the following cardiovascular-related conditions: 
o 
Cerebrovascular disease with a history of stroke or transient ischemic 
attack; 
o 
Aneurysmal vascular disease (including intracranial, thoracic, or 
abdominal aorta, or peripheral arterial vessels); 
o 
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 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; 
o 
Hemodynamically significant valvular heart disease such as mitral 
regurgitation, aortic stenosis, or aortic regurgitation;  
o 
New York Heart Association (NYHA) Class III-IV heart failure of any 
etiology. 
9. 
Subject has a history of uncontrolled hypertension despite diet, exercise, or 
antihypertensive therapy at the start of the screening phase or any past history of 
hypertensive crisis or ongoing evidence of uncontrolled hypertension defined as a 
supine SBP >140 mm Hg or DBP >90 mm Hg during screening phase, which 
continues to be above this range with repeated testing during this phase. Note: On 
Day 1 prior to randomization a supine SBP >140 mm Hg or DBP >90 mm Hg is 
exclusionary. 
A potential subject may have his/her current antihypertensive medication(s) adjusted 
during the screening phase and be reevaluated to assess their blood pressure control. 
The subject must be on a stable regimen for at least 2 weeks before Day 1 of the 
double-blind induction phase. 
10. 
Subject has a current or past history of significant pulmonary insufficiency/condition 
or with an arterial blood oxygen saturation (SpO2) of <93% at the start of the 
prospective lead-in phase or Day 1 prior to randomization. 
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11. 
Criterion modified per amendment 3 
11.1 Criterion modified per amendment 5 
11.2 Subject has clinically significant ECG abnormalities at the start of the screening 
phase or on Day 1 prior to randomization, defined as: 
o 
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 3 ECGs 
recorded 4 minutes apart must not be ≥450 msec. 
o 
On Day 1 (predose), a 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 3 ECGs recorded 4 minutes apart 
must not be ≥450 msec. 
o 
Evidence of 2nd and 3rd degree atrioventricular (AV) block, or complete 
left bundle branch block (LBBB).  
o 
Features of new ischemia. 
o 
Arrhythmia (except premature atrial contractions [PACs] and premature 
ventricular contractions [PVCs]). 
12. 
Subject has a history of additional risk factors for Torsades des Pointes (eg, heart 
failure, hypokalemia, family history of Long QT Syndrome). 
13. 
Criterion modified per amendment 5 
13.1 Subject has a history of, or symptoms and signs suggestive of, liver cirrhosis (eg, 
esophageal varices, ascites, and increased prothrombin time) OR alanine 
aminotransferase or aspartate aminotransferase values 3× the upper limit of normal 
or total bilirubin >1.5×ULN in the screening phase. 
o 
Repeat of screening test for abnormal alanine aminotransferase and 
aspartate aminotransferase is permitted once during the screening phase 
per investigator discretion and provided there is an alternative 
explanation for the out of range value. 
o 
For elevations in bilirubin, if in the opinion of the investigator and 
agreed upon by the sponsor’s medical officer, the elevation in bilirubin 
is consistent with Gilbert’s disease, the subject may participate in the 
study. 
14. 
Subject has positive test result(s) for drugs of abuse (including barbiturates, 
methadone, opiates, cocaine, phencyclidine, and amphetamine/methamphetamine) at 
the start of the screening phase. 
o 
Subjects who have a positive test result at screening due to prescribed 
opiates, barbiturates, or amphetamines may be permitted to continue in 
the screening/prospective lead-in phase if the medication is discontinued 
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at least 1 week or 5 half-lives, whichever is longer, before Day 1 of 
randomization. They need to have an additional test for drugs of abuse 
on Day 1 (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. 
o 
Retesting is not permitted for positive test result(s), except for reasons 
stated above. 
15. 
Subject has uncontrolled diabetes mellitus, as evidenced by glycated hemoglobin 
(HbA1c) >9% in the prospective lead-in phase or history in the prior 3 months prior to 
the start of the prospective lead-in phase of diabetic ketoacidosis, hyperglycemic 
coma, or severe hypoglycemia with loss of consciousness. 
16. 
Subject has untreated glaucoma, current penetrating or perforating eye injury, brain 
injury, hypertensive encephalopathy, intrathecal therapy with ventricular shunts, or 
any other condition associated with increased intracranial pressure or increased 
intraocular pressure or planned eye surgery. 
17. 
Subject has any anatomical or medical condition that, per the investigator’s clinical 
judgment based on assessment, may impede delivery or absorption of intranasal study 
drug. 
18. 
Subject has a history of malignancy within 5 years before screening phase (exceptions 
are squamous and basal cell carcinomas of the skin and carcinoma in situ of the 
cervix, or malignancy that, in the opinion of the investigator, with concurrence with 
the sponsor's medical monitor, is considered cured with minimal risk of recurrence). 
19. 
Subject has known allergies, hypersensitivity, or intolerance contraindications to 
esketamine/ketamine or its excipients (refer to Investigator's Brochure).32 
20. 
Subject has taken any prohibited therapies that would not permit dosing on Day 1. 
21. 
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 phase. 
22. 
Subject has an obstructive sleep apnea, which must be ruled out (eg, apnea-hypopnea 
index [AHI] must be <30). A subject with obstructive sleep apnea can be included if 
he or she is using a positive airway pressure device or other treatment/therapy that is 
effectively treating (ie, AHI<30) his or her sleep apnea. 
23. 
Subject has received an investigational drug (including investigational vaccines) or 
used an invasive investigational medical device within 90 days before the start of the 
screening phase, or has participated in 2 or more MDD or other psychiatric condition 
clinical interventional studies (with different investigational medication) in the 
previous 1 year before the start of the screening phase, or is currently enrolled in an 
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investigational interventional study. 
24. 
Subject is a woman who is pregnant, breastfeeding, or planning to become pregnant 
while enrolled in this study or within 6 weeks after the last dose of intranasal study 
drug. 
25. 
Subject has a diagnosis of acquired immunodeficiency syndrome (AIDS). Human 
immunodeficiency virus (HIV) testing is not required for this study. 
26. 
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. 
27. 
Subject has had major surgery, (eg, requiring general anesthesia) within 12 weeks 
before the start of the screening 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 in the study. 
28. 
Subject has severe renal impairment (creatinine clearance <30 mL/min). 
29. 
Subject has taken any disallowed therapies before the planned first dose of study drug. 
30. 
Subject is an employee of the investigator or study-site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study-site, as 
well as family members of the employees or the investigator. 
NOTE: Investigators should ensure that all study enrollment criteria have been met. If a subject's 
status changes (including laboratory results or receipt of additional medical records) before the 
first dose of study drug is given such that he or she no longer meets all eligibility criteria, then 
the subject should be excluded from participation in the study. Section 17.4, Source 
Documentation, describes the required documentation to support meeting the enrollment criteria. 
The sponsor will evaluate and approve/reject requests to rescreen an individual subject on a 
case-by-case basis. Rescreening will be allowed only once basically. 
4.3. 
Criteria for Double-blind and Open-label Induction Phases and 
Posttreatment Phase 
4.3.1. 
Criteria to Enter Double-blind Induction Phase 
After treatment with OL new oral antidepressant for 6 weeks during the prospective lead-in 
phase, subjects must have a nonresponse to the oral antidepressant medication. Nonresponse at 
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the end of the prospective lead-in phase is defined as ≤25% improvement in the MADRS total 
score from Visits 2.1 to each of Visit 2.3 and 3.1 (prerandomization) respectively, and a MADRS 
total score of ≥28 on each of the Visits 2.1, 2.3 and 3.1 (prerandomization). Only nonresponders 
at the end of the prospective lead-in phase will be eligible to proceed to the double-blind 
induction phase.  
4.3.2. 
Criteria to Enter Posttreatment Phase 
Subjects must be responders (50% reduction from baseline in MADRS total score) to the study 
treatment at the end of the 4-week induction phase to enter the posttreatment phase; 
nonresponders will proceed to the 4-week follow-up phase. 
4.3.3. 
Criteria to Enter Open-label Induction Phase 
Subjects who relapse within 20 weeks after the start of the posttreatment phase will transit to an 
OL induction phase and receive 4 weeks of OL treatment course with intranasal esketamine. See 
Section 9.2.1.2.3 for details on relapse criteria. 
4.4. 
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. 
Agree to follow all requirements that must be met during the study as noted in the 
Section 4.1 (Inclusion Criteria) and Section 4.2 (Exclusion Criteria) (eg, contraception 
requirements). 
2. 
Refer to Section 8 (Prestudy and Concomitant Therapy) and Attachment 1 (Prohibited 
Concomitant Medications for Intranasal Study Medication [Esketamine or Placebo]) 
for further information on prohibited therapies. 
3. 
Subjects who were taking benzodiazepines (at doses equal to or less than the 
equivalent of 6 mg/day of lorazepam) or permitted non-benzodiazepine sleep 
medications (eg, zolpidem, eszopiclone and zopiclone) or both during the screening 
phase, can continue these medications throughout the study; however, dose increases 
or starting new benzodiazepine medications are not permitted. Benzodiazepines and 
non-benzodiazepine sleeping medications (eg, zolpidem, zaleplon, eszopiclone, and 
ramelteon) are prohibited within 12 hours prior to the start of each intranasal treatment 
session. 
4. 
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 1 
and TIME AND EVENTS SCHEDULE 3). 
5. 
On all intranasal study treatment sessions, all subjects must remain at the clinical 
study-site until study procedures have been completed and the subject is ready for 
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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. 
6. 
Subjects must adhere to prohibitions of the new oral antidepressants which are shown 
in their prescribing information. 
7. 
Electroconvulsive therapy, deep brain stimulation, transcranial magnetic stimulation, 
and vagal nerve stimulation are prohibited from study entry through the end of the 
double-blind induction phase. 
5. 
TREATMENT ALLOCATION AND BLINDING 
5.1. 
Treatment Allocation 
Procedures for Randomization 
Randomization will be employed only in the double-blind induction phase of the study. Central 
randomization will be implemented in this study. Subjects will be randomly assigned to 1 of 
4 treatment groups in a 2:1:1:1 ratio based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor. Randomization will be 
balanced by using randomly permuted blocks across the 4 treatment groups. 
The interactive web response system (IWRS) will assign a unique treatment code, which will 
dictate the treatment assignment and matching study drug kit for the subject. The requestor must 
use his or her own user identification and personal identification number when contacting the 
IWRS, and will then give the relevant subject details to uniquely identify the subject. 
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed.  
5.2. 
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 
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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, time, 
and reason for the unblinding must be documented in the appropriate section of the electronic 
case report form (eCRF), and in the source document.  
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled evaluations. 
At the end of the double-blind induction 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. 
To maintain the blinding of intranasal study drug, 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.  
6. 
DOSAGE AND ADMINISTRATION 
6.1. 
Screening Phase 
As described in Section 3.1, unless prohibited per protocol, subjects taking benzodiazepines (at 
dosages equal to or less than the equivalent of 6 mg/day of lorazepam) or permitted 
non-benzodiazepine sleep medications (eg, zolpidem, eszopiclone and zopiclone) or both during 
screening phase, can continue these medications throughout the study, but dose increases or 
starting new benzodiazepine medications are not permitted. Subject’s current antidepressant 
treatment(s), including adjunctive treatment for MDD, should be tapered and discontinued in this 
phase per the local prescribing information.  
6.2. 
Prospective Lead-in Phase 
All subjects will initiate a physician-determined new OL oral antidepressant daily for the 
duration of this phase. If clinically indicated, cross-tapering is allowed. Cross-tapering is defined 
as discontinuation of previous antidepressant treatment(s) by lowering the dose(s) per the local 
prescribing information and simultaneously increasing the dose of single new antidepressant 
treatment within the first 2 weeks of the prospective lead-in phase. New oral antidepressant 
treatment should be titrated to the approved maximum dose, to optimize the potential for 
response. The up-titration schedule should be per prescribing information. 
Oral Antidepressant Medication 
At the start of the prospective lead-in phase, all enrolled subjects will be switched to a new 
single-agent oral antidepressant therapy determined by the investigator. The oral antidepressant 
will be 1 of the following: selective serotonin reuptake inhibitors or SSRIs, SNRIs, or 
mirtazapine (ie, escitalopram, paroxetine CR, sertraline, duloxetine, venlafaxine XR, or 
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mirtazapine), which the subject has not previously had a nonresponse to in the current depressive 
episode or has not been previously intolerant to (lifetime). If clinically indicated, cross-tapering 
is allowed in the first 2 weeks during the prospective lead-in phase. In the last 4 weeks during the 
prospective lead-in phase, 'oral antidepressant' must be single treatment of switched new oral 
antidepressant. New oral antidepressant treatment should be titrated to the approved maximum 
dose, to optimize the potential for response. Up-titration of the antidepressant may be performed 
per investigator’s discretion based on prescribing information in the prospective lead-in phase. 
The dose, which is above the minimum therapeutic dose defined in MGH-ATRQ should be kept 
at last 4 weeks during the prospective lead-in phase, in case they start at lower doses. Refer 
Attachment 3 (Example of the Up-titration Schedule for a New Oral Antidepressant Therapy 
[Physician Determined] in Prospective Lead-in Phase) for further information on up-titration. 
Following completion of this phase, subjects entering the subsequent phases of the study will 
continue to receive the oral antidepressant at a stable dose through EOS/study discontinuation. 
Subjects must continue the new antidepressant throughout the study, except follow up phase. In 
follow-up phase, standard of care is allowed. However, oral antidepressant medication must be 
continued in the follow-up phase unless determined as not clinically appropriate. Study-site 
personnel will instruct subjects on how to take and store the oral antidepressant medications 
during this study for at-home use. A subject diary to capture oral antidepressant use will be 
provided. Missing >2 days of the new antidepressant medication per consecutive 7 days from the 
beginning of the prospective lead-in phase, will be considered as inadequate adherence and the 
subject should withdraw from the study. 
Subjects will be instructed not to consume their assigned oral antidepressant until at least 3 hours 
after an intranasal treatment session. 
6.3. 
Double-blind Induction Phase 
During this phase, subjects will self-administer double-blind intranasal treatment either placebo, 
esketamine 28 mg, esketamine 56 mg, or esketamine 84 mg add-on to the continued oral 
antidepressant from the prospective lead-in phase. The oral antidepressant must be administered 
at a stable dose during this phase and through EOS/study discontinuation.  
Intranasal Study Drug 
On all intranasal treatment session days, a medical doctor or nurse of a site must be present with 
the subject during the intranasal treatment session and the postdose observation period. In 
addition, equipment for supportive ventilation and resuscitation needs to be present. 
The subjects must be upright, in a semi-reclining position when intranasal study drug is 
administered. Table 2 describes how each intranasal treatment session will be administered in the 
double-blind induction phase. Please refer to Section 6.3.1 for guidance on Blood Pressure 
Monitoring on intranasal dosing days. 
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Table 2: 
Intranasal Treatment Administration During the Double-blind Induction Phase 
Intranasal Treatment 
Time of Intranasal Device Administrationa 
0 minuteb 
5 minutes
10 minutes
Intranasal device c 
1st
2nd 
3rd 
Placebo 
1 spray of placebo to 
each nostril 
1 spray of placebo to 
each nostril 
1 spray of placebo to 
each nostril 
Esketamine 28 mg 
1 spray of esketamine to 
each nostril 
1 spray of placebo to 
each nostril 
1 spray of placebo to 
each nostril 
Esketamine 56 mg  
1 spray of esketamine to 
each nostril 
1 spray of esketamine to 
each nostril 
1 spray of placebo to 
each nostril 
Esketamine 84 mg 
1 spray of esketamine to 
each nostril 
1 spray of esketamine to 
each nostril 
1 spray of esketamine to 
each nostril 
a. The 3 intranasal devices for each intranasal treatment session should be administered in the medication kit order 
provided by the interactive web response system (IWRS) 
b. Time 0 is defined as the time of administration of the first intranasal spray to 1 nostril from the first intranasal 
device.  
c. 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) 
 
Instructions for use documents (healthcare provider versions) for intranasal study drug 
administration will be provided as separate documents. Details regarding study drug 
administration will be recorded in the source documents and the eCRF. In the event of a missed 
dose, ensure to contact to sponsor immediately. 
Prior to the first intranasal dose on Day 1, subjects will practice spraying (into the air, not 
intranasally) with a demonstration intranasal device that is filled with placebo solution. 
The intranasal treatment sessions (esketamine or placebo) will occur twice weekly. Subjects will 
self-administer the intranasal study drug (esketamine 28 mg, 56 mg, 84 mg, or placebo) at 
treatment sessions occurring 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. 
To improve tolerability, subjects who will be randomly assigned to esketamine 84 mg will start 
at 56 mg on Day 1 and then the dose will increase to 84 mg on Day 4 as a forced titration and 
remain at 84 mg for all subsequent intranasal treatment sessions. Subjects who are randomly 
assigned to 28 mg and 56 mg dose groups will remain on that dose for all subsequent intranasal 
treatment sessions. No adjustment to the intranasal esketamine dose is permitted for the duration 
of the double-blind induction phase. 
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 Schedules). If an intranasal decongestant is used to reduce congestion, it cannot be 
used within 1 hour prior to intranasal study drug administration. 
On all intranasal treatment sessions, subjects must remain at the clinical site until study 
procedures have been completed and the subject is ready for discharge. Subjects should be 
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accompanied by a responsible adult when released from the clinical study site. Subjects must not 
drive a car or work with machines for 24 hours after the intranasal treatment session. 
6.3.1. 
Guidance on Blood Pressure Monitoring on Intranasal Treatment 
Session Days 
Given the potential for treatment-emergent transient elevation in SBP and DBP, 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 predose SBP is >140 mm Hg 
or DBP is >90 mm Hg or both, it is recommended to repeat the blood pressure measurement 
after subject rests in sitting or recumbent position. If after rest and repeated measurements, 
predose SBP is >140 mm Hg or DBP is >90 mm Hg or both (except for Day 1), then dosing 
should be postponed and the subject must be scheduled to return on the following day or 
within the given visit window (if it is shown on Day 1, the subject should be excluded from 
the study). 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 mm Hg but <200 mm Hg or 
the DBP is 110 mm Hg but <120 mm Hg or both, 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 predose blood pressure at the next scheduled visit is within the 
acceptable range (see bullet point above). 
 
If at any postdose time point on the dosing day the SBP is 200 mm Hg or the DBP is 
120 mm Hg or both, 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 induction phase, at 1.5 hours postdose, if the SBP is 160 mm Hg or the 
DBP 100 mm Hg or both, assessments should continue every 30 minutes until:  
 
Blood pressure is <160 mm Hg SBP and <100 mm Hg DBP, or 
 
In the investigator’s clinical judgment, the subject is clinically stable and can be discharged 
from the study-site, or  
 
Subject is referred for appropriate medical care, if clinically indicated. 
 
If the blood pressure remains ≥180 mm Hg SBP or ≥110 mm Hg DBP or both, 2 hours after 
dosing, the subject should be referred for immediate medical treatment. 
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6.4. 
Posttreatment Phase 
Subjects who relapse within 20 weeks after the start of the posttreatment phase will transit to an 
OL induction phase and receive 4 weeks of OL treatment course with intranasal esketamine. 
Subjects who meet the criteria of relapse, they need to join OL induction phase before next 
remote MADRS assessment. Subjects who relapse more than 20 weeks after the start of the 
posttreatment phase will withdraw from the study and clinical/standard-of-care treatment will be 
arranged by the study investigator after relapse. Subjects who have no relapse throughout this 
24-week posttreatment phase will complete this study without 4-week follow-up phase. The oral 
antidepressant must be continued at a stable dose during post treatment phase. 
6.4.1. 
Open-label Induction Phase 
Subjects who relapsed in the posttreatment phase will receive a 4-week OL induction treatment 
course of intranasal esketamine. During this phase, subjects will continue to receive their 
switched oral antidepressant medication. The beginning of the OL induction phase should be at 
least 2 weeks (14 calendar days) after the last dose in the double-blind induction phase. Subjects 
who meet the relapse criteria before 2 weeks after the last dose in the double-blind induction 
phase will not have an option for joining open label induction phase. They will withdraw from 
the post treatment phase and move forward to the follow up phase. 
Eligible subjects will start treatment sessions with 56 mg of intranasal esketamine on the first 
day of OL induction phase (Day OL1). On Day OL4, the dose must be increased to 84 mg. On 
Day OL8 and OL11, the dose could be maintained, increased, or reduced by 28 mg as 
determined by the investigator based on efficacy and tolerability. On Day OL15, a dose 
reduction is permitted, if required for tolerability; no dose increase is permitted on Day OL15. 
After Day OL15, the dose should be stable (unchanged). If needed for tolerability, a dose 
reduction is permitted from Day OL15 until Day OL25. Intranasal treatment sessions should not 
take place on consecutive days. 
6.5. 
Follow-up Phase 
Following subjects will have follow-up Visits; subjects who withdraw from double-blind 
induction phase, nonresponders after double-blind induction phase, responders who withdraw 
within 4 weeks after the last dose of double blind intranasal drug and all subjects who receive 
open label intranasal drug. During this phase, further clinical/standard-of-care treatment will be 
arranged by the study investigator however, in order to better assess potential withdrawal 
symptoms from intranasal study drug, the oral antidepressant medication must be continued for 
the follow-up phase unless determined as not clinically appropriate. 
7. 
TREATMENT COMPLIANCE 
The investigator or designated study-site personnel will maintain a log of all intranasal study 
drug. Supplies of intranasal study drug for each subject will be inventoried and accounted for 
throughout the study. 
Subjects will receive instructions on compliance with the oral antidepressant medication. During 
the course of the study, the investigator or designated study-site personnel will be responsible for 
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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 use.  
Antidepressant treatment adherence during the entire study will be assessed using subject diary. 
All doses of intranasal study drug will be self-administered by the subjects at the investigative 
site under the direct supervision of the investigator or designee, and will be recorded in the eCRF. 
8. 
PRESTUDY AND CONCOMITANT THERAPY 
Prestudy non-antidepressant therapies administered up to 30 days before obtaining IC must be 
recorded at the start of this phase. 
All antidepressant treatments, including adjunctive treatment for MDD, taken during the current 
depressive episode (ie, including those taken more than 30 days prior to obtaining IC) will be 
recorded at the start of the screening phase. Information will also be obtained regarding any 
history of intolerance to any of the following antidepressant choices: SSRIs, SNRIs, or 
mirtazapine (ie, escitalopram, paroxetine CR, sertraline, duloxetine, venlafaxine XR, or 
mirtazapine). Antidepressant treatments, which are not listed on the MGH-ATRQ but were used, 
or are currently being used in the current depressive episode must be recorded in ‘Concomitant 
Therapy’ section of the eCRF. 
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 AEs until 
resolution of the event. 
Subjects receiving benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day 
of lorazepam) or permitted non-benzodiazepine sleep medications (eg, zolpidem, eszopiclone, 
and zopiclone) or both during the screening phase can continue these medications throughout the 
study; however, dose increases or starting new benzodiazepine medications are not permitted. 
Benzodiazepines and non-benzodiazepine sleeping medications (eg, zolpidem, eszopiclone, and 
zopiclone) are prohibited within 12 hours prior to the start of each intranasal treatment session. 
Subjects should continue to take their permitted concomitant medications (eg, antihypertensive 
medications) at their regular schedule; however, restrictions as outlined in Section 4.4 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. For any concomitant medication given as a treatment for a new or worsening condition, 
the condition must be documented in the Adverse Event section of the eCRF. 
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic 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 
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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 TEAEs 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 
 
For nausea: As required, ondansetron 8 mg sublingually, metoclopramide (10 mg orally or 
IV or IM) or dimenhydrinate (25 to 50 mg, IV or IM) 
 
Unless clinically indicated, it is recommended that transient increases in blood pressure not 
be treated, as the blood pressure typically returns to predose values in 2 hours. The effect of 
any treatment may result in hypotension. 
Prohibited Medications 
A list of prohibited medications is provided in Attachment 1 as a 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 1 summarizes the frequency and timing of efficacy, PK, 
biomarker, pharmacogenomic, and safety measurements applicable to screening, prospective 
lead-in and double-blind induction phases of this study. 
The TIME AND EVENTS SCHEDULE 2 summarizes the frequency and timing of efficacy and 
safety measurements applicable to posttreatment and follow-up phases of this study. 
The TIME AND EVENTS SCHEDULE 3 summarizes the frequency and timing of efficacy, PK, 
ongoing subject review and safety measurements applicable to OL induction phase of this study. 
With the exception of postdose assessments, visit-specific assessments for subject-reported 
outcomes should be conducted or completed before any tests, procedures, or other consultations 
for that study-site visit to prevent influencing subject perceptions. When multiple 
patient-reported outcomes (PRO) and clinician-administered assessments are scheduled for the 
same time point, it is recommended they be performed in the following sequence. Actual dates 
and times of assessments will be recorded in the source documentation and eCRF. 
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PRO: GAD-7, SDS, POMS-2 
Clinician-administered: CGI-S, C-SSRS, PWC-20, BPRS+, CADSS, MOAA/S, CGADR 
Remote MADRS interview should be conducted at predose on intranasal dosing days during the 
double blind induction phase and the open label induction phase.  
The maximum total blood volume to be collected from each subject will be approximately 
112.5 mL (Table 3). 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.  
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Table 3: 
Approximate 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 Phase 
TSH, FT4 and FT3[d] 
3.5 
1 
3.5 
Hematology[b] 
2 
1 
2 
Chemistry panel[c] 
2.5 
1 
2.5 
Approximate total blood volume for screening phase 
8 
Prospective Lead-in Phase
Chemistry panel[e] 
2.5 
1 
2.5 
Approximate total blood volume for Prospective Lead-in Phase 
2.5 
Double-blind Induction Phase 
Hematology 
2 
2 
4 
Chemistry panel 
2.5 
2 
5 
Pharmacokinetics 
4 
6 
24 
Biomarkers: protein[f] 
10 
3 
30 
Pharmacogenomic (DNA) 
6 
3 
18 
Approximate total blood volume for double-blind induction treatment phase 
81 
Double-blind Early Withdrawal Visit (if applicable)
Hematology 
2 
1 
2 
Chemistry panel 
2.5 
1 
2.5 
Biomarkers: protein[f] 
10 
1 
10 
Pharmacogenomic (DNA) 
6 
1 
6 
Approximate total blood volume for double-blind early withdrawal 
20.5 
Open-label Induction Treatment Phase[g] 
Hematology 
2 
2 
4 
Chemistry panel 
2.5 
2 
5 
Pharmacokinetics 
4 
3 
12 
Approximate total blood volume for open-label induction treatment phase 
21 
Open-label Early Withdrawal Visit (if applicable)
Hematology 
2 
1 
2 
Chemistry panel 
2.5 
1 
2.5 
Approximate total blood volume for open-label early withdrawal 
4.5 
Retest (if applicable) 
TSH 
3.5 
1 
3.5 
Hematology 
2 
1 
2 
Chemistry panel 
2.5 
1 
2.5 
Biomarkers: protein[f] 
10 
1 
10 
 
18 
Approximate total blood volume for the study[g], [h] 
112.5 
DNA-deoxyribonucleic acid; FT3-free triiodothyronine; FT4-free thyroxine; TSH-thyroid-stimulating hormone. 
a. 
Calculated as number of samples multiplied by volume of blood per sample. 
b. 
HbA1c will be measured from the sample collected for hematology. 
c. 
Serum chemistry including serum -hCG pregnancy tests (for women of childbearing potential). 
d. 
For any subject (regardless of thyroid history), if the TSH value is out of range, a free thyroxine (FT4) will be 
conducted 
e. 
Serum chemistry including lipid panel. 
f. 
This sample will provide serum for all of the following assays: IL-10, IL-1b, IL-6, TNFa, Adiponectin, Cortisol, hs-
CRP (non-cardiac), IL-6R, BDNF, IGF-1, Leptin and IL-17A. 
g. 
The second induction treatment phase is optional. 
h. 
Blood volume of the following visits is not included in the total volume: Double-blind Early Withdrawal, Open-label 
Early Withdrawal, and Retest. 
 
9.1.2. 
Informed Consent Procedure 
Informed consent must be obtained prior to the subject entering the study, and before any 
protocol-directed procedures (eg, washout of prohibited medications) are performed. Signing 
ICF is not required at the same day of the Screening Visit 1.1. Investigators can observe the 
subjects until Screening Visit 1.1 after obtaining IC, if clinically indicated (eg, washout of 
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prohibited medications). If Screening Visit 1.1 is on more than 28 days after singing ICF, 
investigators must obtain informed consent again, to confirm their willingness. 
9.1.3. 
Screening Phase 
Up to 4 weeks before entry into the prospective lead-in phase, all subjects will undergo screening 
procedures. After signed informed consent has been obtained, the inclusion and exclusion criteria 
will be reviewed to verify the subjects’ eligibility. 
After signing the ICF, subjects who are 20 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).  
At the start of this phase, subjects must have had nonresponse (≤25% improvement) to 1 but <5 
oral antidepressant medications 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 this study, 
outpatients and inpatients are allowed for enrollment. Hospitalization for the study is allowed, 
subject must remain hospitalized from the beginning of the prospective lead-in phase to the end 
of the double-blind induction phase, maintaining the stable environment for 10 weeks. 
Temporary discharge is not permitted basically during the 10-week hospitalization. As a general 
rule, going out from the hospital (leaving the site during hospitalization for reasons other than 
temporary discharge regardless of the attendant’s presence) is to be within 6 hours at a time and 
not to exceed twice in 7 contiguous days. 
Subject’s current antidepressant treatment(s), including adjunctive treatment for MDD, should be 
tapered and discontinued in this phase per the prescribing information. Down-titration of 
antidepressants will be started after SAFER interview and will be completed in the screening 
phase basically. However, if clinically indicated, cross-tapering is allowed. Cross-tapering is 
defined as discontinuation of previous antidepressant treatment(s) by lowering the dose(s) per the 
local prescribing information and simultaneously increasing the dose of single new 
antidepressant treatment within the first 2 weeks of the prospective lead-in phase. 
The subject’s current major depressive episode, depression symptom severity (MADRS total 
score ≥28 required), and treatment response to antidepressant medication used in the current 
episode (retrospectively assessed) must be deemed valid for participation in the clinical study 
based on the SAFER interview, which is administered by remote, independent raters.  
Clinical safety assessments including physical examination, examination of vital signs, recording 
of weight, ECG, C-SSRS scale, as well as clinical laboratory assessments will be performed as 
outlined in the TIME AND EVENTS SCHEDULE 1. Prestudy and concomitant therapies and 
ongoing antidepressant therapy will be recorded in the eCRF. 
Subjects taking benzodiazepines or permitted non-benzodiazepine sleep medications or both 
during screening phase, can continue these medications throughout the study, but dose increases 
or starting new benzodiazepine medications are not permitted.  
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All AEs and special reporting situations, whether serious or non-serious, will be reported from 
the time a signed and dated ICF is obtained until completion of the subject's last study visit. 
At the screening visit, subjects who continue to fulfill all inclusion criteria and none of the 
exclusion criteria will be able to proceed to the prospective lead-in phase. 
9.1.4. 
Prospective Lead-in Phase 
All subjects will initiate a physician-determined new OL oral antidepressant daily for the 
duration of this phase. The oral antidepressant will be 1 oral antidepressant medication of SSRIs, 
SNRIs or mirtazapine (ie, escitalopram, paroxetine CR, sertraline, duloxetine, venlafaxine XR, 
or mirtazapine), that the subject has not previously had a nonresponse to in the current depressive 
episode, has not been previously intolerant to (lifetime). If clinically indicated, cross-tapering is 
allowed in the first 2 weeks during the prospective lead-in phase. In the last 4 weeks during the 
prospective lead-in phase, 'oral antidepressant' must be single treatment of switched new oral 
antidepressant to keep the same condition to compare the MADRS throughout the period. New 
oral antidepressant treatment should be titrated to the approved maximum dose, to optimize the 
potential for response. The up-titration schedule should be per prescribing information. The dose, 
which is above the minimum therapeutic dose defined in MGH-ATRQ should be kept at last 
4 weeks during the prospective lead-in phase, in case they start at lower doses at the start the 
prospective lead-in phase. 
After 6 weeks, subjects who are nonresponders to the new oral antidepressant medication at the 
end of the prospective lead-in phase can be eligible to proceed to the double-blind induction 
phase. Nonresponse at the end of the prospective lead-in phase is defined as ≤25% improvement 
in the MADRS total score from Visits 2.1 to each of Visit 2.3 and 3.1 (prerandomization) 
respectively, and a MADRS total score of ≥28 on each of the Visits 2.1, 2.3 and 3.1 
(prerandomization). 
Efficacy assessments including MADRS (7-day recall) assessment by an independent, remote, 
blinded rater and CGI-S will be performed. Clinical safety assessments including examination of 
vital signs, lipid panel (fasting) and C-SSRS (baseline/screening version) assessments will be 
performed as outlined in the TIME AND EVENTS SCHEDULE 1. Concomitant therapies and 
antidepressant therapy will be recorded in the eCRF. 
At the baseline visit, subjects who continue to fulfill all inclusion criteria and none of the 
exclusion criteria will be enrolled and randomized. All other subjects who do not proceed to the 
double-blind induction phase will end study participation at this time. No further study visits or 
follow-up is required. 
9.1.5. 
Double-blind Induction Phase 
Approximately 183 subjects will be randomly assigned at a 2:1:1:1 ratio to receive double-blind 
intranasal treatment with either placebo, esketamine 28 mg, esketamine 56 mg, or esketamine 
84 mg add-on to continued stable oral antidepressant.  
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Safety, efficacy, and PK evaluations to be performed at each visit during this phase are described 
in the TIME AND EVENTS SCHEDULE 1. All assessments performed prior to the first dose of 
intranasal esketamine in the double-blind induction treatment phase will be considered baseline 
assessments. 
Prior to the first intranasal dose on Day 1, subjects will practice spraying (into the air, not 
intranasally) with a demonstration intranasal device that is filled with placebo solution. 
During this phase, subjects will self-administer (under clinical supervision) intranasal study drug 
(esketamine 28 mg, 56 mg, or 84 mg, or placebo) at treatment sessions occurring twice a week 
for 4 weeks at the clinical site (see Section 6.3, Dosage and Administration for details).  
The new oral antidepressant medication, which is ongoing and stable from prospective lead-in 
phase, will be continued throughout the study. 
Benzodiazepines and non-benzodiazepine sleeping medications (eg, zolpidem, eszopiclone and 
zopiclone) are prohibited within 12 hours prior to the start of each intranasal treatment session. 
Clinic visits and remote assessment visits will be performed as specified in the TIME AND 
EVENTS SCHEDULE 1. 
Early Withdrawal 
If a subject withdraws before the end of the 1st induction treatment phase for reasons other than 
withdrawal of consent, the EW Visit should be conducted within 1 week of the date of 
discontinuation, followed by the 4-week follow-up phase. If the EW Visit occurs on the same 
day as a scheduled visit, the EW 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. The study investigator will determine whether or not the current oral antidepressant 
medication will continue. All subjects who are discontinued must be treated with an oral 
antidepressant after completion of the study, unless it is clinically inappropriate.  
9.1.6. 
Posttreatment Phase 
Responders (subjects with ≥50% reduction from baseline in MADRS total score) at the end of 
the intranasal esketamine double-blind induction phase will enter this 24-week posttreatment 
phase. 
During this phase, subjects will be evaluated for sustained efficacy after cessation of add-on 
intranasal esketamine treatment while continuing the oral antidepressant medication regimen, as 
assessed by the time to relapse and proportion of responders and remitters at each visit in this 
phase. Clinic visits and remote assessment visits will be performed as specified in the TIME 
AND EVENTS SCHEDULE 2. 
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MADRS assessments will be performed weekly through Week 24 or relapse, whichever occurs 
first. Relapse based on MADRS assessment is defined as MADRS total score ≥22 for 
2 consecutive visits (See Section 9.2.1.2.3). Other efficacy assessments during the posttreatment 
phase include CGI-S and SDS. 
Safety assessments includes C-SSRS scoring, evaluation of withdrawal or rebound symptoms or 
both using PWC-20 and evaluation of potential abuse-liability using POMS-2. 
9.1.7. 
Open-label Induction Phase 
Subjects who relapse in the posttreatment phase will receive a 4-week induction treatment course 
of intranasal esketamine (OL this time) add-on to continued stable oral antidepressant. The 
beginning of the 2nd induction treatment phase should be at least 2 weeks (14 calendar days) after 
the last dose in the double-blind induction treatment phase. Subjects who meet the relapse 
criteria before 2 weeks after the last dose in the double-blind induction phase will not have an 
option for joining open label induction phase. They will withdraw from the posttreatment phase 
and move forward to the follow-up phase. 
Safety, efficacy, and PK evaluations to be performed at each visit are described in the TIME 
AND EVENTS SCHEDULE 3. All assessments performed prior to the first dose of intranasal 
esketamine in the OL induction treatment phase will be considered baseline (prior to the first 
dose of OL induction phase) assessments. 
Eligible TRD subjects will start treatment sessions with 56 mg of intranasal esketamine on the 
first day of OL induction phase (Day OL1). On Day OL4, the dose must be increased to 84 mg. 
On Day OL8 and OL11, the dose could be maintained, increased or reduced by 28 mg as 
determined by the investigator based on efficacy and tolerability. On Day OL15, a dose 
reduction is permitted, if required for tolerability; no dose increase is permitted on Day OL15. 
After Day OL15, the dose should be stable (unchanged). If needed for tolerability, a dose 
reduction is permitted from Day OL15 until Day OL25. This phase will evaluate if subjects will 
respond again to a second induction treatment course without any new safety signal compared to 
the double-blind induction treatment course. 
During this phase, eligible subjects will receive intranasal esketamine as per the details provided 
in Dosage and Administration section (Refer Section 6.4.1). 
After completion of this phase, a follow-up phase will be scheduled for 4 weeks. 
If a subject withdraws before the end of the OL induction phase (ie, before completing 
Visit 5.10/Day OL28) for reasons other than withdrawal of consent, an EW Visit should be 
conducted within 1 week of the date of discontinuation, followed by the follow-up phase. If the 
EW Visit is conducted on the same day as a scheduled visit, duplicate assessments are not 
required. 
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9.1.8. 
Follow-up Phase 
Following subjects will have follow-up visits; subjects who withdraw from double blind 
induction phase, nonresponders after double-blind induction phase, responders who withdraw 
within 4 weeks after the last dose of double blind intranasal drug and all subjects who receive 
open label intranasal drug. 
During this period subjects will have 3 clinic visits to evaluate the safety, as specified in the 
TIME AND EVENTS SCHEDULE 2. 
During this phase, further clinical/standard-of-care treatment will be arranged by the study 
investigator. The decision to continue the oral antidepressant medication in this phase will be at 
the discretion of the investigator, however, in order to better assess potential withdrawal 
symptoms from intranasal study drug, the oral antidepressant medication must be continued for 
the follow-up phase unless determined as not clinically appropriate. 
Any clinically significant abnormalities persisting at the end of the study will be followed by the 
investigator until resolution or until a clinically stable endpoint is reached. All AEs and special 
reporting situations, whether serious or non-serious, will be reported until completion of the 
subject's last study-related procedure. 
9.2. 
Efficacy 
9.2.1. 
Evaluations 
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 induction phase. 
In addition to being the primary efficacy measure, the MADRS will also be used to evaluate the 
following secondary efficacy endpoints of the double-blind induction phase: proportion of 
responders (50% reduction from baseline in MADRS total score), proportion of remitters 
(MADRS total score 12); time to relapse (in subjects who remit [MADRS total score 12] and 
in subjects with response but not remit); and proportion of subjects showing onset of clinical 
response (ie, antidepressant effect) by Day 2 that is maintained for the duration of the 
double-blind induction phase. Onset of clinical response is defined as 50% reduction in the 
MADRS total score by the day after taking the first dose of double-blind medication (Day 2) that 
continued through the end of the 4-week double-blind induction phase with one excursion. 
Subjects are allowed one excursion (nonresponse) on Days 8, 15 or 22. Subjects who discontinue 
the study prior to the end of the double-blind induction phase will not be considered to have 
maintained clinical response. Other secondary evaluations include CGI-S, SDS and GAD-7. 
Every effort should be made to ensure that all clinician-administered efficacy assessments are 
completed by a qualified assessor at the baseline and subsequent assessments are performed by 
the same individual. It is recommended that the various subject-reported outcome assessments be 
completed prior to other procedures. 
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9.2.1.1. 
Primary Efficacy Evaluation 
9.2.1.1.1. 
MADRS (7-day Recall) 
The primary efficacy evaluation will be the MADRS total score. The MADRS will be performed 
by independent remote raters during the study, using the Structured Interview Guide for the 
Montgomery-Asberg Depression Rating Scale (SIGMA: Williams 2008). The remote MADRS 
interviews will be recorded to assess accuracy and thoroughness of the interviews and measure 
overall quality assurance. 
The MADRS is a clinician-rated scale designed to measure depression severity and detects 
changes due to antidepressant treatment.39 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 typical recall period for the MADRS is 7 days and will be used for the primary efficacy 
evaluation. In this study, the MADRS will also be administered using modified recall period of 
24 hours (see Section 9.2.1.2.1). 
9.2.1.2. 
Secondary Efficacy Evaluation (Clinician-completed) 
9.2.1.2.1. 
MADRS (24-hour Recall) 
The MADRS will also be administered using a modified recall period of 24 hours for the key 
secondary efficacy evaluation related to onset of clinical response by Day 2 that is maintained 
for the duration of the double-blind induction phase.  
The MADRS with a 24-hour recall period will be used on Day 2. The feasibility of this shortened 
recall period has been confirmed with subjects, and physicians, and there are data supporting the 
psychometric properties of this shortened recall period (data on file). The MADRS with a 7-day 
recall will be used for all subsequent MADRS assessments used for the key secondary efficacy 
evaluation (maintenance of clinical response achieved on Day 2 for duration of double-blind 
induction phase). 
9.2.1.2.2. 
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.29 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 subjects. The CGI-S permits a global evaluation of the subject’s 
condition at a given time. 
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9.2.1.2.3. 
Time to Relapse 
Relapse is defined as any of the following: 
 
MADRS total score 22 for 2 consecutive assessments. The date of the second MADRS 
assessment will be used for the date of relapse. 
 
Hospitalization for worsening depression or any other clinically relevant event determined 
per clinical judgment to be suggestive of a relapse of depressive illness such as suicide 
attempt, completed suicide, or hospitalization for suicide prevention. If hospitalized for any 
of these events, the start date of hospitalization will be used for the date of relapse. 
Otherwise the date of the event will be used if the subject is not hospitalized. 
 
In case both relapse criteria are met, the earlier date will be defined as the date of relapse for 
this subject. 
9.2.1.3. 
Secondary Efficacy Evaluations (Patient-reported Outcomes) 
9.2.1.3.1. 
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 and is a 5-item questionnaire which 
has been widely used and accepted for assessment of functional impairment and associated 
disability.37,62 The first 3 items assess disruption of (1) work/school, (2) social life, and 
(3) family life/home responsibilities using a 0 to 10 rating scale. The score for the first 3 items 
are summed to create a total score of 0 to 30 where a higher score indicates greater impairment. 
It also has 1 item on days lost from school or work and 1 item on days when underproductive. 
The recall period for this study is 7 days. 
9.2.1.3.2. 
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). 65 Item responses are summed to yield a total score (range of 0 to 21), with higher 
scores indicating more anxiety. The recall period is 2 weeks. 
9.2.2. 
Endpoints 
9.2.2.1. 
Primary Endpoint 
The primary efficacy endpoint is the change in the MADRS total score as measured by the 
change from baseline (prior to randomization) to the end of the 4-week double-blind induction 
phase. 
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9.2.2.2. 
Secondary Endpoints 
The secondary endpoints include the following: 
1. Proportion of responders ( 50% reduction from baseline in MADRS total score) in the 
double-blind induction phase. 
2. Proportion of remitters (MADRS total score  12) in the double-blind induction phase. 
3. Proportion of subjects showing onset of clinical response in the double-blind induction 
phase.  
4. Change from baseline in CGI-S in the double-blind induction phase. 
5. Change from baseline in GAD-7 in the double-blind induction phase.  
6. Change from baseline in SDS total score in the double-blind induction phase. 
7. Time to relapse: 
a. 
In subjects who remit (MADRS total score 12) at the end of the double-blind induction 
phase.  
b. In subjects with response (≥50% reduction from baseline in MADRS total score) but 
who are not in remission at the end of the double-blind induction phase. 
8. Change from baseline in SDS total score in the posttreatment phase.  
9. Change from baseline (prior to the first dose of OL induction phase) in MADRS total score 
in the OL induction phase. 
10. Proportion of responders (50% reduction from baseline in MADRS total score) in the OL 
induction phase. 
11. Proportion of remitters (MADRS total score 12) in the OL induction phase. 
12. Change from baseline (prior to the first dose of OL induction phase) in CGI-S in the OL 
induction phase. 
9.3. 
Pharmacokinetics 
Whole blood samples will be used to evaluate the PK of esketamine (and noresketamine or 
additional metabolites, if warranted). 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 plasma samples. Subject confidentiality will be 
maintained. 
9.3.1. 
Evaluations 
Venous blood samples of approximately 4 mL will be collected for measurement of plasma 
concentrations of esketamine and if warranted, noresketamine or additional metabolites at the 
time points specified in the TIME AND EVENTS SCHEDULE 1 and TIME AND EVENTS 
SCHEDULE 3. The exact dates and times of PK blood sampling must be recorded. Additional 
information about the collection, handling, and shipment of biological samples can be found in 
the Laboratory Manual. 
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9.3.2. 
Analytical Procedures 
Plasma samples will be analyzed to determine concentrations of esketamine (and noresketamine 
or additional metabolites, if warranted) using a validated, specific, achiral, 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 addendum. 
9.3.3. 
Pharmacokinetic Parameters 
The plasma concentration-time data of esketamine (and noresketamine or additional metabolites, 
if warranted) will be analyzed using population PK modeling. Typical population values of basic 
PK parameters (eg, esketamine clearance, distribution volume) 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. 
Pharmacokinetic/Pharmacodynamic Evaluations 
The PK/PD relationship of intranasal esketamine and MADRS total score (and possibly selected 
AEs as additional PD parameters) may be evaluated. If there is any visual trend in graphical 
analysis, suitable models will be applied to describe the PK/PD relationships. The results of the 
PK/PD evaluations will be presented in a separate report. 
9.5. 
Biomarker and Pharmacogenomic (DNA) Evaluations 
During the study, blood will be collected for assessment of biomarkers at the time points 
indicated in the TIME AND EVENTS SCHEDULE 1. 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. Participants also should avoid strenuous exercise for 24 hours prior to sample 
collection. 
In blood, biomarkers (protein) related to (but not limited to) the immune system activity, 
hypothalamic 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. 
Blood samples for DNA analyses will be collected at the time points indicated in the TIME AND 
EVENTS SCHEDULE 1 for the assessment of genetic and epigenetic variation in genes in 
pathways relevant to the effect of esketamine (eg, HPA axis, inflammation, growth factors, 
monoamine transporters, ion channels, and circadian rhythm). 
Genotyping will be conducted only on a single sample; pharmacogenomics and epigenetic 
evaluations may be performed on any/all collected samples. 
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DNA samples will be used for research related to esketamine. They may also be used to develop 
tests/assays related to esketamine. Pharmacogenomic research may consist of the analysis of 1 or 
more candidate genes or of the analysis of genetic and epigenetic markers throughout the 
genome (as appropriate) in relation to esketamine. 
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. 
Further information regarding handling, shipment, and labeling of biological samples will be 
provided in a separate laboratory manual. 
9.6. 
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 EOS/EW 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 1, TIME AND EVENTS 
SCHEDULE 2, and TIME AND EVENTS SCHEDULE 3. Where clinician-administered 
efficacy assessments are concerned, every effort should be made to ensure that all assessments 
are completed by a qualified assessor at the baseline and subsequent assessments are performed 
by the same individual. 
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. 
The TEAEs of special interest will be examined separately (please refer to Section 3.2.6 and 
Section 11.8). 
Clinical Laboratory Tests  
Blood samples for serum chemistry and hematology and a random 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. 
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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 count 
 
-white blood cell count with differential 
 
 
 
Serum Chemistry Panel  
-sodium 
-alkaline phosphatase 
-potassium 
-creatine phosphokinase 
-chloride 
-calcium 
-bicarbonate 
-phosphate 
-blood urea nitrogen 
-albumin 
-creatinine 
-total protein 
-glucose 
 
-aspartate aminotransferase 
 
-alanine aminotransferase 
 
-gamma-glutamyltransferase 
 
-total bilirubin 
 
 
 
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 1, TIME AND EVENTS SCHEDULE 2, and TIME AND EVENTS SCHEDULE 3. 
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 
Lipid panel: total cholesterol, low density lipoprotein (LDL) cholesterol, high density 
lipoprotein (HDL) cholesterol, and triglycerides 
 
Serum and urine pregnancy testing (for women of childbearing potential only) 
 
Urine Drug Screen: barbiturates, methadone, opiates, cocaine, phencyclidine, and 
amphetamine/methamphetamine 
 
The central laboratory will analyze the urine drug screen performed at screening. 
 
TSH (screening only) 
 
HbA1c test (screening only) 
Electrocardiogram (ECG)  
The 12-lead ECG will be collected at time points specified in the TIME AND EVENTS 
SCHEDULE 1 and TIME AND EVENTS SCHEDULE 3. 
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. 
If blood sampling or vital sign measurement is scheduled for the same time point as ECG 
recording, the procedures should be performed in the following order: ECG(s), vital signs, blood 
draw. 
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 exclusionary conditions prior to dosing. 
Vital Signs (Temperature, Heart Rate, Respiratory Rate, Blood Pressure)  
Blood pressure and heart rate measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. For further 
details regarding blood pressure, please see Guidance for Blood Pressure Monitoring on 
Intranasal Dosing Days (Section 6.3.1). 
Blood pressure and heart rate measurements should be preceded by at least 5 minutes of rest in a 
quiet setting without distractions (eg, television, cell phones). 
Tympanic temperature is recommended, but axillary temperature is also allowed. Throughout the 
study, the tempreture condition should be same. 
Pulse Oximetry 
Pulse oximetry will be used to measure arterial oxygen saturation. 
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On each dosing day, the device will be attached to the finger, toe, or ear before the first nasal 
spray of esketamine. Pulse oximetry will be performed every 15 minutes from predose to 
1.5 hours postdose. If <93% at any time during the 1.5-hour postdose interval, pulse oximetry 
will be performed every 5 minutes until returns to 93% or until the subject is referred for 
appropriate medical care, if clinically indicated. Any arterial blood oxygen saturation <93% and 
lasting for more than 2 minutes, and confirmed by an additional manual measurement on another 
part of the body, will be reported as an AE. 
Physical Examination, Height, and Body Weight 
Physical examinations, body weight, and height will be performed or measured as per the TIME 
AND EVENTS SCHEDULE 1 and TIME AND EVENTS SCHEDULE 3. 
BPRS+ 
Four items of the BPRS will be administered to assess treatment-emergent psychotic symptoms. 
The BPRS48 is an 18-item rating scale, which is used to assess a range of psychotic and affective 
symptoms rated from both observation of the subject and the subject's own report. It reportedly 
provides a rapid and efficient evaluation of treatment response in clinic drug studies and in 
clinical settings.57 
Only the 4-item positive symptom subscale (consisting of: suspiciousness, hallucinations, 
unusual thought content and conceptual disorganization) will be used in this study. It is highly 
sensitive to change, and excellent inter-rater reliability can be achieved with training and a 
standard interview procedure. 
C-SSRS 
The C-SSRS will be performed to assess 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.53 It is a 
clinical interview providing a summary of both ideation and behavior that can be administered 
during any evaluation or risk assessment to identify the level and type of suicidality present. The 
C-SSRS can also be used during treatment to monitor for clinical worsening. 
Two versions of the C-SSRS will be used in this study, the baseline/screening version, and the 
Since last visit version. The baseline/screening version of the C-SSRS will be used in the 
screening 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 will be administered to assess treatment-emergent dissociative symptoms. 
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The CADSS is an instrument for the measurement of present-state dissociative symptoms. The 
CADSS comprises 23 subjective items, divided into 3 components: depersonalization (Items 3 to 
7, 20, 23), derealization (Items 1, 2, 8 to 13, 16 to 19, 21) and amnesia (Items 14 and 15, 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. 
CGADR 
The CGADR will be used to measure the subject’s current clinical status and is the clinician’s 
assessment of the readiness to be discharged from the study-site.  
The clinician will answer “Yes” or “No” to the question “Is the subject considered ready to be 
discharged based on their overall clinical status (eg, sedation, blood pressure, and other AEs)?” 
On intranasal treatment session days, the CGADR will be performed at 1 hour, and 1.5 hours 
postdose; if the response is not “Yes” at 1.5 hours postdose, the assessment will be repeated 
every 15 minutes until a “Yes” response is achieved or until the subject is referred for 
appropriate medical care if clinically indicated. A subject should not be discharged prior to the 
1.5-hour time point. 
On all intranasal treatment session days, subjects must remain at the clinical site until study 
procedures have been completed and the subject is ready for discharge. 
MOAA/S 
The MOAA/S will be used to measure treatment-emergent sedation with correlation to levels of 
sedation defined by the American Society of Anesthesiologists (ASA).50 
The MOAA/S scores range from 0 (no response to painful stimulus; corresponds to ASA 
continuum for general anesthesia) to 5 (readily responds to name spoken in normal tone [awake]; 
corresponds to ASA continuum for minimal sedation). 
On each intranasal treatment session day, the MOAA/S will be performed every 15 minutes from 
predose to 1.5 hours postdose.  
 
If the score is 3 at any time during the 1.5-hour postdose interval, the MOAA/S will be 
performed every 5 minutes until a score of 4 is reached (at which point a frequency of every 
15 minutes can be resumed until 1.5-hour postdose).  
 
If a subject does not have a score of at least 5 at 1.5-hour postdose, he/she should continue 
to be monitored. For subjects with a score of 4, the assessment should be repeated every 
15 minutes. And for subjects with a score of 3, the assessment should be repeated every 
5 minutes until the score returns to 5 or the subject is referred for appropriate medical care, 
if clinically indicated. 
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POMS-2 
The POMS-2 will be used to measure the abuse-liability of intranasal esketamine administered 
twice a week for 4 weeks, at time points outlined in TIME AND EVENTS SCHEDULE 1 and 
TIME AND EVENTS SCHEDULE 2.  
The POMS-2 is a self-report measure that allows for the quick assessment of transient, 
fluctuating feelings, and enduring affect states. Full-length versions (65 items) yield several scale 
scores: Anger-Hostility, Confusion- Bewilderment, Depression-Dejection, Fatigue-Inertia, 
Tension-Anxiety, and Vigor-Activity. Total Mood Disturbance is a function of these 6 scale 
scores. The recall period for this study is 7 days. 
PWC-20 
The PWC-20 will be administered to assess potential withdrawal symptoms following cessation 
of intranasal esketamine treatment at time points outlined in TIME AND EVENTS SCHEDULE 
1, TIME AND EVENTS SCHEDULE 2, and TIME AND EVENTS SCHEDULE 3. 
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.55 Discontinuation symptoms occur 
early and disappear rather swiftly, depending upon speed of taper, daily medication dose, and 
drug elimination half-life. 
9.7. 
Other Evaluations 
MINI 
The MINI is a short structured diagnostic interview for DSM-5. It has an administration time of 
approximately 15 minutes to provide accurate structured psychiatric interview for multicenter 
clinical trials. 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. 
MGH-ATRQ 
The MGH-ATRQ is used to determine treatment resistance in MDD.21 Information regarding all 
antidepressant therapies used in the current depressive episode will be recorded on the ATRQ.  
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. 
SAFER Criteria Interview 
Remote, independent psychiatrists/psychologists will perform the SAFER Interview66 for all 
subjects to assess the validity of a diagnosis of depression and eligibility for the study. 
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SAFER refers to: 
S 
State versus trait 
The identified symptoms must reflect the current state of illness and 
not longstanding traits. Traits do not generally change in 4–12 
weeks. 
A 
Assessibility 
The patient’s symptoms are measurable with standard, reliable rating 
instruments. The symptoms of valid subjects can be reliably assessed 
with standardized measurement tools 
F 
Face validity 
The patient’s presentation is consistent with our knowledge of the 
illness (symptoms map to the nosological entity; clear change from 
previous level of function; similar to previous episodes if recurrent) 
E 
Ecological validity 
The patient’s symptoms reflect the characteristics of the illness in a 
real-world setting (frequency, intensity, duration, course, impact over 
at least 4 weeks) 
R 
Rule of the 3 P’s 
Identified symptoms must be pervasive, persistent, and pathologic 
and interfere with function and quality of life 
9.8. 
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 1, TIME AND EVENTS SCHEDULE 2, and 
TIME AND EVENTS SCHEDULE 3 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 study: 
 
If he or she do not respond at the end of 4-week double-blind induction phase; 
 
If he or she relapse during posttreatment phase and complete the OL phase; 
 
If he or she complete 24-week posttreatment phase without relapse. 
Subjects who prematurely discontinue study treatment for any reason before completion of the 
double-blind induction phase will not be considered to have completed the double-blind 
induction phase of the study. In addition, subjects who prematurely discontinue study treatment 
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for any reason before completion of the posttreatment or OL phases, will not be considered to 
have completed the posttreatment phase of the study. 
10.2. 
Withdrawal From the Study 
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 EW 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 induction phase) 
 
Lack of efficacy 
 
The investigator or sponsor believes (eg, that for safety or tolerability reasons such as an 
AE) 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 6.3.1).  
 
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. 
 
Noncompliance to switched oral antidepressant therapy (missing >2 days per consecutive 
7 days) 
 
Subject becomes pregnant 
 
Study is terminated by sponsor for futility 
 
Death 
If the subject withdraws from the study before the end of the double-blind induction phase, an 
EW visit is to be performed. 
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. 
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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 AE 
or lack of efficacy). 
Subjects who wish to withdraw from the study should be asked if they are agreeable 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 induction phase with the reason noted as “Other” and will specify the reason why.  
For a subject who “withdraws consent”, it is recommended that the subject withdraw consent in 
writing; if the subject refuses or is physically unavailable, the study-site should document and 
sign the reason for the subject’s failure to withdraw consent in writing and maintain it with the 
subjects source records. 
The investigator will be responsible for making all required notifications to the Institutional 
Review Board (IRB). 
10.3. 
Withdrawal From the Use of Research Samples 
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 ICF. 
11. 
STATISTICAL METHODS 
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan (SAP). 
11.1. 
Subject Information 
The primary efficacy (FAS) and safety analysis sets are defined below. 
 
Full Analysis Set: All randomized subjects who receive at least 1 dose of intranasal study 
drug in the double-blind induction phase.  
 
Open-label Analysis Set: All subjects who receive at least 1 dose of intranasal study drug 
in the OL induction phase.  
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 
Safety Analysis Set: All randomized subjects who receive at least 1 dose of intranasal study 
drug in the double-blind induction phase. 
11.2. 
Sample Size Determination 
The sample size for this study was calculated assuming a treatment difference for the double-
blind induction phase of 4, 4.5, 5 points in MADRS total score between each dose (28 mg, 56 mg, 
84 mg) of esketamine and the placebo respectively, a SD of 10 for each treatment group, a 1-
sided significance level of 0.05 and a drop-out rate of 12.5%. A total of 183 subjects will need to 
be randomized to treatment in a 2:1:1:1 ratio (72 subjects on placebo group and 37 subjects per 
intranasal esketamine dose group) to achieve 80% power to detect difference for at least one 
dose group of intranasal esketamine to placebo using a Dunnett adjustment. The treatment 
difference and SD used in this calculation were assumed based on results of Panel B of the 
ESKETINTRD2003 study with clinical consideration.16 
11.3. 
Interim Analysis 
No interim analysis is planned. The first database lock will occur after that all subjects will 
complete the double-blind induction phase. 
11.4. 
Efficacy Analyses  
Efficacy analysis will be performed on the FAS, which will include all randomized subjects who 
receive at least 1 dose of intranasal study drug in the double-blind induction phase. Unless 
otherwise specified, a 1-sided significance level of 0.05 will be used. For the primary efficacy 
analysis, change from baseline in MADRS total score at Week 4 in the double-blind induction 
phase will be analyzed using a MMRM. The model will include baseline MADRS total score as 
a covariate, and treatment, day, and day-by-treatment interaction as fixed effects. An 
unstructured variance-covariance matrix will be used. Comparison of each esketamine dose 
groups with the placebo group will be performed with the appropriate contrast using a Dunnett 
adjustment. 
The impact of the missing data on the efficacy results will be assessed using sensitivity analyses. 
The follow-up data from subjects who discontinued the double-blind induction phase will be 
incorporated in the sensitivity analyses. Methods of sensitivity analyses will be specified in the 
SAP. 
For the secondary efficacy analysis, the dose-response relationship will be investigated using the 
MCP-Mod procedure. Details will be provided in the SAP. 
The other secondary efficacy endpoints, the endpoints with continuous values will be analyzed 
by using MMRM similar to the primary endpoint. Comparison of each esketamine group versus 
placebo group will be performed using the appropriate contrast. Binary endpoints will be 
analyzed using Fisher’s exact test with 90% CIs for the proportion provided for each treatment 
group. 
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Time to relapse will be defined as the time between the end of the double-blind induction phase 
and the first documentation of a relapse event during the posttreatment phase. This will be 
analyzed separately either remitters or responders (but who are not remitters) at the end of the 
double-blind induction phase. Summary statistics (eg, number of relapses, number of censored 
subjects, median 25th and 75th percentile) will be provided from the Kaplan-Meier method. 
Additionally, scores and the changes from baseline of all efficacy endpoints will be summarized 
for all visits in the each induction phase. Data from the OL induction phase will be summarized 
based on subjects who received treatment during the OL induction phase. 
11.5. 
Pharmacokinetic Analyses 
Plasma esketamine (and noresketamine and other metabolites, if needed) concentrations will be 
listed for all subjects. Descriptive statistics of plasma esketamine (and noresketamine or other 
metabolites, if needed) concentration at each PK assessment time points will be calculated by 
dose. 
All concentrations below the lowest quantifiable sample concentration of the assay (BQL) or 
missing data will be labeled as such in the concentration data listing. All subjects and samples 
excluded from the analysis will be clearly documented in the study report. 
Population PK analysis of plasma concentration-time data of esketamine (and noresketamine or 
other metabolites, if needed) will be performed with non-linear mixed-effects modeling 
(NONMEM) approach. If deemed necessary, data will be combined with data from other studies. 
Details will be given in a population PK analysis plan and the results of the population PK 
analyses will be presented in a separate report. 
11.6. 
Biomarker and Pharmacogenomic Analyses 
Baseline biomarker values and changes from baseline to the time points specified in the TIME 
AND EVENTS SCHEDULE 1 will be assessed. Biomarker values will be tabulated by treatment 
group over time points and summary statistics will be calculated. Associations between 
biomarkers and clinical endpoints will be explored. Correlations between baseline values and 
change in baseline values with efficacy and other clinical evaluations will be assessed, including 
the relation with response, maintenance of response, illness relapse, and nonresponse.  
Pharmacogenomic analyses may include candidate gene analyses or genome-wide association 
analyses in relation to treatment response, maintenance/stabilization of response, relapse, and 
nonresponse.  
Details of the analysis plan and summary of results from both biomarker and pharmacogenomics 
analyses will be provided in a separate report. 
11.7. 
Pharmacokinetic/Pharmacodynamic Analyses 
The PK/PD relationship of intranasal esketamine and MADRS total score (and possibly selected 
AEs as additional PD parameters may be evaluated. If there is any visual trend in graphical 
analysis, suitable models will be applied to describe the PK/PD relationships. The results of the 
PK/PD evaluation will be presented in a separate report. 
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11.8. 
Safety Analyses 
Safety analysis set will consist of all randomized subjects who receive at least 1 dose of 
intranasal study drug in the double-blind induction phase. Safety data for the double-blind period 
will be analyzed for this population. For the analysis of safety data in the OL induction phase, all 
subjects who received at least 1 dose of intranasal study drug in this period will be analyzed.  
Adverse Events 
For each AE, the number of subjects who experience at least 1 occurrence of the given event will 
be summarized by treatment group.  
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). The TEAEs are AEs with onset during 
the treatment phase or that are a consequence of a preexisting condition that has worsened since 
baseline. All reported AEs 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. In addition, comparisons between treatment groups will be provided if 
appropriate. 
The TEAEs of special interest will be examined separately (please refer to Section 3.2.6). The 
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 AE, or who experience a severe or an 
SAE. 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test. Markedly abnormal results 
(specified in the SAP) will be used in the summary of laboratory data. Descriptive statistics will 
be calculated for each laboratory analyte at each respective scheduled time point in each phase of 
the study. Changes from baseline results will be presented. Frequency tabulations of the 
abnormalities will be made. A listing of subjects with any markedly abnormal laboratory results 
will also be provided. 
Electrocardiogram (ECG) 
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. These tables will include observed values and changes from baseline 
values. 
Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will be 
calculated at baseline and for observed values and changes from baseline at each scheduled time 
point. Frequency tabulations of the abnormalities will be made. 
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The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, 
and corrected QT (QTc) interval using the following correction methods: QT corrected according 
to Bazett's formula (QTcB) and QTcF.2,31,60 
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each 
scheduled time point. The percentage of subjects with QTc interval >450 milliseconds, 
>480 milliseconds, or >500 milliseconds will be summarized, as will the percentage of subjects 
with QTc interval increases from baseline >30 milliseconds or >60 milliseconds. 
All clinically relevant 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, heart rate, pulse oximetry, respiratory rate, 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. 
Physical Examination 
Results of physical examinations (abnormalities) will be listed. 
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.  
PWC-20, CADSS, CGADR, MOAA/S, BPRS+, and POMS-2 
Physician Withdrawal Checklist; 20-item (PWC-20) rating scale, dissociative data from the 
CADSS, alertness data from the CGADR, sedation data from the MOAA/S, psychosislike effect 
data from the BPRS+ and abuse-liability data from POMS-2 will be summarized descriptively at 
each scheduled visit by treatment group. 
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 AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonization [ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 12.3.1, All 
AEs, for time of last AE recording). Exacerbation of primary disease is not defined as AE. 
Serious Adverse Event 
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is a suspected transmission of any infectious agent via a medicinal product 
 
Is Medically Important* 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent 1 of the other outcomes listed in the definition above. 
These should usually be considered serious. 
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
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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 AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For esketamine, the expectedness of an AE will be 
determined by whether or not it is listed in the Investigator's Brochure.  
Adverse Event Associated With the Use of the Drug 
An AE is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 12.1.2, Attribution Definitions. 
12.1.2. 
Attribution Definitions 
Not Related 
An AE that is not related to the use of the drug. 
Doubtful 
An AE 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 AE 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 AE 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 AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in time 
is very suggestive (eg, it is confirmed by dechallenge and rechallenge). 
12.1.3. 
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors: 
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities. 
Moderate: Sufficient discomfort is present to cause interference with normal activity. 
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Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities. 
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities). 
12.2. 
Special Reporting Situations 
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation or both include, but are not limited to: 
 
Overdose of a sponsor study drug 
 
Suspected abuse/misuse of a sponsor study drug 
 
Accidental or occupational exposure to a sponsor study drug 
 
Medication error involving a sponsor product (with or without subject exposure to the 
sponsor study drug, eg, name confusion) 
 
Exposure to a sponsor study drug from breastfeeding 
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the eCRF. 
12.3. 
Procedures 
12.3.1. 
All Adverse Events 
All AEs and special reporting situations, whether serious or non-serious, will be reported from 
the time a signed and dated ICF is obtained until completion of the subject's last study-related 
procedure, which may include contact for follow-up of safety. Serious AEs, including those 
spontaneously reported to the investigator until completion of the subject's last study-related 
procedure, must be reported using the SAE 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 an SAE will be reported as SAEs, regardless of whether 
they are protocol-specific assessments.  
All AEs, 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 AE to study therapy. All measures required for AE management must be recorded in the 
source document and reported according to sponsor instructions. 
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
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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 OL studies, the subject must be provided with 
a "wallet (study) card" and instructed to carry this card with them for the duration of the study 
indicating the following:  
 
Study number 
 
Statement, in the local language(s), that the subject is participating in a clinical study 
 
Investigator's name and 24-hour contact telephone number 
 
Local sponsor's name and 24-hour contact telephone number (for medical staff only) 
 
Site number 
 
Subject number 
 
Any other information that is required to do an emergency breaking of the blind 
12.3.2. 
Serious Adverse Events 
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event. 
Information regarding SAEs will be transmitted to the sponsor using the SAE 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 an SAE should be made by facsimile (fax). 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
 
The event resolves 
 
The event stabilizes 
 
The event returns to baseline, if a baseline value/status is available 
 
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
 
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts) 
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
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course of a subject's participation in a study must be reported as an SAE, except hospitalizations 
for the following: 
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as 
pending placement in long-term care facility). 
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE. 
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 an SAE. 
12.3.3. 
Pregnancy 
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs 
and must be reported using the SAE 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. 
12.4. 
Contacting Sponsor Regarding Safety 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document. 
13. 
PRODUCT QUALITY COMPLAINT HANDLING 
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. 
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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 an SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.3.2, Serious Adverse 
Events). A sample of the suspected product should be maintained for further investigation if 
requested by the sponsor. 
13.2. 
Contacting Sponsor Regarding Product Quality 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document. 
14. 
STUDY DRUG INFORMATION 
14.1. 
Physical Description of Study Drugs 
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/mL 
of esketamine base) formulated in 0.12 mg/mL ethylenediaminetetraacetic acid (EDTA) and 
1.5 mg/mL citric acid at a pH of 4.5 in water for injection. It is provided in a nasal spray pump, 
which delivers 16.14 mg esketamine hydrochloride (14 mg esketamine base) per 100 L spray. 
Each individual nasal spray pump (device) contains a total of 28 mg (ie, 2 sprays).  
The placebo solution will be supplied as a clear, colorless intranasal solution of water for injection, 
with a bittering agent (denatonium benzoate [Bitrex®] at a final concentration of 0.001mg/mL) 
added to simulate the taste of the intranasal solution with active drug. 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.32 
14.2. 
Packaging 
Intranasal Study Drug 
Study drug (ie, intranasal esketamine and placebo solution) will be supplied by the sponsor in a 
bi-dose nasal spray device. The devices will contain 200 µL. Each device delivers 16.14 mg 
esketamine hydrochloride (14 mg esketamine base) or 0.1 µg of denatonium benzoate per 100 µL 
spray. 
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Each nasal spray device will be individually packaged in a blister tray and subsequently put into a 
carton box. Each carton box constitutes a non-child-resistant subject kit, labeled with a unique 
medication kit number. 
Device for Practicing Intranasal Study Drug Administration 
The demonstration intranasal device will also be supplied by the sponsor and will contain placebo 
solution. Subjects will practice spraying into the air and will not spray intranasally. 
14.3. 
Labeling 
Study drug labels will contain information to meet the applicable regulatory requirements. 
14.4. 
Preparation, Handling, and Storage 
Study drug will be stored at the study-site in a secure area with restricted access until dispensed to 
the subjects.  
All study drugs must be stored at controlled temperatures as indicated on the product-specific 
labeling. 
Please refer to the pharmacy manual/study-site investigational product (IP) 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 drugs 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 drug return form. When the study-site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form. 
Potentially hazardous materials such as used ampoules, 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.  
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Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject.  
Whenever a subject brings his or her study drug to the study-site for pill count, this is not seen as 
a return of supplies. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study-sites agreed upon with the sponsor. 
15. 
STUDY-SPECIFIC MATERIALS 
The investigator will be provided with the following supplies: 
 
Practice intranasal devices 
 
Investigator's Brochure for esketamine 
 
IP Binder, including the IP Procedures Manual 
 
Laboratory manual and materials 
 
Clinician-administered and subject-reported outcome assessments (paper versions, as 
applicable) 
 
IWRS Manual 
 
ECG equipment and associated materials (eg, manual) 
 
Instructions for Use documents (healthcare provider versions) for intranasal study drug 
 
Rater qualifications/requirements for select clinician-administered assessments 
 
Procedural documents for SAFER interview 
 
Procedural documents for remote MADRS interviews 
 
MGH-ATRQ Guidance document 
 
Sample ICF 
 
CRF completion guideline 
 
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 TRD. 
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Studies with esketamine have shown robust antidepressant effects in several clinical studies and 
it has been well-tolerated in these clinical studies. 
Selection of Subjects 
The primary aim of the study is to evaluate the efficacy of fixed dosed intranasal esketamine 
compared to intranasal placebo, as an add-on to an oral antidepressant in Japanese subjects with 
TRD, in improving depressive symptoms.  
Potential subjects will be fully informed of the risks and requirements of the study and, during 
the study, subjects will be given any new information that may affect their decision to continue 
participation. 
They will be told that their consent to participate in the study is voluntary and may be withdrawn 
at any time with no reason given and without penalty or loss of benefits to which they would 
otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential AEs of the study, and provide their consent voluntarily will be enrolled. 
Justification for Using Placebo 
Intranasal placebo is being used as a double-blind for intranasal esketamine to maintain study 
blinding. All subjects will also receive an oral antidepressant from the prospective lead-in 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 to intranasal placebo, 
as an add-on to an oral antidepressant. 
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.56 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.35 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 induction phase is relatively short (4-week duration). 
Subjects will visit the study-site at least twice a week during the double-blind induction phase, 
and their symptoms will be carefully monitored during each study visit. Safety evaluations will 
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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. 
Subjects who relapsed in the posttreatment phase will receive a 4-week OL induction treatment 
course of intranasal esketamine. 
During follow-up phase further clinical/standard-of-care treatment will be arranged by the study 
investigator. 
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 an oral antidepressant). Potential disadvantages and AEs 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. 
The primary ethical concerns of this study is that exposure to esketamine in Japanese subjects 
may be higher compared with non-Japanese populations at the same dose. Plasma esketamine 
Cmax and AUC values were up to 48% higher in Japanese subjects compared with Caucasian 
subjects following intranasal doses of 28 mg, 56 mg, and 84 mg of esketamine 
(ESKETINTRD1002).13 In Phase 2 Study, plasma esketamine concentrations in Japanese 
patients who received 56 mg of esketamine were higher relative to the corresponding 
concentrations produced by the same esketamine dose administered in non-Japanese patients, 
consistent with results from Phase 1 Study ESKETINTRD1002.13 Assuming the increase in 
exposure due to an increase in ethnicity is observed, exposure to esketamine may be up to 48% 
higher than non-Japanese patients for the 84 mg dose. However, this exposure to esketamine is 
still expected to be lower than the exposure typically used to induce and maintain anesthesia. 
Dosing of subjects within a treatment group will be staggered to provide sufficient time for 
adequate safety monitoring. Vital signs will be assessed before and repeatedly following study 
drug administration, particularly to monitor transient increases in blood pressure. If blood 
pressure exceeds predefined limits before dosing, study drug administration may be postponed or 
the subject may be withdrawn from the study after repeated predose blood pressure exceeds the 
predefined limits. Refer Section 6.3.1 for guidance on blood pressure monitoring on intranasal 
treatment session days. 
Compensation for any procedure will be fair per local standards and approved by the 
participating sites IEC/IRB in order to not offer any undue incentive to participate in the study. 
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Subjects will be carefully monitored during the study and subjects who are unable to tolerate 
study drug during the double-blind induction 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 6.3.1). 
Only subjects who had nonresponse to their current oral antidepressant medication, 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 volume of blood collected is considered to be a clinically acceptable volume of blood 
to be collected over this time period for biomarkers, PK, pharmacogenomic and safety tests in 
this study and is less than the standards of the Japan Red Cross for blood donations. 
16.2. 
Regulatory Ethics Compliance 
16.2.1. 
Investigator Responsibilities 
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible. 
16.2.2. 
Independent Ethics Committee or Institutional Review Board 
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations): 
 
Final protocol and, if applicable, amendments 
 
Sponsor-approved ICF (and any other written materials to be provided to the subjects) 
 
Investigator's Brochure (or equivalent information) and amendments/addenda 
 
Sponsor-approved subject recruiting materials 
 
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 
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 
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, unless required locally), the ICF, applicable recruiting materials, 
and subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved. 
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate: 
 
Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct) 
 
Revision(s) to ICF and any other written materials to be provided to subjects 
 
If applicable, new or revised subject recruiting materials approved by the sponsor 
 
Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable 
 
New edition(s) of the Investigator's Brochure and amendments/addenda 
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually) 
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug 
 
New information that may adversely affect the safety of the subjects or the conduct of the 
study 
 
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
 
Report of deaths of subjects under the investigator's care 
 
Notification if a new investigator is responsible for the study at the site 
 
Development Safety Update Report and Line Listings, where applicable 
 
Any other requirements of the IEC/IRB 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).  
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required. The reapproval should be documented in writing (excluding the ones that are purely 
administrative, with no consequences for subjects, data, or study conduct). 
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion. 
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16.2.3. 
Informed Consent 
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-
related activity. The ICF(s) that is/are used must be approved by both the sponsor and by the 
reviewing IEC/IRB and be in a language that the subject can read and understand. The informed 
consent should be in accordance with principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy. 
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his or her disease. Subjects will be told 
that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow-up if needed and that their records 
may be accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject is authorizing such access, which includes permission to obtain 
information about his or her survival status. It also denotes that the subject agrees to allow his or 
her study physician to recontact the subject for the purpose of obtaining consent for additional 
safety evaluations, if needed. 
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject. 
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 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. 
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The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries. 
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations. 
Exploratory DNA and biomarker research is not conducted under standards appropriate for the 
return of data to subjects. In addition, the sponsor cannot make decisions as to the significance of 
any findings resulting from exploratory research. Therefore, exploratory research data will not be 
returned to subjects or investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data. 
16.2.5. 
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand esketamine to 
understand differential drug responders, and to develop tests/assays related to esketamine. The 
research may begin at any time during the study or the poststudy 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. 
17. 
ADMINISTRATIVE REQUIREMENTS 
17.1. 
Protocol Amendments 
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, 
or when the relevant competent authority has raised any grounds for non-acceptance, except 
when necessary to eliminate immediate hazards to the subjects, in which case the amendment 
must be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When 
the change(s) involves only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified. 
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate 
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document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it. 
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) 
 
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) 
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 
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 documents consistent in the type and level of detail with that commonly 
recorded at the study-site as a basis for standard medical care must be available for the 
following: subject identification, eligibility, and study identification; study discussion and date of 
signed informed consent; dates of visits; results of safety and efficacy parameters as required by 
the protocol; record of all AEs and follow-up of AEs; 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.  
In addition, the author of an entry in the source documents should be identifiable. 
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study-site as a basis for standard medical care. 
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document). 
The following data will be recorded directly into the eCRF and will be considered source data:  
 
Race 
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 
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 
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 eCRF 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 eCRF. Data in this system 
may be considered source documentation. 
17.5. 
Case Report Form Completion 
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
All eCRF entries, corrections, and alterations must be made by the investigator or authorized 
study-site personnel. The investigator must verify that all data entries in the eCRF are accurate 
and correct. 
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. Study-specific data will be 
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. Data must be entered into 
eCRF in English. The eCRF must be completed as soon as possible after a subject visit and the 
forms should be available for review at the next scheduled monitoring visit. 
If necessary, queries will be generated in the eDC tool. If corrections to a 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, uploading data 
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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.  
The sponsor will review eCRF for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources. 
17.7. 
Record Retention 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each 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 IP. These documents will be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the sponsor. 
It is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor. 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports. 
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 data entered into the eCRF with the source documents (eg, 
hospital/clinic/physician’s office medical records); a sample may be reviewed. The nature and 
location of all source documents will be identified to ensure that all sources of original data 
required to complete the eCRF are known to the sponsor and study-site personnel and are 
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accessible for verification by the sponsor study-site contact. If electronic records are maintained 
at the study-site, the method of verification must be discussed with the study-site personnel.  
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the data recorded are consistent with the original source data. Findings from this 
review will be discussed with the study-site personnel. The sponsor expects that, during 
monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related documents. 
The monitor will meet with the investigator on a regular basis during the study to provide 
feedback on the study conduct. 
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site. 
17.9. 
Study Completion/Termination 
17.9.1. 
Study Completion/End of Study 
The study is considered completed with the last scheduled study assessment for the last subject 
participating in the study. The final data from the study-site will be sent to the sponsor (or 
designee) after completion of the final subject assessment at that study-site, in the time frame 
specified in the Clinical Trial Agreement. 
17.9.2. 
Study Termination 
The sponsor reserves the right to close the study-site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study-sites will be closed upon study completion. A 
study-site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study-site by the sponsor or investigator may include but are 
not limited to: 
 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines 
 
Inadequate recruitment of subjects by the investigator  
 
Discontinuation of further study drug development 
17.10. On-Site Audits 
Representatives of the sponsor's clinical quality assurance department may visit the study-site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
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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. 
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of esketamine, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information 
derived from the clinical studies to be used, the investigator is obligated to provide the sponsor 
with all data obtained in the study. 
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study-sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of 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 
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for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study-site until the combined results from the completed study 
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version. 
Registration of Clinical Studies and Disclosure of Results 
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law. 
 
 
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Attachment 1: Prohibited Concomitant Medications 
This list of medications is not all-inclusive; if necessary, please contact the medical monitor for any 
questions regarding a medication(s). 
Please refer to the prescribing information of the subject’s oral antidepressant medication for information 
regarding prohibited concomitant medications (if subjects don't have the follow up phase, they are 
prohibited until end of study).  
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 drug until the 
beginning of the follow up phase.  
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 prospective lead-in 
phase of the study) 
N 
N 
- Only 1 of the 6 predefined oral 
antidepressant treatment options are 
permitted 
- If a subject is taking a monoamine 
oxidase inhibitor (MAOI), there must 
be a minimum washout interval of 2 
weeks prior to the first dose of 
intranasal study drug. 
- Even if used for indication other than 
MDD (eg, trazodone or low dose 
tricyclic antidepressants for sleep), the 
use of any medication listed on the 
ATRQ, is not permitted during the 
treatment phase.   
Safety and PD 
interaction 
Antipsychotics (including 
sulpiride) 
N 
N 
 
PD interaction
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Drug Class 
Episodic 
Use (as 
needed) 
Continuous 
Use 
Comments 
Reason for 
Prohibition 
Benzodiazepines (at 
dosages equal to or less 
than the equivalent of 
6 mg/day lorazepam) and 
non-benzodiazepine 
sleeping medication 
(including: zolpidem, 
zaleplon, eszopiclone, and 
ramelteon) 
N 
Y 
Subjects who were taking these during 
the screening phase, can continue them 
throughout the study; however, dose 
increases or starting new 
benzodiazepine medications are not 
permitted. Prohibited within 12 hours 
prior to the start of each intranasal 
treatment session 
Safety and PD 
interaction 
Benztropine 
Y 
N 
 
Safety and PD 
interaction.  
Chinese herbal medicine, 
which are psychoactive 
N 
N 
 
PD interaction
Chloral hydrate, 
melatonin, valerian 
N 
N 
 
Safety and PD 
interaction 
Clonidine 
N 
N 
 
Safety and PD 
interaction 
Corticosteriods (systemic) 
Y 
N 
Inhaled, intranasal, topical, and 
ophthalmic steroids are not prohibited. 
Intermittent IM/IV corticosteroids are 
permitted (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 drug 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 drug 
until at least 24 hours after the last 
intranasal dose of study drug. 
 
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 
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Drug Class 
Episodic 
Use (as 
needed) 
Continuous 
Use 
Comments 
Reason for 
Prohibition 
Dopamine agonists 
N 
Y 
Subjects who were taking these 
medications at the start of the screening 
phase, can continue them throughout the 
study; however, dose increases or 
starting new dopamine agonists are not 
permitted. 
The dopamine agonists must be 
continued at a stable dose for 1 month 
prior to the beginning of the screening 
phase. 
PD interaction
Ketanserin 
N 
N 
 
Safety 
Lithium 
N 
N 
 
PD interaction
Memantine 
N 
N 
 
PD interaction
Methyldopa 
N 
N 
 
Safety and PD 
Interaction 
Metyrosine 
N 
N 
 
Safety and PD 
interaction 
Non-vitamin K antagonist 
oral anticoagulation agents 
(eg, dabigatran, 
rivaroxaban, apixaban 
N 
N 
 
Safety 
Opioids 
N 
N 
 
PD interaction
Psychostimulants  
(eg, amphetamines, 
methylphenidate, and 
modafanil, armodafinl) 
N 
N 
 
Cardiovascular 
safety 
ADHD medications (eg, 
atomoxetine, guanfacine) 
N 
N 
See also “Psychostimulants” row. 
Safety 
Reserpine 
N 
N 
 
PD interaction
Scopolamine 
N 
N 
 
PD interaction
St. John’s Wort 
N 
N 
 
PD interaction 
and PK 
Thyroid hormone 
supplement for treatment 
of thyroid condition only 
(not for depression) 
N 
Y 
 
Safety 
Thyroxine/ 
triiodothyronine (T3), 
thyroid hormone 
prescribed for depression 
N 
N 
 
PD interaction
Warfarin 
N 
N 
 
Primary 
condition 
where used is 
excluded 
Abbreviations: N, Prohibited; PD, pharmacodynamics; PK, pharmacokinetics; Y, Permitted, with restrictions (please 
refer to the column labeled “Comments” for additional guidance). 
 
 
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Attachment 2: New York Heart Association Classification of Cardiac Disease 
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: Example of the Up-titration Schedule for a New Oral Antidepressant Therapy 
(Physician Determined) in Prospective Lead-in Phase 
 
Antidepressant 
 
Approved 
Dose in Japan  
(Min./ Max.) 
Example of Up-titration Schedule in Prospective Lead-in Phase 
Class 
Drug 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
SSRI 
Escitalopram 
10/ 20 mg 
10 mga 
20 mg 
20 mg 
20 mg 
20 mg 
20 mg 
  
Paroxetine 
CR 
12.5/ 50 mg 
12.5 mg
25 mga 
37.5 mg
50 mg 
50 mg 
50 mg 
  
Sertraline 
25/ 100 mg 
25 mg 
50 mga 
100 mg 
100 mg 
100 mg 
100 mg 
SNRI 
Duloxetine 
20/ 60 mg 
20 mg 
40 mga 
60 mg 
60 mg 
60 mg 
60 mg 
  
Venlafaxine 
XR 
37.5/ 225 mg 
37.5 mg
75 mg 
150 mga
225 mg 
225 mg 
225 mg 
NaSSA 
Mirtazapine 
15/ 45 mg 
15 mga 
30 mg 
45 mg 
45 mg 
45 mg 
45 mg 
 
Note: New oral antidepressant treatment should be titrated to the approved maximum dose, to optimize the potential 
for response. The uptitration schedule should follow respective prescribing information in Japan. The dose, 
which is above the minimum therapeutic dose defined in MGH-ATRQ should be kept at last 4 weeks during the 
prospective lead-in phase, in case they start at lower doses. 
a. Minimum effective dose for oral antidepressant drug which is defined in MGH-ATRQ.  
 
 
 
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JNJ-54135419 (esketamine) 
 
 
 
Clinical Protocol 54135419TRD2005 Amendment 5 
142 
Approved, Date: 21 December 2018  
INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality. 
 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date:
 
 
 
 
(Day Month Year) 
 
Sponsor's Responsible Medical Officer: 
 
Name (typed or printed): 
Takuto Tokudome 
Signature: 
electronic signature appended at the end of the protocol 
Date:
 
 
 
 
(Day Month Year) 
 
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required. 
 
NCT02918318


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Takuto Tokudome
21Dec2018, 07:38:07 AM, UTC
Document Approval
NCT02918318

SAP_001.pdf: 
1 
Approved, Date: 14 January 2020 
 
Janssen Pharmaceutical K.K.  
 
 
Statistical Analysis Plan 
 
A Randomized, Double-blind, Multicenter, Placebo-controlled Study to Evaluate the 
Efficacy, Safety and Tolerability of Fixed Doses of Intranasal Esketamine in Japanese 
Subjects With Treatment Resistant Depression 
 
Protocol 54135419TRD2005; Phase 2b 
 
JNJ-54135419 (esketamine) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Status: 
Approved 
Date: 
14 January 2020 
Prepared by: 
Janssen Pharmaceutical K.K. 
Document No.: EDMS-ERI-133038896 
 
 
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. 
NCT02918318


JNJ-54135419  (esketamine) 
 
 
 
Statistical Analysis Plan 54135419TRD2005 
2 
Approved, Date: 14 January 2020 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
AMENDMENT HISTORY .............................................................................................................................. 4 
ABBREVIATIONS ........................................................................................................................................ 6 
1. 
INTRODUCTION .................................................................................................................................. 7 
1.1. 
Trial Objectives ................................................................................................................................ 7 
1.2. 
Trial Design ...................................................................................................................................... 8 
1.3. 
Statistical Hypotheses for Trial Objectives ..................................................................................... 12 
1.4. 
Sample Size Justification ............................................................................................................... 12 
1.5. 
Randomization and Blinding .......................................................................................................... 13 
2. 
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 14 
2.1. 
Analysis Phases ............................................................................................................................. 14 
2.1.1. 
Study Reference Start and End Dates ....................................................................................... 14 
2.1.2. 
Analysis Phase Start and End Dates .......................................................................................... 14 
2.1.3. 
Study Day and Relative Day ....................................................................................................... 15 
2.2. 
Baseline and End Point .................................................................................................................. 15 
2.3. 
Visit Windows ................................................................................................................................. 16 
2.4. 
Analysis Sets .................................................................................................................................. 21 
2.4.1. 
All Randomized Analysis Set ...................................................................................................... 21 
2.4.2. 
Full Analysis Set (FAS) ............................................................................................................... 21 
2.4.3. 
Safety Analysis Set ..................................................................................................................... 21 
2.4.4. 
Follow-up Analysis Set ............................................................................................................... 21 
2.4.5. 
Pharmacokinetic Analysis Set .................................................................................................... 22 
2.4.6. 
Pharmacokinetic/pharmacodynamic (PK/PD) Analysis Set ....................................................... 22 
2.5. 
Definition of Subgroups .................................................................................................................. 22 
2.6. 
Imputation Rules for Missing Adverse Event (AE) Dates .............................................................. 22 
2.7. 
Imputation Rules for Missing AE Time of Onset/Resolution .......................................................... 23 
2.8. 
Imputation Rules for Missing Concomitant Medication Dates ....................................................... 23 
3. 
SUBJECT INFORMATION ................................................................................................................ 24 
3.1. 
Demographics and Baseline Characteristics ................................................................................. 24 
3.2. 
Disposition Information ................................................................................................................... 25 
3.3. 
Extent of Exposure ......................................................................................................................... 26 
3.4. 
Protocol Deviations ........................................................................................................................ 26 
3.5. 
Prior and Concomitant Medications ............................................................................................... 27 
4. 
EFFICACY ......................................................................................................................................... 27 
4.1. 
Analysis Specifications ................................................................................................................... 27 
4.1.1. 
Level of Significance ................................................................................................................... 27 
4.1.2. 
Data Handling Rules ................................................................................................................... 27 
4.1.3. 
Imputation Methods for Missing Items ........................................................................................ 27 
4.2. 
Primary Efficacy Endpoint .............................................................................................................. 28 
4.2.1. 
Definition ..................................................................................................................................... 28 
4.2.2. 
Primary Estimand ....................................................................................................................... 28 
4.2.3. 
Analysis Methods ........................................................................................................................ 28 
4.2.3.1. 
MMRM ..................................................................................................................................... 28 
4.2.3.2. 
Model Diagnostics ................................................................................................................... 29 
4.2.3.3. 
MCP-Mod Analysis .................................................................................................................. 29 
4.2.3.4. 
Missing Data Sensitivity Analysis ............................................................................................ 31 
4.2.3.5. 
Subgroup Analysis ................................................................................................................... 31 
4.3. 
Secondary Endpoints ..................................................................................................................... 32 
4.3.1. 
Responders ................................................................................................................................ 32 
4.3.1.1. 
Definition .................................................................................................................................. 32 
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Statistical Analysis Plan 54135419TRD2005 
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4.3.1.2. 
Analysis Methods .................................................................................................................... 32 
4.3.2. 
Remitters .................................................................................................................................... 32 
4.3.2.1. 
Definition .................................................................................................................................. 32 
4.3.2.2. 
Analysis Methods .................................................................................................................... 32 
4.3.3. 
Time to Relapse .......................................................................................................................... 33 
4.3.3.1. 
Definition .................................................................................................................................. 33 
4.3.3.2. 
Analysis Methods .................................................................................................................... 33 
4.3.4. 
Onset of Clinical Response ........................................................................................................ 33 
4.3.4.1. 
Definition .................................................................................................................................. 33 
4.3.4.2. 
Analysis Methods .................................................................................................................... 34 
4.3.5. 
CGI-S .......................................................................................................................................... 34 
4.3.5.1. 
Definition .................................................................................................................................. 34 
4.3.5.2. 
Analysis Methods .................................................................................................................... 34 
4.3.6. 
Sheehan Disability Scale (SDS) ................................................................................................. 34 
4.3.6.1. 
Definition .................................................................................................................................. 34 
4.3.6.2. 
Analysis Methods .................................................................................................................... 35 
4.3.7. 
GAD-7 ......................................................................................................................................... 35 
4.3.7.1. 
Definition .................................................................................................................................. 35 
4.3.7.2. 
Analysis Methods .................................................................................................................... 35 
4.3.8. 
MADRS ....................................................................................................................................... 35 
4.3.8.1. 
Definition .................................................................................................................................. 35 
4.3.8.2. 
Analysis Methods .................................................................................................................... 36 
5. 
SAFETY ............................................................................................................................................. 36 
5.1. 
Adverse Events .............................................................................................................................. 36 
5.2. 
Clinical Laboratory Tests................................................................................................................ 37 
5.3. 
Vital Signs, Weight, and BMI ......................................................................................................... 38 
5.4. 
Electrocardiogram .......................................................................................................................... 39 
5.5. 
Other Safety Parameters ............................................................................................................... 40 
5.5.1. 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................... 40 
5.5.2. 
Clinician Administered Dissociative States Scale (CADSS) ....................................................... 41 
5.5.3. 
Brief Psychiatric Rating Scale (BPRS) ....................................................................................... 41 
5.5.4. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) .......................................... 42 
5.5.5. 
Clinical Global Assessment of Discharge Readiness (CGADR) ................................................ 42 
5.5.6. 
Physician Withdrawal Checklist (PWC-20) ................................................................................. 43 
5.5.7. 
Profile of Mood States 2nd edition (POMS-2) .............................................................................. 43 
6. 
PHARMACOKINETICS/PHARMACODYNAMICS ANALYSIS ........................................................ 44 
6.1. 
Pharmacokinetics (Plasma concentrations) ................................................................................... 44 
6.1.1. 
Statistical Analysis of Pharmacokinetics: (Descriptive Statistics) ............................................... 44 
6.1.2. 
Generating Pharmacokinetic Profiles ......................................................................................... 45 
6.2. 
Pharmacokinetic/Pharmacodynamic Relationships ....................................................................... 45 
REFERENCES ............................................................................................................................................ 47 
ATTACHMENTS ......................................................................................................................................... 48 
ATTACHMENT 1: 
CRITERIA OF MARKEDLY ABNORMAL LABORATORY VALUES ...................... 48 
 
 
 
 
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Statistical Analysis Plan 54135419TRD2005 
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Approved, Date: 14 January 2020 
AMENDMENT HISTORY 
SAP Version  
Issue Date 
Original SAP 
20 Oct 2017 
Amendment 1 
29 June 2018 
Amendment 2 
10 Sep 2019 
Amendment 3 
14 Jan 2020 
 
Amendments below are listed beginning with the most recent amendment. 
Amendment 3 (14 Jan 2020) 
The overall reason for the amendment: to add additional PK/PD analysis 
 
Applicable Section(s) 
Description of Change (s) 
Section 2.3 
In visit window: Added week 6 (PT) and week 8 (PT) for PWC-20 
Section 6.1 
Added timepoints to boxplots 
Section 6.2 
PK/PD analysis: a) Added a safety parameter (CADSS total score); b) Added 
changes from predose for CADSS, SBP and DBP, changes from baseline for 
QTcF; c) By phases 
 
Amendment 2 (10 Sep 2019) 
The overall reason for the amendment: to update and clarify the details 
 
Applicable Section(s) 
Description of Change (s) 
Section 2.3 
In visit window: a) corrected the baseline for OL phase, ‘Baseline (DB)’ to 
‘Baseline (OL). b) updated HR to PULSE under vital signs part 
Section 2.5 
Added subgroup ‘Concomitant use of benzodiazepine including sleep aids (Y/N)’ 
Sections 2.5, 3.1 
Added ‘1’ to the number of major depressive episodes (allowed enrollment of 
subjects with single episodes in protocol amend 4) 
Added “Had been considered to be eligible for electroconvulsive therapy (Y/N)” 
Clarified the definition for previous treatment as ‘Number of Previous Treatments 
in Current Episode’. 
Section 3.1 
Added ‘Functional Impairment based on Baseline SDS Total Score (not impaired 
[0-3], mild [4-11], moderate [12-19], marked [20-26] or extreme [27-30])’ 
Section 3.3 
Clarified the rule of mode dose by adding ‘The lowest mode dose is selected in 
case of ties’ 
Section 4.2.3.1 
Specified the denominator degrees of freedom method 
Section 4.3.3.2 
Time to relapse analysis by combined esketamine groups and placebo is added 
Section 5.1 
AE of special interest has been updated to follow global phase 3 trials. 
 
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Statistical Analysis Plan 54135419TRD2005 
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Approved, Date: 14 January 2020 
Amendment 1 (29 June 2018) 
The overall reason for the amendment: to update analysis phases by separating posttreatment phase from double-
blind follow-up phase 
 
Applicable Section(s) 
Description of Change (s) 
Section 2.1 
Updated analysis phases. ‘A Double-blind Follow-up Phase’ is splitted into ‘A 
Double-blind Follow-up Phase (Non-Responders or subjects who withdraw from 
DB induction phase)’ and ‘A Posttreatment Phase (Responders only). 
Updated the definition of analysis phases and the start and end dates. 
Sections 2.4.3, 2.4.4 
Updated analysis sets based on analysis phases. 
Section 2.5 
Removed subgroup ‘Concomitant use of Adjunctive antipsychotics (Y/N)’ 
Sections 2.5, 3.1 
Excluded sleep aids from benzodiazepine. 
Section 4.2.3.3 
To follow TRD2003, the method to select the dose-response model is changed from 
‘Tmax’ to ‘AIC’. 
One candidate model changed from exponential(δ=-58.2) to exponential(δ=58.2).  
Section 5.1 
Added additional analysis for AE 
AE of special interest has been updated to follow global phase 3 trials 
Section 5.3 
Added additional analysis for vital signs.  
Sections 5.5.4, 5.5.6, 5.5.7 
Added additional analysis for MOAA/S, PWC-20 and POMS-2 
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JNJ-54135419  (esketamine) 
 
 
 
Statistical Analysis Plan 54135419TRD2005 
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Approved, Date: 14 January 2020 
ABBREVIATIONS 
 
AD 
antidepressant 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ASA 
American Society of Anesthesiologists 
BMI 
body mass index 
BP 
Blood Pressure 
BPRS+ 
Four-item positive symptom subscale of the Brief Psychiatric Rating Scale 
CADSS 
Clinician Administered Dissociative States Scale 
CGADR 
Clinical Global Assessment of Discharge Readiness 
CGI-S 
Clinical Global Impression – Severity 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DB 
Double-blind 
D/C 
discontinued 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
F/U 
Follow-Up 
GAD-7 
Generalized Anxiety Disorder 7-item scale 
ICH 
International Conference on Harmonization 
LOCF 
last observation carried forward 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effects model using repeated measures 
MOAA/S 
Modified Observer’s Assessment of Alertness/Sedation 
OL 
open-label 
PBO 
placebo 
PD 
Pharmacodynamics 
PK 
pharmacokinetic(s) 
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 
XR 
extended release 
 
 
 
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JNJ-54135419  (esketamine) 
 
 
 
Statistical Analysis Plan 54135419TRD2005 
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Approved, Date: 14 January 2020 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analyses for the clinical study report (CSR) for study 
54135419TRD2005. 
This SAP does not include planned analyses on biomarkers or pharmacogenomics data which 
will be specified as appropriate in separate documents. 
1.1. 
Trial Objectives 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of fixed dosed intranasal 
esketamine compared to intranasal placebo, as an add-on to an oral antidepressant in Japanese 
subjects with treatment-resistant depression (TRD), in improving depressive symptoms.  
Secondary Objective 
 
To assess the effect of intranasal esketamine compared with intranasal placebo as an add-on 
to an oral antidepressant in Japanese subjects with TRD, including the following parameters: 
 
Dose response; 
 
Depression response rates; 
 
Depression remission rates; 
 
Onset of clinical response; 
 
Overall severity of depressive illness; 
 
Anxiety symptoms; 
 
Functioning and associated disability. 
 
To investigate the safety and tolerability of intranasal esketamine compared with intranasal 
placebo as an add-on to an oral antidepressant in Japanese subjects with TRD, including the 
following parameters: 
 
TEAEs, including AEs of special interest; 
 
Potential withdrawal or rebound symptoms or both following cessation of intranasal 
esketamine treatment; 
 
Perceptual changes (dissociative symptoms); 
 
Effects on alertness and sedation; 
 
Effects on heart rate, blood pressure, respiratory rate, and blood oxygen saturation; 
 
Potential effects on suicidal ideation/behavior; 
 
Potential abuse-liability; 
 
Potential psychosis-like effects. 
NCT02918318


JNJ-54135419  (esketamine) 
 
 
 
Statistical Analysis Plan 54135419TRD2005 
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Approved, Date: 14 January 2020 
 
To evaluate the durability of intranasal esketamine as an add-on to an oral antidepressant in 
Japanese subjects with TRD, with attention to: 
 
Time to relapse in the posttreatment phase for subjects in remission and for subjects 
who respond but are not in remission, at the end of the double-blind induction phase. 
 
To evaluate the PK of intranasally administered esketamine in Japanese subjects with TRD 
Exploratory Objective 
 
To assess the comparability of the efficacy and safety of intranasal esketamine as an add-on 
to an oral antidepressant between the double-blind and open-label intranasal esketamine 
induction treatment courses; 
 
To evaluate the PK/PD relationship of intranasal esketamine and MADRS total score (and 
possibly selected AEs as additional PD parameters) in Japanese subjects with TRD; 
 
To examine the relationship between deoxyribonucleic acid (DNA) single nucleotide 
polymorphisms (SNPs) (including, but not limited to BDNF) with clinical outcome to 
intranasal esketamine in Japanese subjects with TRD; 
 
To assess the potential relationship of biomarkers with response, maintenance, relapse, and 
nonresponse to intranasal esketamine in Japanese subjects with TRD. 
1.2. 
Trial Design 
This is a randomized, double-blind, placebo-controlled, multicenter study designed to evaluate 
the efficacy, safety and tolerability of fixed dose of intranasal esketamine (28 mg, 56 mg, or 
84 mg) as an add-on therapy to an oral antidepressant in Japanese subjects with TRD. A total of 
183 subjects are planned to be enrolled in this study. 
The study consists of the following phases: a screening phase (up to 4 weeks); a 6-week 
prospective oral antidepressant lead-in phase; a 4-week double-blind induction phase; a 
posttreatment phase (up to 24 weeks comprising of only oral antidepressant therapy), including 
an optional 4-week open-label induction phase; and a 4-week follow-up phase. 
Thus, the duration of a subject’s participation will be a maximum of 42 weeks, depending on 
whether they meet phase-specific criteria for response or relapse. The end-of-study (EOS) will 
occur when the last subject in the study completes his/her last study assessment (ie, last follow-
up Visit). 
Screening Phase 
Japanese men and women aged 20 to 64 years old (both inclusive), who meet Diagnostic and 
Statistical Manual of Mental Disorders (fifth edition) (DSM-5) diagnostic criteria for recurrent 
major depressive disorder (MDD) without psychotic features, based upon clinical assessment, 
and confirmed by the MINI will be screened according to the inclusion/exclusion criteria. 
To confirm eligibility for participation in the prospective lead-in phase, subjects will have a 
review of the inclusion/exclusion criteria in the screening phase. Subjects must not have 
responded to ≥1 but <5 different oral antidepressants taken at adequate dosage and for adequate 
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Statistical Analysis Plan 54135419TRD2005 
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duration, as assessed on the Massachusetts General Hospital – Antidepressant Treatment 
Response Questionnaire (MGH-ATRQ) and documented by medical history/prescription records, 
for the current episode of depression. The subject’s current major depressive episode, depression 
symptom severity (MADRS total score ≥28 required), and treatment response to antidepressant 
medication used in the current episode (retrospectively assessed) must be deemed valid for 
participation in the clinical study based on the SAFER interview, which is administered by a 
remote, independent rater. At the screening visit, subjects who continue to fulfill all inclusion 
criteria and none of the exclusion criteria will be enrolled. 
SAFER interview will be conducted as early as feasible during the screening period, preferably 
in the first week after signing of informed consent form (ICF) before down-titration of 
antidepressants to avoid change of depressive symptoms because of tapering. 
Subject’s current antidepressant treatment(s), including adjunctive treatment for MDD, should be 
tapered and discontinued in this phase per the local prescribing information. Down-titration of 
antidepressants will be started after SAFER interview and will be completed in the screening 
phase basically. However, if clinically indicated, cross-tapering is allowed. Cross-tapering is 
defined as discontinuation of previous antidepressant treatment(s) by lowering the dose(s) per the 
local prescribing information and simultaneously increasing the dose of single new 
antidepressant treatment within the first 2 weeks of the prospective lead-in phase. 
The subject’s current antidepressant treatment(s) will not be discontinued for the sole purpose of 
participating in the study. 
Prospective Lead-in Phase 
After enrollment, eligible subjects will enter the 6-week OL prospective lead-in phase during 
which, subjects will receive a new antidepressant therapy (physician determined) daily for the 
duration of this phase. 
The oral antidepressant will be 1 of the following: selective serotonin reuptake inhibitors or 
serotoninspecific reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors 
(SNRIs), ormirtazapine (ie, escitalopram, paroxetine controlled-release [CR], sertraline, 
duloxetine, venlafaxine extended-release [XR], or mirtazapine), which the subject has not 
previously had a nonresponse to in the current depressive episode or has not been previously 
intolerant to (lifetime). 
In the last 4 weeks during the prospective lead-in phase, 'oral antidepressant' must be single 
treatment of switched new oral antidepressant. New oral antidepressant treatment should be 
titrated to the approved maximum dose, to optimize the potential for response. The up-titration 
schedule should be per prescribing information. The dose, which is above the minimum 
therapeutic dose defined in MGH-ATRQ should be kept at last 4 weeks during the prospective 
lead-in phase, in case they start at lower doses.  
The criteria of TRD is defined as nonresponse (≤25% improvement) to at least 1 antidepressant 
treatment determined retrospectively and 1 antidepressant prospectively in the current episode of 
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Statistical Analysis Plan 54135419TRD2005 
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depression. After 6 weeks, subjects who are nonresponders to the new oral antidepressant 
treatment at the end of the prospective lead-in phase can be eligible to proceed to the double-
blind induction phase. Nonresponse at the end of the prospective lead-in phase is defined as 
≤25% improvement in the MADRS total score from Visits 2.1 to each of Visit 2.3 and 3.1 
(prerandomization) respectively, and a MADRS total score of ≥28 on each of the Visits 2.1, 2.3, 
and 3.1 (prerandomization). Assessment of antidepressant treatment response at the end of the 
prospective lead-in phase will be performed by investigators. All other subjects who do not 
proceed to the double-blind induction phase will end study participation at this time. No follow-
up or further study visits will be performed for these subjects. All subjects who are discontinued 
must be treated with an oral antidepressant after completion of the study, unless it is clinically 
inappropriate. 
MADRS assessment throughout the study will be performed by an independent, remote, blinded 
rater. The remote MADRS interviews will be recorded to assess accuracy and thoroughness of 
the interviews and measure overall quality assurance. 
Double-blind Induction Phase 
The 4-week fixed dose double-blind induction phase will start on Day 1 and end at Day 28. A 
total of 183 subjects will be randomly assigned in a 2:1:1:1 ratio to receive double-blind 
intranasal treatment with either placebo, esketamine 28 mg, esketamine 56 mg, or esketamine 
84 mg add-on to the continued stable oral antidepressant initiated in the prospective lead-in 
phase. The intranasal treatment sessions (esketamine or placebo) will occur twice weekly. 
Subjects will self-administer the intranasal study drug (esketamine 28 mg, 56 mg, 84 mg, or 
placebo) at treatment sessions occurring twice a week for 4 weeks at the clinical site under 
clinical supervision. The first treatment session will be on Day 1. Responders (subjects who have 
≥50% reduction from baseline in MADRS total score) at the end of the double-blind induction 
phase will be eligible to proceed to the posttreatment phase; those who do not (ie, nonresponders) 
will proceed to the 4-week follow-up phase. Given the potential for treatment-emergent transient 
elevation in SBP and DBP, the guidance on Blood Pressure Monitoring should be followed on 
intranasal dosing days during the double-blind induction phase. 
Posttreatment Phase 
Responders who completed the double-blind induction phase will enter the 24-week 
posttreatment phase to evaluate durability of efficacy after cessation of add-on intranasal 
esketamine or placebo treatment while continuing the oral antidepressant treatment regimen, as 
assessed by the time to relapse and proportion of responders and remitters at each visit in this 
phase. All subjects who are discontinued must be treated with an oral antidepressant after 
completion of the study, unless it is clinically inappropriate. 
Open-label Induction Phase 
Subjects who relapsed in the posttreatment phase will receive a 4-week open-label induction 
treatment course of intranasal esketamine. The beginning of the OL induction phase should be at 
least 2 weeks (14 calendar days) after the last dose in the double-blind induction phase. Subjects 
who meet the relapse criteria before 2 weeks after the last dose in the double-blind induction 
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Statistical Analysis Plan 54135419TRD2005 
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phase will not have an option for joining open label induction phase. They will withdraw from 
the posttreatment phase and move forward to the follow up phase. 
Subjects who enter the OL induction phase will start treatment sessions with 56 mg of intranasal 
esketamine on the first day of OL induction phase (Day 1 OL). On the fourth day (Day 4 OL), 
the dose will be increased to 84 mg. On Day 8 OL and Day 11 OL, the dose may remain the 
same as 84 mg or could be reduced by 28 mg as determined by the investigator based on efficacy 
and tolerability. On Day 15 OL, a dose reduction is permitted if required for tolerability; no dose 
increase is permitted on Day 15 OL. After Day 15 OL, the dose should be stable (unchanged). If 
needed for tolerability, a dose reduction is permitted from Day 15 OL until Day 25 OL. 
The oral antidepressant medication initiated from the prospective lead-in phase, which will 
continue in the posttreatment phase will also be maintained throughout this phase. 
Follow-up Phase 
Following subjects will have follow-up Visits; subjects who withdraw from double blind 
induction phase, nonresponders after double-blind induction phase, responders who withdraw 
within 4 weeks after the last dose of double blind intranasal drug and all subjects who receive 
open label intranasal drug. During this phase, further clinical/standard-of-care treatment will be 
provided by the study investigator however, in order to better assess potential withdrawal 
symptoms from intranasal study drug, the oral antidepressant medication must be continued for 
the follow-up phase unless determined as not clinically appropriate. 
A schematic overview of the study design is provided in Figure 1. 
NCT02918318


JNJ-54135419  (esketamine) 
 
 
 
Statistical Analysis Plan 54135419TRD2005 
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Figure 1: 
Schematic Overview of the Study Design 
 
Esk: esketamine; IN: intranasal; AD: Antidepressant Day 1: The first day in the double-blind induction phase.  
* Only responders after completion of the double-blind induction phase are eligible to join the posttreatment phase. 
In the posttreatment phase, subjects who relapse within 20 weeks after the start of the posttreatment phase will 
receive an open-label treatment course of esketamine. Subjects who relapse more than 20 weeks after the start of 
the posttreatment phase will withdraw from the study and clinical/standard-of-care treatment will be arranged by 
the study investigator after relapse. The beginning of the open-label induction phase should be at least 2 weeks 
after the last dose in the double-blind induction phase. 
** Following subjects will have follow-up Visits; subjects who withdraw from double blind induction phase, 
nonresponders after double-blind induction phase, responders who withdraw within 4 weeks after the last dose of 
double blind intranasal drug and all subjects who receive open label intranasal drug. 
1.3. 
Statistical Hypotheses for Trial Objectives 
The hypothesis for this study is that, at least one dose of intranasal esketamine (28, 56, and 
84 mg) is superior to intranasal placebo in improving depressive symptoms in Japanese subjects 
with TRD, as assessed by the change from baseline in the MADRS total score at the end of the 
double-blind induction phase. 
1.4. 
Sample Size Justification 
The sample size for this study was calculated assuming a treatment difference for the double-
blind induction phase of 4, 4.5, 5 points in MADRS total score between each dose (28 mg, 56 mg, 
84 mg) of esketamine and the placebo respectively, a SD of 10 for each treatment group, a 1-
NCT02918318


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Statistical Analysis Plan 54135419TRD2005 
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sided significance level of 0.05 and a drop-out rate of 12.5%. A total of 183 subjects will need to 
be randomized to treatment in a 2:1:1:1 ratio (72 subjects on placebo group and 37 subjects per 
intranasal esketamine dose group) to achieve 80% power to detect difference for at least one 
dose group of intranasal esketamine to placebo using a Dunnett adjustment. The treatment 
difference and SD used in this calculation were assumed based on results of Panel B of the 
ESKETINTRD2003 study with clinical consideration. 
1.5. 
Randomization and Blinding 
Randomization will be with an allocation ratio of 2:1:1:1 to intranasal placebo, intranasal 
esketamine 28 mg, intranasal esketamine 56 mg, or intranasal esketamine 84 mg. Randomization 
will be used in the double-blind induction phase to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg, 
demographics and baseline characteristics) are evenly balanced across treatment groups, and to 
enhance the validity of statistical comparisons across treatment groups. Blinded treatment will be 
used to reduce potential bias during data collection and evaluation of clinical endpoints in this 
phase. Measures will be taken to ensure that the study subjects and study staff are not unblinded. 
The placebo group is included in this design to maintain blinding in the double-blind phase of the 
study. A placebo group is necessary to allow an accurate assessment of the safety and efficacy of 
the study drug. 
Randomization will be employed only in the double-blind induction phase of the study. Central 
randomization will be implemented in this study. Subjects will be randomly assigned to 1 of 4 
treatment groups in a 2:1:1:1 ratio based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor. Randomization will be 
balanced by using randomly permuted blocks across the 4 treatment groups. The interactive web 
response system (IWRS) will assign a unique treatment code, which will dictate the treatment 
assignment and matching study drug kit for 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. 
At the end of the double-blind induction 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. 
NCT02918318


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Statistical Analysis Plan 54135419TRD2005 
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2. 
GENERAL ANALYSIS DEFINITIONS 
2.1. 
Analysis Phases 
There are 5 analysis phases defined in this study:  
 
A Double-blind Induction Phase  
 
A Double-blind Follow-up Phase (Non-Responders or subjects who withdraw from DB 
induction phase) 
 
A Posttreatment Phase (Responders only) 
 
An Open-Label Induction Phase (Responders only) 
 
An Open-Label Follow-up Phase (Responders only) 
Each analysis phase has its own analysis phase start and end dates. 
2.1.1. 
Study Reference Start and End Dates 
The reference start date for the study is defined as the date of the first dose of intranasal study 
medication (the date is missing for screened subjects who did not take any intranasal study 
medication). The reference end date for the study is the end of trial date including the last follow-
up visit. 
2.1.2. 
Analysis Phase Start and End Dates 
Double-blind Induction Phase 
The start date of the double-blind induction phase (referred to as ‘DB start date’) is the date of 
the first dose of intranasal study medication. The double-blind induction phase end date (referred 
to as ‘DB end date’) is the maximum of the date of the last visit in the double-blind induction 
phase and the date of completion/withdrawal from the double-blind induction phase.  
The start date/time of the double-blind induction phase (referred to as, ‘DB start date/time’) is 
the DB start date and the time of the first dose of intranasal study medication. 
Double-blind Follow-up Phase 
The start date of the double-blind follow-up phase (referred to as ‘DB FU start date’) is the day 
after the DB end date. The double-blind follow-up phase end date (referred to as ‘DB FU end 
date’) is the maximum of the last DB follow-up visit date or the end of trial date. 
Posttreatment Phase 
The start date of the posttreatment phase (referred to as ‘PT start date’) is the day after the DB 
end date. The posttreatment phase end date (referred to as ‘PT end date’) is defined as: for 
subjects who entered OL phase, the day of OL start date (defined below); for subjects who did 
not enter OL, including responders who withdraw within 4 weeks after the last dose of DB 
intranasal drug, the maximum of the last posttreatment visit date or the end of trial date. 
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Statistical Analysis Plan 54135419TRD2005 
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For subjects who entered OL phase, PT end date/time is one minute before OL start date/time 
(defined below). 
Open-Label Induction Phase 
The start date of the open-label induction phase (referred to as ‘OL start date’) is the date of the 
first dose of intranasal study medication in a second induction treatment course. The open-label 
induction phase end date (referred to as ‘OL end date’) is the maximum of the date of the last 
visit in the open-label induction phase and the date of completion/withdrawal from the open-
label induction phase.  
The start date/time of the open-label induction phase (referred to as, ‘OL start date/time’) is the 
OL start date and the time of the first dose of intranasal study medication in the second induction 
treatment course. 
Open-Label Follow-up Phase  
The start date of the open-label follow-up phase (referred to as ‘OL FU start date’) is the day 
after the OL end date. The open-label follow-up phase end date (referred to as ‘OL FU end date’) 
is the maximum of the last OL follow-up visit date or the end of trial date. 
2.1.3. 
Study Day and Relative Day 
Study day is calculated relative to the reference start date for the study. Relative day is calculated 
relative to the start date of the analysis phase in which the data are captured. A minus (-) sign 
indicates days prior to the start of study or prior to the start of the analysis phase. 
Study day for an event on or after the start of the study is calculated as: 
event date - reference start date+1. 
Study day for an event prior to the start of the study is calculated as: 
event date - reference start date  
Relative day for an event on or after the analysis phase start date is calculated as: 
event date - analysis phase start date + 1. 
Relative day for an event prior to the analysis phase start date is calculated as: 
event date - analysis phase start date. 
There is no study Day 0 or relative Day 0. 
2.2. 
Baseline and End Point 
Baseline is defined for each parameter/assessment. 
 
Baseline (DB): The last assessment before receiving the first dose of intranasal study 
medication in the double-blind induction phase.  
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Statistical Analysis Plan 54135419TRD2005 
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 
Baseline (OL): The last assessment before receiving the first dose of intranasal study 
medication in the open-label induction phase. 
Baseline (DB) will be used for DB induction phase, DB follow-up phase and posttreatment (PT) 
phase. Baseline (OL) will be used for OL induction phase and OL follow-up phase. 
The ‘End Point (DB)’ value is defined as the last post baseline assessment value during the double-
blind induction phase.  
The ‘End Point (OL)’ value is defined as the last post baseline assessment value during the open-
label induction phase.  
2.3. 
Visit Windows 
As subjects do not always adhere to the protocol visit schedule (including permitted visit 
windows), the following rules are applied to assign actual visits to protocol visits. Listed below 
are the visit windows for analysis and the target days for each visit. The reference day is Study 
Day 1 (which is the first day that study drug was taken in the double-blind phase). 
If a subject has 2 or more scheduled or unscheduled visits in one visit window, the visit closest to 
the target day will be used as the protocol visit for that visit window. If 2 actual visits are 
equidistant from the target day within a visit window, the later visit is used. If a visit window has 
no scheduled visits but does have unscheduled visits, then the unscheduled visit closest to the 
scheduled visit will be used. 
All assignments will be made in chronological order. Once a visit is assigned to a visit window, 
it will no longer be used for a later time point except for the end point.  
Listed below are the visit windows and the target days (if applicable) for each visit defined in the 
protocol for all phases (Table 1).  
Table 1:  
Analysis Visits 
Parameter 
Analysis Phase 
Scheduled  
Daya 
Time Interval 
(label on output) 
Time Intervala 
(Day) 
Target Time Pointa 
(Day) 
MADRS 
Screening /lead-
in  
 
Week -6 (SL) 
 
 
 
Week -4 (SL) 
 
 
 
Week -2 (SL) 
 
 
DB 
1 
Baseline (DB) 
≤1 (predose) 
1 
2 
Day 2 (DB) 
2 
2 
8 
Day 8 (DB) 
3-11 
8 
15 
Day 15 (DB) 
12-18 
15 
22 
Day 22 (DB) 
19-25 
22 
28 
Day 28 (DB) 
26 to end of DB 
28 
DB final visit 
End Point (DB) 
2 to end of DB 
 
DB FU 
 DB F/U 7 
Week 1 (DB F/U) 
DB F/U start day-10 
7 
 DB F/U 14 
Week 2 (DB F/U) 
11-21 
14 
 DB F/U 28 
Week 4 (DB F/U) 
22 to end of DB F/U 
28 
DB F/U final visit
End Point (DB F/U) 
1 to end of DB F/U 
 
PTf 
Weekly 1 
 
32 
Week 1 (PT) 
PT start day to 
35 
32 
PTf 
Weekly 
x=2,3,…. 
25 + x*7 
Week x (PT) 
22 + x*7 to 
28 + x*7 
25 + x*7 
OL 
OL 1 
Baseline (OL) 
≤1 (predose) 
1 
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JNJ-54135419  (esketamine) 
 
 
 
Statistical Analysis Plan 54135419TRD2005 
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Table 1:  
Analysis Visits 
Parameter 
Analysis Phase 
Scheduled  
Daya 
Time Interval 
(label on output) 
Time Intervala 
(Day) 
Target Time Pointa 
(Day) 
OL 8 
Day 8 (OL) 
2-11 
8 
OL 15 
Day 15 (OL) 
12-18 
15 
OL 22 
Day 22 (OL) 
19-25 
22 
OL 28 
Day 28 (OL) 
26 to end of OL 
28 
OL final visit 
End Point (OL) 
2 to end of OL 
 
OL FU 
 OL F/U 7 
Week 1 (OL F/U) 
OL FU start day-10 
7 
 OL F/U 14 
Week 2 (OL F/U) 
11-21 
14 
 OL F/U 28 
Week 4 (OL F/U) 
22 to end of OL F/U 
28 
OL F/U final visit
End Point (OL F/U) 
1 to end of OL F/U 
 
POMS-2 
DB 
25 
Day 25 (DB) 
2 to end of DB 
25 
DB FU 
 DB F/U 7 
Week 1 (DB F/U) 
DB F/U start day-10 
7 
 DB F/U 14 
Week 2 (DB F/U) 
11-21 
14 
 DB F/U 28 
Week 4 (DB F/U) 
22 to end of DB F/U 
28 
DB F/U final visit
End Point (DB F/U) 
1 to end of DB F/U 
 
PT 
32 
Week 1 (PT) 
PT start day to 35 
32 
39 
Week 2 (PT) 
36-46 
39 
53 
Week 4 (PT) 
47-60 
53 
67 
Week 6 (PT) 
61-74 
67 
81 
Week 8 (PT) 
75-95 
81 
109 
Week 12 (PT) 
96-123 
109 
137 
Week 16 (PT) 
124-151 
137 
165 
Week 20 (PT) 
152-179 
165 
193 
Week 24 (PT) 
180 to end of PT 
193 
OL FU 
 OL F/U 7 
Week 1 (OL F/U) 
OL FU start day-10 
7 
 OL F/U 14 
Week 2 (OL F/U) 
11-21 
14 
 OL F/U 28 
Week 4 (OL F/U) 
22 to end of OL F/U 
28 
OL F/U final visit
End Point (OL F/U) 
1 to end of OL F/U 
 
SDS 
DB 
1 
Baseline (DB) 
≤1 (predose) 
1 
28 
Day 28 (DB) 
2 to end of DB 
28 
PT 
39 
Week 2 (PT) 
PT start day to 
46 
39 
53 
Week 4 (PT) 
47-60 
53 
67 
Week 6 (PT) 
61-74 
67 
81 
Week 8 (PT) 
75-95 
81 
109 
Week 12 (PT) 
96-123 
109 
137 
Week 16 (PT) 
124-151 
137 
165 
Week 20 (PT) 
152-179 
165 
193 
Week 24 (PT) 
180 to end of PT 
193 
CGI-S 
Screening /lead-
in 
 
Week -6 (SL) 
 
 
 
Week -4 (SL) 
 
 
 
Week -2 (SL) 
 
 
DB 
1 
Baseline (DB) 
≤1 (predose) 
1 
8 
Day 8 (DB) 
2-11 
8 
15 
Day 15 (DB) 
12-18 
15 
22 
Day 22 (DB) 
19-25 
22 
28 
Day 28 (DB) 
26 to end of DB 
28 
DB final visit 
End Point (DB) 
2 to end of DB 
 
DB FU 
 DB F/U 7 
Week 1 (DB F/U) 
DB F/U start day-10 
7 
 DB F/U 14 
Week 2 (DB F/U) 
11-21 
14 
 DB F/U 28 
Week 4 (DB F/U) 
22 to end of DB F/U 
28 
DB F/U final visit
End Point (DB F/U) 
1 to end of DB F/U 
 
PT 
32 
Week 1 (PT) 
PT start day to 
35 
32 
39 
Week 2 (PT) 
36-42 
39 
46 
Week 3 (PT) 
43-49 
46 
53 
Week 4 (PT) 
50-60 
53 
67 
Week 6 (PT) 
61-74 
67 
81 
Week 8 (PT) 
75-95 
81 
109 
Week 12 (PT) 
96-123 
109 
137 
Week 16 (PT) 
124-151 
137 
165 
Week 20 (PT) 
152-179 
165 
193 
Week 24 (PT) 
180 to end of PT 
193 
OL 
OL 1 
Baseline (OL) 
≤1 (predose) 
1 
OL 8 
Day 8 (OL) 
2-11 
8 
OL 15 
Day 15 (OL) 
12-18 
15 
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JNJ-54135419  (esketamine) 
 
 
 
Statistical Analysis Plan 54135419TRD2005 
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Approved, Date: 14 January 2020 
Table 1:  
Analysis Visits 
Parameter 
Analysis Phase 
Scheduled  
Daya 
Time Interval 
(label on output) 
Time Intervala 
(Day) 
Target Time Pointa 
(Day) 
OL 22 
Day 22 (OL) 
19-25 
22 
OL 28 
Day 28 (OL)
26 to end of OL 
28 
OL final visit 
End Point (OL) 
2 to end of OL 
 
OL FU 
 OL F/U 7 
Week 1 (OL F/U) 
OL FU start day-10 
7 
 OL F/U 14 
Week 2 (OL F/U) 
11-21 
14 
 OL F/U 28 
Week 4 (OL F/U) 
22 to end of OL F/U 
28 
OL F/U final visit
End Point (OL F/U) 
1 to end of OL F/U 
 
GAD-7 
DB 
1 
Baseline (DB) 
≤1 (predose) 
1 
15 
Day 15 (DB) 
2-21 
15 
28 
Day 28 (DB) 
22 to end of DB 
28 
DB final visit 
End Point (DB) 
2 to end of DB 
 
Vital Signs 
(TEMP [predose 
at each visit], 
BPb, PULSE, 
RESP [at each 
visit, predose, 
40M, 1H, 1.5H]) 
Screening /lead-
in 
 
Week -10 (SL) 
 
 
 
Week -6 (SL) 
 
 
 
Week -4 (SL) 
 
 
DB 
1 
Baseline (DB) 
Day 1: 40M (DB) 
Day 1: 1H (DB) 
Day 1: 1.5H (DB) 
≤ 1 / predose 
1 
4 
Day 4: Predose (DB) 
Day 4: 40M (DB) 
Day 4: 1H (DB) 
Day 4: 1.5H (DB) 
2-6 
4 
8 
Day 8: Predose (DB) 
Day 8: 40M (DB) 
Day 8: 1H (DB) 
Day 8: 1.5H (DB) 
7-9 
8 
11 
Day 11: Predose (DB) 
Day 11: 40M (DB) 
Day 11: 1H (DB) 
Day 11: 1.5H (DB) 
10-13 
11 
15 
Day 15: Predose (DB) 
Day 15: 40M (DB) 
Day 15: 1H (DB) 
Day 15: 1.5H (DB) 
14-16 
15 
18 
Day 18: Predose (DB) 
Day 18: 40M (DB) 
Day 18: 1H (DB) 
Day 18: 1.5H (DB) 
17-20 
18 
22 
Day 22: Predose (DB) 
Day 22: 40M (DB) 
Day 22: 1H (DB) 
Day 22: 1.5H (DB) 
21-23 
22 
25 
Day 25: Predose (DB) 
Day 25: 40M (DB) 
Day 25: 1H (DB) 
Day 25: 1.5H (DB) 
24 to end of DB 
25 
DB final visit 
End Point (DB) 
Day 1: 40M to end of DB 
 
OL 
OL 1 
Baseline (OL) 
Day 1: 40M (OL) 
Day 1: 1H (OL) 
Day 1: 1.5H (OL) 
≤ 1 / predose 
1 
OL 4 
Day 4: Predose (OL) 
Day 4: 40M (OL) 
Day 4: 1H (OL) 
Day 4: 1.5H (OL) 
2-6 
4 
OL 8 
Day 8: Predose (OL) 
Day 8: 40M (OL) 
Day 8: 1H (OL) 
Day 8: 1.5H (OL) 
7-9 
8 
OL 11 
Day 11: Predose (OL) 
Day 11: 40M (OL) 
Day 11: 1H (OL) 
Day 11: 1.5H (OL) 
10-13 
11 
OL 15 
Day 15: Predose (OL) 
Day 15: 40M (OL) 
Day 15: 1H (OL) 
Day 15: 1.5H (OL) 
14-16 
15 
NCT02918318


JNJ-54135419  (esketamine) 
 
 
 
Statistical Analysis Plan 54135419TRD2005 
19 
Approved, Date: 14 January 2020 
Table 1:  
Analysis Visits 
Parameter 
Analysis Phase 
Scheduled  
Daya 
Time Interval 
(label on output) 
Time Intervala 
(Day) 
Target Time Pointa 
(Day) 
OL 18 
Day 18: Predose (OL) 
Day 18: 40M (OL) 
Day 18: 1H (OL) 
Day 18: 1.5H (OL) 
17-20 
18 
OL 22 
Day 22: Predose (OL) 
Day 22: 40M (OL) 
Day 22: 1H (OL) 
Day 22: 1.5H (OL) 
21-23 
22 
OL 25 
Day 25: Predose (OL) 
Day 25: 40M (OL) 
Day 25: 1H (OL) 
Day 25: 1.5H (OL) 
24 to end of DB 
25 
OL final visit 
End Point (OL) 
Day 1: 40M to end of OL 
 
Weight and BMI 
DB 
Screening, 1 
Baseline (DB) 
≤ 1 / predose 
1 
15 
Day 15 (DB) 
2-21 
15 
28 
Day 28 (DB) 
22 to end of DB 
28 
DB final visit 
End Point (DB) 
2 to end of DB 
 
OL 
OL 1 
Baseline (OL) 
≤ 1 / predose 
1 
OL 15 
Day 15 (OL) 
2-21 
15 
OL 28 
Day 28 (OL) 
22 to end of OL 
28 
OL final visit 
End Point (OL) 
2 to end of OL 
 
ECG 
DB 
Screening, 1 
Baseline (DB) 
≤ 1 / predose 
1 
1 
Day 1: 1H (DB) 
1 
1 
8 
Day 8: 1H (DB) 
2-11 
8 
15 
Day 15: 1H (DB) 
12-20 
15 
25 
Day 25: 1H (DB) 
21 to end of DB 
25 
DB final visit 
End Point (DB) 
2 to end of DB 
 
OL 
OL 1 
Day 1: 1H (OL) 
1 
1 
OL 15 
Day 15: 1H (OL) 
2-20 
15 
OL 25 
Day 25: 1H (OL) 
21 to end of OL 
25 
OL final visit 
End Point (OL) 
2 to end of OL 
 
Lab 
(Hematology, 
Chemistry) 
Screening /lead-
in 
 
Screening 
 
 
DB 
Screening, 1 
Baseline (DB) 
≤ 1 / predose 
1 
28 
Day 28 (DB) 
2 to end of DB 
28 
OL 
OL 1 
Baseline (OL) 
≤ 1 / predose 
1 
OL 28 
Day 28 (OL) 
2 to end of OL 
28 
C-SSRS 
Screening /lead-
in 
 
Week -10 (SL) 
 
 
 
Week -6 (SL) 
 
 
 
Week -4 (SL) 
 
 
 
Week -2 (SL) 
 
 
DB 
1 
Baseline (DB) 
≤1 (predose) 
1 
4 
Day 4 (DB) 
2-6 
4 
8 
Day 8 (DB) 
7-9 
8 
11 
Day 11 (DB) 
10-13 
11 
15 
Day 15 (DB) 
14-16 
15 
18 
Day 18 (DB) 
17-20 
18 
22 
Day 22 (DB) 
21-23 
22 
25 
Day 25 (DB) 
24-26 
25 
28 
Day 28 (DB) 
27 to end of DB 
28 
DB final visit 
End Point (DB) 
2 to end of DB 
 
DB FU 
 DB F/U 7 
Week 1 (DB F/U) 
DB F/U start day-10 
7 
 DB F/U 14 
Week 2 (DB F/U) 
11-21 
14 
 DB F/U 28 
Week 4 (DB F/U) 
22 to end of DB F/U 
28 
DB F/U final visit
End Point (DB F/U) 
1 to end of DB F/U 
 
PT 
32 
Week 1 (PT) 
PT start day to 
35 
32 
39 
Week 2 (PT) 
36-42 
39 
46 
Week 3 (PT) 
43-49 
46 
53 
Week 4 (PT) 
50-60 
53 
67 
Week 6 (PT) 
61-74 
67 
81 
Week 8 (PT) 
75-95 
81 
109 
Week 12 (PT) 
96-123 
109 
137 
Week 16 (PT) 
124-151 
137 
165 
Week 20 (PT) 
152-179 
165 
NCT02918318


JNJ-54135419  (esketamine) 
 
 
 
Statistical Analysis Plan 54135419TRD2005 
20 
Approved, Date: 14 January 2020 
Table 1:  
Analysis Visits 
Parameter 
Analysis Phase 
Scheduled  
Daya 
Time Interval 
(label on output) 
Time Intervala 
(Day) 
Target Time Pointa 
(Day) 
193 
Week 24 (PT) 
180 to end of PT 
193 
OL 
OL 1 
Baseline (OL) 
≤1 (predose) 
1 
OL 4 
Day 4 (OL) 
2-6 
4 
OL 8 
Day 8 (OL) 
7-9 
8 
OL 11 
Day 11 (OL)
10-13 
11 
OL 15 
Day 15 (OL) 
14-16 
15 
OL 18 
Day 18 (OL) 
17-20 
18 
OL 22 
Day 22 (OL) 
21-23 
22 
OL 25 
Day 25 (OL) 
24-26 
25 
OL 28 
Day 28 (OL) 
27 to end of OL 
28 
OL final visit 
End Point (OL) 
2 to end of OL 
 
OL FU 
 OL F/U 7 
Week 1 (OL F/U) 
OL FU start day-10 
7 
 OL F/U 14 
Week 2 (OL F/U) 
11-21 
14 
 OL F/U 28 
Week 4 (OL F/U) 
22 to end of OL F/U 
28 
OL F/U final visit
End Point (OL F/U) 
1 to end of OL F/U 
 
MOAA/Sc 
Oxygen 
Saturationd 
(predose and 
every 15 minutes 
to 1.5H) 
 
BPRS+ and 
CADSS (predose, 
40M, 1.5H) 
 
CGADR e (1H, 
1.5H) 
DB 
1 
Baseline (DB) 
≤1 
1 
4 
Day 4 (DB) 
2-6 
4 
8 
Day 8 (DB) 
7-9 
8 
11 
Day 11 (DB) 
10-13 
11 
15 
Day 15 (DB) 
14-16 
15 
18 
Day 18 (DB) 
17-20 
18 
22 
Day 22 (DB) 
21-23 
22 
25 
Day 25 (DB) 
24 to end of DB 
25 
DB final visit 
End Point (DB) 
2 to end of DB 
 
OL 
OL 1 
Baseline (OL) 
≤1 (predose) 
1 
OL 4 
Day 4 (OL) 
2-6 
4 
OL 8 
Day 8 (OL) 
7-9 
8 
OL 11 
Day 11 (OL) 
10-13 
11 
OL 15 
Day 15 (OL) 
14-16 
15 
OL 18 
Day 18 (OL) 
17-20 
18 
OL 22 
Day 22 (OL) 
21-23 
22 
OL 25 
Day 25 (OL) 
24 to end of OL 
25 
OL final visit 
End Point (OL) 
2 to end of OL 
 
PWC-20 
DB 
25 
Day 25 (DB) 
2 to end of DB 
25 
DB FU 
 DB F/U 7 
Week 1 (DB F/U) 
DB F/U start day-10 
7 
 DB F/U 14 
Week 2 (DB F/U) 
11-21 
14 
 DB F/U 28 
Week 4 (DB F/U) 
22 to end of DB F/U 
28 
DB F/U final visit
End Point (DB F/U) 
1 to end of DB F/U 
 
PT 
32 
Week 1 (PT) 
PT start day to 
35 
32 
39 
Week 2 (PT) 
36-42 
39 
46 
Week 3 (PT) 
43-49 
46 
53 
Week 4 (PT) 
50-60 
53 
67 
Week 6 (PT) 
61-74 
67 
81 
Week 8 (PT) 
75-95 
81 
OL 
OL 25 
Day 25 (OL) 
2 to end of OL 
25 
OL FU 
 OL F/U 7 
Week 1 (OL F/U) 
OL FU start day-10 
7 
 OL F/U 14 
Week 2 (OL F/U) 
11-21 
14 
 OL F/U 28 
Week 4 (OL F/U) 
22 to end of OL F/U 
28 
OL F/U final visit
End Point (OL F/U) 
1 to end of OL F/U 
 
Pharmacokinetics 
DB 
4 
Day 4 (DB) 
2-6 
4 
25 
Day 25 (DB) 
24 to end of DB 
25 
OL 
OL 25 
Day 25 (OL) 
24 to end of OL 
25 
a  
For DB and posttreatment phases, the time interval is relative to the first day of DB phase. For other phases, the time interval is relative to the 
first day of that phase. 
b  
During the DB phase, at 1.5 hours post dose if the SBP is ≥160 and/or DBP≥100, assessments should continue every 30 minutes until the 
blood pressure is <160 and/or <100 or investigator’s clinical judgment the subject it is clinical stable and can be discharged from the clinical 
site or subject is referred for appropriate medical care, if clinically indicated or the blood pressure remains ≥180 mm Hg SBP or 
≥110 mm Hg DBP or both, 2 hours after dosing, the subject should be referred for immediate medical treatment.  
c  
If the MOAA/S score is ≤ 3 at any time during the 1.5 hour postdose interval, the MOAA/S will be performed every 5 minutes until a score 
of 4 is reached (at which point a frequency of every 15 minutes can be resumed until t=+1.5 hours post dose). 
d  
If pulse oximetry is <93% at any time during the 1.5 hour postdose interval, pulse oximetry will be performed every 5 minutes until oxygen 
saturation returns to ≥93% or until the subject is referred for appropriate medical care, if clinically indicated. 
e  
If the response is not “Yes” at 1.5 hour postdose, the assessment will be repeated every 15 minutes until a “Yes” response is achieved or until 
the subject is referred for appropriate medical care if clinically indicated. 
f 
In the posttreatment phase, MADRS assessments will be performed weekly through Week 24 or relapse, whichever occurs first.  
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2.4. 
Analysis Sets 
Subjects will be classified into the following analysis sets: all randomized, full, safety, 
pharmacokinetic and PK/PD. 
2.4.1. 
All Randomized Analysis Set 
This analysis set will include all subjects who were randomized (ie, 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. 
2.4.2. 
Full Analysis Set (FAS) 
Efficacy analysis will be performed on the following FAS.  
FAS (DB): All randomized subjects who received at least 1 dose of intranasal study medication 
during the DB induction phase. 
FAS (OL): All subjects who received at least 1 dose of intranasal study medication during the 
OL induction phase. 
FAS (responders): All randomized subjects who receive at least 1 dose of intranasal study 
medication during the double-blind induction phase and who are responders at the end of the 
double-blind induction phase and entered the posttreatment phase. 
2.4.3. 
Safety Analysis Set 
The following safety analysis sets are defined for each phase. Analyses of change from baseline 
will include only those subjects who have baseline and at least 1 postbaseline observation in that 
phase.  
Safety (DB): All randomized subjects who receive at least 1 dose of intranasal study medication 
in the DB induction phase.  
Safety (OL): All subjects who receive at least 1 dose of intranasal study medication in the OL 
induction phase. 
Safety (responders): All randomized subjects who receive at least 1 dose of intranasal study 
medication during the double-blind induction phase and who are responders at the end of the 
double-blind induction phase and entered the posttreatment phase. 
Screen failures and randomized subjects who received no study medication will be excluded 
from the safety analysis set. Subjects who received an incorrect treatment will be analyzed under 
the planned treatment. 
2.4.4. 
Follow-up Analysis Set 
The following FU analysis sets are defined for each phase and will be used for both safety and 
efficacy analyses. 
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 
FU (DB): All subjects who are not respond at the end of DB induction phase and enter the 
DB follow-up phase 
 
FU (OL): All Safety (OL) subjects who enter the OL follow-up phase 
2.4.5. 
Pharmacokinetic Analysis Set 
The PK Analysis Set includes all subjects, regardless of their compliance with the protocol, who 
received at least 1 dose of intranasal esketamine and at least 1 evaluable concentration data. 
2.4.6. 
Pharmacokinetic/pharmacodynamic (PK/PD) Analysis Set 
Blood pressure (DBP and SBP) and QTcF will be selected for safety parameter. The PK/PD 
analysis set includes all subjects who received at least 1 dose of intranasal esketamine, and have 
at least 1 time point with nominal time-matched plasma concentration and safety parameter.  
2.5. 
Definition of Subgroups 
Analyses will be provided for the primary endpoint, changes from baseline in MADRS total 
score, using the following subgroups. 
 
Sex 
 
Age Group (<45 years, ≥45 years) 
 
Number of Previous Treatments in Current Episode 
 
Functional Impairment based on Baseline SDS Total Score (not impaired [0-3], mild [4-11], 
moderate [12-19], marked [20-26] or extreme [27-30]) 
 
Baseline MADRS total score (≤/> Median) 
 
Class of oral antidepressant (SNRI, SSRI or mirtazapine) 
 
BMI (≤/> Median) 
 
Number of major depressive episodes including current episode (1, 2-3, 3<) 
 
Duration of the current episode (≤ 26, >26-52, >52-104, >104 weeks) 
 
Concomitant use of benzodiazepine excluding sleep aids (Y/N) 
 
Concomitant use of benzodiazepine including sleep aids (Y/N) 
 
Had been considered to be eligible for electroconvulsive therapy (Y/N) 
2.6. 
Imputation Rules for Missing Adverse Event (AE) Dates  
Treatment-emergent adverse events (TEAEs) are those events with an onset date/time on or after 
the start of study medication during induction phase (DB/OL), and occurred on or before the end 
of the corresponding induction phases (DB/OL). Adverse events (AEs) for the follow-up 
(DB/OL) phase are those events with an onset date on or after the start of the follow-up (DB/OL) 
phase, and occurred on or before the end of the follow-up (DB/OL) phase. Adverse events (AEs) 
for the posttreatment phase are those events with an onset date on or after the start of the 
posttreatment phase, and occurred on or before the end of the posttreatment phase. A 
conservative approach will be used to handle the missing dates for adverse events. 
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Onset Date 
If the onset date of an AE is missing day only, it will be set to: 
1. First day of the month that the AE occurred, if month/year of the onset of AE is different 
than the month/year of DB start date 
2. 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 
3. 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 the same. 
If the onset date of an AE is missing both day and month, it will be set to the earliest of: 
1. January 1 of the year of onset, as long as this date is after the DB start date.  
2. One day after the DB start date, if this date is the same year that the AE occurred. 
3. The day of AE resolution date, if this date is the same year that the AE occurred. 
A completely missing onset date of an adverse event will be set to the day of DB start date or day 
of AE resolution date, whichever is earliest.  
Similar rules will be applied for OL missing onset date. 
Resolution Date 
The missing day of resolution of an AE will be set to the last day of the month of resolution. 
If the resolution date of an AE is missing both day and month, it will be set to the earlier of the 
date of withdrawal, study completion, or December 31 of the year. 
A completely missing resolution date of an AE that is not recorded as ongoing will be set to the 
date of study completion/discontinuation. 
2.7. 
Imputation Rules for Missing AE Time of Onset/Resolution 
If the time of onset is missing, it will be imputed as follows: 
1. 00:00 if the date of onset is after DB start date 
2. The time of intranasal medication start in the double-blind induction phase 
If the time of resolution is missing, it 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. 
2.8. 
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 
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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 
induction 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 induction phase and earlier than the study end date, then the estimated start date of the 
concomitant medication is the first day of the month;  
 
If the month of the concomitant medication start date is greater than the month of the study 
end date, then no imputation will be done; 
 
If the month and year of the concomitant medication start date are known and the 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. 
SUBJECT INFORMATION 
3.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics (Table 2) and psychiatric history at baseline (Table 3) 
will be summarized by treatment group and overall for the FAS (DB), FAS (responders) and 
FAS (OL) (described in Section 2.4). Continuous variables will be summarized using descriptive 
statistics (N, mean, standard deviation [SD], median, minimum, and maximum). Categorical 
variables will be summarized using a frequency distribution with the number and percentage of 
subjects in each category. Baseline (DB) will be used for these summaries. 
Table 2: 
Demographic Variables and Baseline Characteristics 
Continuous Variables: 
 Age (years) 
 Baseline weight (kg) 
 Baseline height (cm) 
 Baseline BMI (kg/m2) calculated as Weight (kg)/[Height (m)]2 
Categorical Variables: 
 Age (<45 years, ≥45 years) 
 Sex (male, female) 
 Baseline BMI (underweight: <18.5 kg/m2, normal: 18.5 to <25 kg/m2, overweight: 
25 kg/m2 to <30 kg/m2, obese: 30 to <40 kg/m2, morbidly obese:40 kg/m2) 
 Employment Status 
 Hypertension statusa 
 Class of antidepressant (SSRI/SNRI/mirtazapine) 
 Oral antidepressant 
 Educational level 
a Hypertension status =Yes if SBP>=140mmHg and/or DBP>=90mmHg at least one timepoint before DB 
Induction Phase. Hypertension status =No if SBP<140mmHg and DBP<90mmHg at all timepoints before DB 
Induction Phase. 
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Table 3: 
Psychiatric History at Baseline Variables 
Continuous Variables: 
 Baseline MADRS total score 
 Baseline CGI-S score 
 Age (years) when diagnosed with MDD 
Categorical Variables: 
 Baseline CGI-S score 
 Baseline C-SSRS category (no event, suicidal ideation, suicidal behavior) 
 Number of Previous Treatments in Current Episode  
 Functional Impairment based on Baseline SDS Total Score (not impaired [0-3], mild [4-11], moderate [12-19], 
marked [20-26] or extreme [27-30]) 
 Family history of 
- 
Depression 
- 
Anxiety Disorder 
- 
Bipolar Disorder 
- 
Schizophrenia 
- 
Alcohol Abuse 
- 
Substance Abuse 
 Number of episodes including current episode (1, 2-3, 3<) 
 Duration of the current episode (≤ 26, >26-52, >52-104, >104 weeks) 
 Use of Adjunctive antipsychotics at IC (Y/N) 
 Use of benzodiazepine excluding sleep aids at IC (Y/N) 
 Had been considered to be eligible for electroconvulsive therapy (Y/N) 
 
A by-subject listing of the demographic and baseline characteristics will be provided. 
Details of the medical history abnormalities will be presented in a by-subject listing. 
3.2. 
Disposition Information 
The number of screen failures will be summarized. A summary of each analysis set (defined in 
Section 2.4) will also be provided.  
The following disposition summaries by treatment groups and overall will be provided for each 
phase separately.  
 
The number of subjects who entered a specific phase (DB induction, DB Follow-up, PT, OL 
induction and OL Follow-up phases) 
 
The number of subjects who completed a specific phase (DB induction, DB Follow-up, PT, 
OL induction and OL Follow-up phases) 
 
The number of subjects who discontinued a specific phase (DB induction, DB Follow-up, 
PT, OL induction and OL Follow-up phases) and their reasons for discontinuation 
The number of subjects who terminated the trial and the reasons for ending study participation 
will also be summarized. 
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3.3. 
Extent of Exposure 
Extent of exposure in terms of total duration of exposure and number of dosing sessions of 
intranasal study medication will be summarized by phase and treatment group for the FAS (DB), 
FAS (responders) and FAS (OL) (described in Section 2.4). 
The total duration of exposure for the intranasal study drug and for each type of oral 
antidepressant (AD) during each phase is defined as the time between the first and the last dose 
of each type of study medication in that specific phase (last day of study medication-first day 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 for each induction phase. The total duration 
of intranasal study drug exposure for each induction 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 for each induction phase will be 
presented, separately. 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 five analysis 
phases (described in Section 2.1): ≤7 days, 8-14 days, 15-21 days, 22-28 days, >28 days. Each 
type of oral AD will be summarized separately. 
Modal dose for a subject is defined as the most frequently taken dose by a subject during that 
phase. Mean dose of a subject is calculated as the sum of doses during the phase divided by the 
total number of days exposed. The final dose is the last nonzero dose received during that phase. 
The calculation of mean, modal and final dose will exclude days off study drug. 
Descriptive statistics (N, mean, SD, median, minimum and maximum) of modal dose, mean and 
final dose of intranasal study drug will be presented for OL induction phase. 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 each analysis phase (DB induction, DB 
follow-up, PT, OL induction and OL follow-up). The lowest mode dose is selected in case of ties. 
In addition, percent compliance of the oral AD calculated as days actual dosed/days expected to 
be dosed*100, will be summarized. 
A by-subject listing of study drug administration and oral AD will be provided. 
3.4. 
Protocol Deviations 
Deviations that occurred during the study will be tabulated for the All Randomized analysis set 
by treatment group. Major deviations will be tabulated as they are grouped prior to unblinding in 
the following categories: subject not withdrawn as per protocol, selection criteria not met, 
excluded concomitant treatment, treatment deviation, noncompliance, regulatory requirement. 
More categories may be included depending on the nature of the protocol deviation. A subject 
may be counted in more than one deviation category. 
A by-subject listing showing the specific major protocol deviations will also be provided. 
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3.5. 
Prior and Concomitant Medications 
Antidepressant medications taken prior to the baseline visit will be summarized by treatment 
group for the Safety (DB) analysis set. 
The number and percent of subjects who receive concomitant therapies will be summarized by 
phase and treatment group using the generic term of the medication for the Safety (DB) and 
Safety (OL) analysis sets (described in Section 2.4). 
A by-subject listing of all prior and concomitant medication will also be provided. 
4. 
EFFICACY 
Efficacy summaries for the DB induction phase and the OL induction phase will be based on 
FAS (DB) and FAS (OL), respectively. FAS (responders) will be applied for the summaries in 
posttreatment phase and for the analysis for time to relapse. Summaries for DB/OL follow up 
phase will be based on FU(DB)/ FU (OL). 
4.1. 
Analysis Specifications 
4.1.1. 
Level of Significance 
The primary efficacy endpoint will be evaluated at a 1-sided significance level of 0.05 (2-sided 
significance level of 0.1) based on MMRM pairwise comparisons using a Dunnett adjustment.  
For all other analyses of the primary efficacy endpoint and for all other endpoints, no multiplicity 
adjustment will be done and nominal p-values will be presented. 
4.1.2. 
Data Handling Rules 
As a sensitivity analysis, the change in MADRS total score will be analyzed using an analysis of 
covariance (ANCOVA) model, using last observation carried forward (LOCF) data. The last post 
baseline observation during the double-blind induction phase will be carried forward as the “End 
Point” for that phase. Besides the observed cases and the end point assessment, the LOCF values 
will be created for intermediate postbaseline time points as well. These imputed time points will 
be labeled ‘DAY X LOCF’.  
For the analyses of responders based on MADRS total score (Section 4.3.1), remitters based on 
MADRS total score (Section 4.3.2), subjects with missing values will be imputed as 
nonresponders/nonremitters. 
4.1.3. 
Imputation Methods for Missing Items 
Imputation of the MADRS total score is described in Section 4.2.1. 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. 
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4.2. 
Primary Efficacy Endpoint 
4.2.1. 
Definition 
The primary efficacy endpoint is the change in MADRS total score as measured by the change 
from baseline (prior to randomization) to the end of the 4-week double-blind induction phase. 
The MADRS is a clinician-rated scale designed to measure depression severity and to detect 
changes due to antidepressant treatment.6 The scale consists of 10 items, each of which is scored 
from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), 
for a total possible score of 60. Higher scores represent a more severe condition. The MADRS 
evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, 
lassitude, interest level, pessimistic thoughts, and suicidal thoughts. The test exhibits high 
inter-rater reliability. 
If 2 or more items are missing, no imputation will be performed and the total score will be left 
missing. Otherwise, the total score will be calculated as sum of the nonmissing items multiplied 
by the ratio of the maximum number of items (ie, 10) to the number of nonmissing items. 
4.2.2. 
Primary Estimand 
The primary estimand, the main clinical quantity of interest to be estimated in the study, is 
defined by the following 4 components: 
Population: Japanese subjects with treatment-resistant depression 
Variable: change from baseline to Day 28 in the MADRS total score (see Section 4.2.1) 
Intervention effect: the effect of the initially randomized treatment that would have been 
observed had all subjects remained on their treatment throughout the double-blind induction 
phase.  
Summary measure: difference in variable means. 
The primary analysis will be based on the FAS (DB), as described in Section 2.4.2, and the 
MADRS total scores collected during the double-blind induction phase. 
4.2.3. 
Analysis Methods 
Descriptive statistics of actual values and changes from baseline by treatment group will be 
presented for MADRS total score. The analysis of primary endpoint will only be applied for FAS 
(DB) during DB induction phase.  
Means (+/-standard error [SE]), mean changes (+/-SE) from baseline, and least square mean 
changes (+/-SE) from baseline will be presented graphically in the double-blind induction phase. 
4.2.3.1. 
MMRM  
The primary efficacy variable, change from baseline in MADRS total score at Day 28 in the 
double-blind induction phase, will be analyzed using a Mixed-Effect Model for Repeated 
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Measures (MMRM) based on observed case data. The models will include baseline MADRS 
total score as a covariate, and treatment, day (see Table 1), and day-by-treatment interaction as 
fixed effects. The between-within approximation will be used to estimate the denominator 
degrees of freedom. 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 each esketamine dose group with the placebo group will 
be performed with the appropriate contrast using a Dunnett adjustment. 
The change from baseline in MADRS total score over time in the double-blind induction phase 
will be analyzed using the same MMRM as described above.  
4.2.3.2. 
Model Diagnostics 
The normality and equal variance assumptions underlying the primary MMRM models 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 including an ANCOVA on 
ranks model or an appropriate transformation of the primary endpoint might be considered. 
4.2.3.3. 
MCP-Mod Analysis 
Based on the MMRM, the least-squares (LS) mean estimates for each esketamine dose group and 
placebo group at Day 28 and the corresponding variances will be obtained. The generalized 
MCP-Mod approach will be applied towards the estimates obtained from the MMRM to analyze 
the dose-response relationship. This approach requires prespecification of a candidate model set. 
Using notation as in Bornkamp et al (2009)1 the candidate set is constituted by the following 5 
model profiles (with the corresponding parameters): Emax (ED50 =9.33), sigmoid Emax (ED50 
=44.86, h=3.5), linear, exponential(δ=58.2) and quadratic(δ=-0.00893). The quadratic covers the 
scenario of a nonmonotonic relationship. The dose-response curves are shown below in Figure 2. 
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Figure 2: 
MCP-Mod Dose Response Curves 
The significance of the dose-response signal associated with each candidate model will be 
determined using trend tests with model-specific optimal contrast coefficients. The maximum of 
the candidate model trend test statistics will be used to evaluate the presence of a dose-response 
signal, properly accounting for multiplicity at an overall level of 5% (1-sided) using MCP-Mod 
methodology. If the maximum test statistic is not significant, no dose-response relationship will 
be further explored. Otherwise, the model families corresponding to individual candidate models 
with significant trend test statistic will be used to fit to the observed data and the one with the 
smallest Akaike Information Criterion (AIC) will be selected to represent the dose-response 
relationship. The corresponding confidence interval (CI) for the response at each dose will be 
computed based on a bootstrap approach. 
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4.2.3.4. 
Missing Data Sensitivity Analysis  
The following table (Table 4) shows the assumptions of each considered analysis for the primary 
efficacy endpoint, all applied to FAS (DB) defined in Section 2.4.2. 
Table 4: 
Analysis Types and Assumptions 
Analysis Type 
Analysis Method 
Assumption 
Primary Analysis  
MMRM  
Missing at Random – MAR 
Sensitivity Analysis 
ANCOVA model using change from 
baseline to Day 28 based on LOCF 
Efficacy scores at time of 
discontinuation (DC) from the DB 
induction phase remain constant up 
to Day 28. 
Sensitivity Analysis 
MMRM model using change from 
baseline to Day 28 based on follow-up 
data 
Efficacy scores during the DB 
follow-up phase can be used for 
the subjects who withdraw from 
the DB induction phase. 
Sensitivity Analysis 
Delta worsening adjustment applied to 
standard multiple imputation 
regression7,8 
Efficacy scores worsen after study 
discontinuation 
ANCOVA 
The sensitivity analysis will be based on an analysis of covariance (ANCOVA) model using 
change from baseline to Day 28 based on LOCF data. The models will include factors for 
treatment and baseline MADRS total score as a continuous covariate. A 90% CI for the 
difference in LSMeans and P-value will be calculated based on the contrast test statistic for each 
esketamine dose level. 
Additional to the ANCOVA model based on LOCF method, another sensitivity analysis using 
the same MMRM model will be done which includes the follow-up data from subjects who 
discontinued the double-blind induction phase. For subjects who discontinued from the double-
blind induction phase, the measures on the follow-up visit will be treated as the data ‘during DB 
induction phase’ and the measure within the visit window for Day 28 and closed to the target 
date will be used. 
The delta worsening adjustment analysis will be done only if the dropout rate is larger than 15%. 
4.2.3.5. 
Subgroup Analysis 
Forest plots will be provided displaying analysis results for each subgroup listed in Section 2.5. 
The point estimate of the treatment difference and its 90% 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, day, subgroup, 
day-by-treatment interaction and treatment-by-subgroup as fixed effects. The terms in the model 
will be adjusted for the subgroup of baseline MADRS total score (≤/>median). Baseline MADRS 
total score (as a continuous covariate) will not be included in the model when the dichotomized 
baseline MADRS total score is included in the model. 
 
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4.3. 
Secondary Endpoints 
4.3.1. 
Responders 
4.3.1.1. 
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 (eg, percent change ≤ -50% indicates improvement 
≥50%). For the open-label induction phase, OL baseline will be used to calculate the percentage 
change as well. 
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%.  
4.3.1.2. 
Analysis Methods 
The proportion of subjects who achieve a response will be summarized at each time point for 
each induction phase (DB and OL). The proportion of responders during the double-blind 
induction phase in the esketamine dose group will be compared with the placebo group using 
Fisher’s exact test with 90% CIs for the proportion provided by treatment group.  
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 for double-blind induction phase. 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 (nonresponse) 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. Those subjects without sustained response will be censored at the last visit during 
double blind induction phase.  
4.3.2. 
Remitters 
4.3.2.1. 
Definition 
Subjects who have a MADRS total score of ≤12 will be considered remitters. 
4.3.2.2. 
Analysis Methods 
The proportion of subjects who achieve remission will be summarized at each time point for 
each induction phase (DB and OL). The proportion of remitters during the double-blind 
induction phase in the esketamine dose group will be compared with the placebo group using 
Fisher’s exact test with 90% CIs for the proportion provided by treatment group.  
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The cumulative distribution function of the time to sustained remission will be estimated by the 
Kaplan-Meier method for double-blind induction phase. Time to sustained remission will be 
summarized (number of sustained remitters, 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. Those subjects without 
sustained remission will be censored at the last visit during double-blind induction phase. 
4.3.3. 
Time to Relapse 
4.3.3.1. 
Definition 
Time to relapse will be defined as the time between the end of the double-blind induction phase 
and the first documentation of a relapse event during the posttreatment phase. The relapse is 
defined as any of the following: 
 
MADRS total score ≥22 for 2 consecutive assessments. The date of the second MADRS 
assessment will be used for the date of relapse. 
 
Hospitalization for worsening depression or any other clinically relevant event determined 
per clinical judgment to be suggestive of a relapse of depressive illness such as suicide 
attempt, completed suicide, or hospitalization for suicide prevention. If hospitalized for any 
of these events, the start date of hospitalization will be used for the date of relapse. 
Otherwise the date of the event will be used if the subject is not hospitalized. 
 
In case both relapse criteria are met, the earlier date will be defined as the date of relapse for 
this subject. 
Those subjects without relapse will be censored at the last visit (complete/withdraw) date in 
posttreatment phase. 
4.3.3.2. 
Analysis Methods 
The cumulative distribution function of the time to relapse will be estimated by the Kaplan-
Meier method. Time to relapse will be summarized (number of relapses, number of censored 
subjects, median, 25th and 75th percentile, if estimable) by treatment group and the combined 
esketamine groups for the following groups separately. 
1. In subjects who remit (MADRS total score ≤12) at the end of the double-blind induction 
phase 
2. In subjects with response (≥50% reduction from baseline in MADRS total score) but who 
are not in remission at the end of the double-blind induction phase 
4.3.4. 
Onset of Clinical Response 
4.3.4.1. 
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 that is maintained to Day 28. Subjects 
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are allowed one excursion (nonresponse) 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 not be considered to have maintained clinical response and 
will be assigned the value of 0 (ie, no). 
4.3.4.2. 
Analysis Methods 
The proportion of subjects showing onset of clinical response by Day 2 that is maintained for the 
duration of the double-blind induction phase in the esketamine dose group will be compared with 
the placebo group using Fisher’s exact test with 90% CIs for the proportion provided by 
treatment group. The proportion of responders with onset by Day 2 that is maintained to Day 8, 
Day 15, Day 22 and Day 28 will be test separately. 
4.3.5. 
CGI-S 
4.3.5.1. 
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 function. 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. 
4.3.5.2. 
Analysis Methods 
Descriptive statistics of actual values and changes from baseline by treatment group will be 
provided. Frequency distributions by treatment group will be provided at each time point for 
each analysis phase (DB induction, DB follow-up, PT, OL induction and OL follow-up). 
The ranks of the change from baseline for CGI-S in the double-blind induction phase will be 
analyzed at each time point based on observed case using the same MMRM as described in 
Section 4.2.3.1 for primary efficacy endpoint, with the covariate “baseline MADRS total score” 
changed to “baseline CGI-S”. 
4.3.6. 
Sheehan Disability Scale (SDS) 
4.3.6.1. 
Definition 
The SDS is a subject-reported outcome measure and is a 5-item questionnaire which has been 
widely used and accepted for assessment of functional impairment and associated disability. The 
first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home 
responsibilities using a 0-10 rating scale. The score for the first three items are summed to create 
a total score of 0-30 where a higher score indicates greater impairment. It also has one item on 
days lost from school or work and one item on days when underproductive. The recall period for 
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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. 
4.3.6.2. 
Analysis Methods 
Descriptive statistics of actual values and changes from baseline by treatment group will be 
provided at each time point for DB induction and PT phases. The total score as well as the 
individual item scores will be summarized separately. Graphical presentations will also be 
provided. In addition, the proportion of subjects who achieve response and remission will be 
summarized at each time point during the double-blind induction phase. 
The change from baseline in SDS total score at Day 28 in the double-blind induction phase will 
be analyzed using the same MMRM as described in Section 4.2.3.1 for primary efficacy 
endpoint, with the covariate “baseline MADRS total score” changed to “baseline SDS total 
score”. 
4.3.7. 
GAD-7 
4.3.7.1. 
Definition 
The GAD-7 (Generalized Anxiety Disorder - 7 Items) is a brief and validated 7-item self-report 
assessment of overall anxiety.10,11 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 day. 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). 
4.3.7.2. 
Analysis Methods 
Descriptive statistics of actual values and changes from baseline by treatment group will be 
provided at each time point during double-blind induction phase. A frequency distribution will 
also be provided for GAD-7 severity categories at each time point. Graphical presentations will 
also be provided. 
The change from baseline in GAD-7 total score over time in the double-blind induction phase 
will be analyzed using the same MMRM as described in Section 4.2.3.1 for primary efficacy 
endpoint, with the covariate “baseline MADRS total score” changed to “baseline GAD-7 total 
score”. 
4.3.8. 
MADRS  
4.3.8.1. 
Definition 
The definition of MADRS is in section 4.2.1. 
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4.3.8.2. 
Analysis Methods 
Descriptive statistics of actual values and changes from baseline will be summarized at each time 
point for each phase (DB induction, DB follow-up, PT, OL induction and OL follow-up). The 
total score as well as the individual item scores will be summarized separately. Graphical 
presentations will also be provided.  
5. 
SAFETY 
All safety summaries for induction phases will be based on the safety analysis sets described in 
Section 2.4.3. Safety summaries for the follow-up phases will be based on the follow-up analysis 
sets described in Section 2.4.4. 
Unless specified otherwise, Baseline (DB) will be used for DB induction phase and DB follow-up 
phase. Baseline (OL) will be used for OL induction phase and OL follow-up phase. 
5.1. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) (version 20.0 or above) will be 
used to classify adverse events (AEs) by system organ class and preferred term. Treatment-
emergent adverse events (TEAEs) that occurred in each analysis phase (DB induction, DB 
follow-up, PT, OL induction, OL follow-up) will be summarized by system organ class and 
preferred term.  
The number (%) of subjects with TEAEs, serious TEAEs (SAEs), and TEAEs that led to study 
drug discontinuation, dose reduction will be summarized by system organ class and preferred 
term. TEAEs will be summarized by onset time (4 week intervals). Data listings will be 
generated for deaths, other SAEs, and discontinuations due to AEs.  
A TEAE is an event that is new in onset or increased in severity following treatment initiation. 
An event that starts prior to, and ends after the initiation of study medication will be considered 
treatment-emergent only if the severity increases after the start of medication.  
Treatment-emergent adverse events (TEAEs) are defined as follows for each analysis phase: 
 
TEAEs in DB induction phase:  
a. 
If AE onset time is not missing: DB start date/time ≤ AE onset date and time ≤ DB end 
date 
b. If AE onset time is missing: DB start date ≤ AE onset date ≤ DB end date 
 
TEAEs in OL induction phase:  
a. 
If AE onset time is not missing: OL start date/time ≤ AE onset date and time ≤ OL end 
date 
b. If AE onset time is missing: OL start date ≤ AE onset date ≤ OL end date 
 
AEs in DB follow-up phase: DB FU start date ≤ AE onset date ≤ DB FU end date  
 
AEs in OL follow-up phase: OL FU start date ≤ AE onset date ≤ OL FU end date  
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 
For the AEs that have both day and month missing, treatment-emergent flag is assigned 
based on the rules presented in Section 2.6. 
In addition, TEAEs will be summarized by severity and relationship to study medication using 
the preferred term. For the summaries of TEAEs by severity/relationship to study medication, the 
observation with the most severe occurrence/closest relationship to study medication will be 
chosen if there is more than one incident of an AE reported during the analysis phase by the 
subject. 
Adverse Events of Special Interest 
Clinically relevant TEAEs of special interest will be examined separately grouped in the 
following categories:  
 
Suggestive of abuse potential (Aggression, Confusional state, Decreased activity, 
Dependence, Disorientation, Dissociation, Dissociative disorder, Dizziness, Drug abuse, 
Drug abuser, Drug dependence, Drug use disorder, Drug detoxification, Drug diversion, 
Drug rehabilitation, Drug tolerance, Drug tolerance increased, Drug withdrawal convulsions, 
Drug withdrawal headache, Drug withdrawal syndrome, Euphoric mood, Feeling abnormal, 
Feeling drunk, Feeling of relaxation, Hallucination, Hallucination, auditory, Hallucination, 
gustatory, Hallucination, olfactory, Hallucination, synaesthetic, Hallucination, tactile, 
Hallucination, visual, Hallucinations, mixed, Inappropriate affect, Mental impairment, 
Product tampering, Psychomotor hyperactivity, Psychotic disorder, Rebound effect, Somatic 
hallucination, Somnolence, Substance abuser, Substance dependence, Substance use, 
Substance use disorder, Substance-induced mood disorder, Substance-induced psychotic 
disorder, Thinking abnormal, Withdrawal arrhythmia, Withdrawal syndrome)  
 
increased blood pressure (Blood pressure increased, Blood pressure diastolic increased, 
Blood pressure systolic increased, Hypertensive crisis, Hypertensive emergency, 
Hypertension) 
 
increased heart rate (Heart rate increased, Tachycardia, Extrasystoles) 
 
transient dizziness/vertigo (Dizziness, Dizziness exertional, Dizziness postural, Procedural 
Dizziness, Vertigo, Vertigo labyrinthine, Vertigo positional, Vertigo CNS origin); 
 
impaired cognition (Cognitive disorder);  
 
cystitis (Allergic cystitis, Chemical cystitis, Cystitis, Cystitis erosive, Cystitis haemorrhagic, 
Cystitis interstitial, Cystitis noninfective, Cystitis ulcerative, Cystitis-like symptom, 
Pollakiuria, Dysuria, Micturition urgency, Nocturia);  
 
anxiety (Anticipatory anxiety, Anxiety, Anxiety disorder, Agitation, Fear, Feeling jittery, 
Irritability, Nervousness, Panic attack, Tension). 
The number and percentage of subjects taking concomitant medication for dissociation events 
(preferred term of Dissociation) at any time during each induction phase will be provided. 
5.2. 
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 for each induction phase (DB and OL).  
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Clinical laboratory tests that meet the criteria for markedly abnormal will be listed by subject for 
each induction phase. The incidence of treatment-emergent markedly abnormal (TEMA) 
laboratory values that occurred at any time during each induction phase will be presented. 
Clinical laboratory test values will be considered TEMA using the criteria defined by 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 postbaseline 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 values >3*upper normal limit (ULN) will be presented for 
each induction phase. Additionally, incidence of hepatic toxicity (Hy’s Law)12 defined as ALT 
values >3*ULN AND total bilirubin values >2*ULN will be presented for each induction phase. 
Similar to the markedly abnormal analysis, only subjects with baseline ALT values ≤3*ULN 
(AND baseline total bilirubin values ≤2*ULN for hepatic toxicity) (or if baseline value is 
missing) will be eligible for these analyses. 
5.3. 
Vital Signs, Weight, and BMI 
Descriptive statistics (N, mean, median, minimum, and maximum) for values and changes from 
baseline at each time point during each induction phase (DB and OL) 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 (defined in 
Table 2, Yes/No). Descriptive statistics for maximum increases and maximum percent increase 
from predose will be provided for each dosing day. Frequency distributions of maximum percent 
change increase from predose and time of maximum percent change increase will also be 
presented. 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 5 
below, during each induction phase will be presented. Both the double-blind/open-label 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 each induction phase. 
Table 5: 
Treatment-Emergent Abnormality Categories for Vital Signs 
 
Vital Parameter 
Postbaseline 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 (mm Hg) 
A decrease from baseline of  20 to a 
value  90 
An increase from baseline of  20 to a 
value  180 
Diastolic BP (mm Hg) 
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 acute hypertension (systolic BP≥180 or diastolic 
BP≥110) at any time during the study will be summarized by analysis phase, treatment group and 
hypertension status. 
Mean (+/-SE) values for systolic BP, diastolic BP and pulse rate will be presented graphically 
over each induction phase by treatment group and hypertension status. In addition, for subjects 
with hypertension who receive antihypertensive medication, the same graphs will be summarized 
by medication type (beta-blockers, all other agents). 
A listing of subjects with oxygen saturation less than 93% will be provided. 
5.4. 
Electrocardiogram 
ECG variables that will be analyzed include heart rate, RR, PR interval, QRS interval, QT 
interval and QTc intervals. The corrected QT (QTc) intervals will include QTcB (Bazett) and 
QTcF (Fridericia). 
Baseline ECG is defined as the average of all ECG results collected up to and including the day 
of the first dose of study medication. This baseline will be used as the baseline for change 
summaries and to determine abnormal values during each induction phase (DB and OL). 
The maximum postbaseline value during each induction phase will be computed for each ECG 
parameter using data from both scheduled and unscheduled visits. 
Summary tables for observed values and changes from baseline will be presented by treatment 
group at each time point during each induction phase. 
The frequency of treatment-emergent abnormalities will be tabulated and presented for each 
induction phase. The identification of treatment-emergent abnormal ECG values is based on the 
postbaseline 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 6. If postbaseline 
ECG results are above the upper limits (abnormally high) and the baseline value is below the 
lower limits (abnormally low), then the postbaseline abnormality will also be considered 
treatment-emergent. The same applies to the postbaseline value being below the lower limits 
(abnormally low) with the baseline value being above the upper limits (abnormally high). 
Abnormal ranges for the HR, PR, QRS and QT intervals are given in Table 6. 
Table 6: 
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 
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given in Table 7 and are derived from the ICH E14 Guidance3 (the same criteria apply to all QT 
corrections). 
Table 7: 
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 predose. 
 
The proportion of subjects with treatment emergent abnormalities will be presented for each 
induction phase. A listing of subjects with abnormalities will also be provided. 
5.5. 
Other Safety Parameters 
5.5.1. 
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 treatment.9 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 
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If no events qualify for a score of 1 to 10, a score of 0 will be assigned (0= “no event that can be 
assessed on the basis of C-SSRS”). Higher scores indicate greater severity. 
The summaries of the C-SSRS outcomes will be applied for subjects who have at least 1 
postbaseline C-SSRS measurement and a pretreatment C-SSRS assessment (assessment at 
Baseline visit). 
A frequency distribution at each scheduled time point will be provided. Shifts from the baseline 
visit to the most severe/maximum score during each analysis phase (DB induction, DB follow-up, 
PT, OL induction and OL follow-up) will be summarized. 
The maximum score assigned for each subject will also be summarized into one of three broad 
categories: No suicidal ideation or behavior (0), Suicidal ideation (1-5), Suicidal behavior (6-10). 
Shifts from the baseline visit to the maximum category during each analysis phase will be 
summarized. 
5.5.2. 
Clinician Administered Dissociative States Scale (CADSS) 
The CADSS (Clinician Administered Dissociative States Scale) is an instrument for the 
measurement of present-state dissociative symptoms, and is administered to assess treatment-
emergent dissociative symptoms.2 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 = “Extremely”). The CADSS is divided into 3 components using the scoring method 
shown in Table 8. 
Table 8: 
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 during each induction phase (DB and OL). 
Descriptive statistics (N, mean, median, minimum, and maximum) of the total scores and 
component scores, changes from the predose at each time point, and the proportion of subjects 
with an increase in CADSS total score from the predose value at any time during the study will 
be summarized. Mean (SE) CADSS values will be presented graphically for each dosing day. 
5.5.3. 
Brief Psychiatric Rating Scale (BPRS) 
The Brief Psychiatric Rating Scale (BPRS) is an 18-item rating scale which is used to assess 
potential treatment-emergent psychotic symptoms. The BPRS assesses a range of psychotic and 
affective symptoms rated from both observation of the subject and the subject's own report. Only 
the four-item positive symptom subscale (BPRS+) will be used in the study to assess treatment-
emergent psychotic symptoms. The BPRS+ consists of: suspiciousness, hallucinations, unusual 
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thought content and conceptual disorganization. Each symptom is rated on a scale of 0 to 6 as 
follows: 0: not present, not evident or absent; 1: very mild; 2: mild; 3: moderate; 4: moderate 
severe; 5: severe; or 6: extreme. A total score will be derived by summing the individual items, 
with a range of 0 to 24 with a higher score representing a more severe condition. 
The BPRS+ is measured prior to each dose, at 40 minutes, and at 1.5 hours postdose during each 
induction phase (DB and OL). 
Descriptive statistics (N, median, minimum, and maximum) of the total scores at each time point, 
the change from the predose at each time point, and the proportion of subjects with an increase in 
BPRS+ from the predose value at any time during the study will be summarized. The proportion 
of subjects with a total score of 3 or more at any time during the study will also be provided. 
Mean (SE) BPRS+ values will be presented graphically for each dosing day. 
5.5.4. 
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) 
The Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) will be used to measure 
treatment-emergent sedation with correlation to levels of sedation defined by the American 
Society of Anesthesiologists (ASA) continuum. The MOAA/S scores range from 0 (No response 
to painful stimulus; corresponds to ASA continuum for general anesthesia) to 5 (Readily 
responds to name spoken in normal tone [awake]; corresponds to ASA continuum for minimal 
sedation). 
The MOAA/S is measured on each dosing day every 15 minutes from predose to 1.5 hours 
postdose or longer, if necessary, until the subject has a score of 5 during each induction phase 
(DB and OL). 
 
If the score is ≤3 at any time during the 1.5 hour postdose interval, the MOAA/S will be 
performed every 5 minutes until a score of 4 is reached (at which point a frequency of every 
15 minutes can be resumed until t=+1.5 hours postdose).  
 
If a subject does not have a score of 5 at t=+1.5 hours postdose, they should continue to be 
monitored. For subjects with a score of 4, the assessment should be repeated every 
15 minutes. For subjects with a score of ≤3, the assessment should be repeated every 
5 minutes until the score returns to 5 or the subject is referred for appropriate medical care, 
if clinically indicated. 
Descriptive statistics (N, mean, median, minimum, and maximum) of the MOAA/S score, 
changes from predose, and the proportion of subjects experiencing sedation (score less than or 
equal to 3) will be summarized at each time point. The proportion of subjects with a total score 
of 3 or less will be summarized at any time during the study and by dose day. Mean (SE) 
MOAA/S values will be presented graphically for each dosing day.  
5.5.5. 
Clinical Global Assessment of Discharge Readiness (CGADR) 
The Clinical Global Assessment of Discharge Readiness (CGADR) will be used to measure a 
subject’s current clinical status and is the clinician’s assessment of the readiness to be discharged 
from the study site.  
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The clinician will answer “Yes” or “No” to the question “Is the subject considered ready to be 
discharged based on their overall clinical status (eg, sedation, blood pressure, and other adverse 
events)?” 
On each intranasal dosing day, the CGADR will be performed at 1 hour and 1.5 hours postdose, 
repeated every 15 minutes if necessary until the response is ‘Yes’. A subject should not be 
discharged prior to the 1.5-hour time point. 
The proportion of subjects with a response of ‘No’ at each time point will be presented by 
treatment group during each induction phase (DB and OL). 
5.5.6. 
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 DB and Day 25 OL to establish a baseline prior to discontinuation of 
esketamine treatment. 
The proportion of subjects with withdrawal symptoms at the end of induction phases (DB and 
OL) or during the DB follow-up phase, PT phase and the OL follow-up phase will be presented. 
In addition, symptoms at PT phase and follow-up phases will be compared to the last assessment 
in the relevant induction phase (DB and OL) and will be summarized using the following 
categories: new or worsened symptoms, symptoms present and unchanged, no symptoms, and 
improved. 
5.5.7. 
Profile of Mood States 2nd edition (POMS-2) 
The POMS-2 is a self-report measure that allows for the quick assessment of transient, 
fluctuating feelings, and enduring affect states.4,5 Full-length versions (65 items) yield several 
scale scores: Anger-Hostility, Confusion-Bewilderment, Depression-Dejection, Fatigue-Inertia, 
Tension-Anxiety, Vigor-Activity and Friendliness. Each item is rated on a scale of 0 to 4 (0= 
“not at all”, 1= “a little”, 2= “moderately”, 3= “quite a bit”, 4= “extremely”). Total Mood 
Disturbance is a function of these 6 scale scores, shown in Table 9. The recall period for this 
study is 7 days. 
Table 9: POMS-2 Scoring 
Component 
Questions 
Anger-Hostility (AH) 
Sum of 3, 14, 21, 28, 30, 35, 38, 43, 48, 49, 52 
Confusion-Bewilderment (CB) 
Sum of 6, 8, 15, 25, 34, 46, 50, 54, 58, 63 
Depression-Dejection (DD) 
Sum of 5, 11, 18, 20, 29, 32, 33, 40, 41, 44, 53, 56, 61 
Fatigue-Inertia (FI) 
Sum of 4, 26, 36, 42, 45, 59 
Tension-Anxiety (TA) 
Sum of 2, 9, 13, 17, 19, 23, 24, 31, 37, 65 
Vigor-Activity (VA) 
Sum of 7, 12, 16, 47, 55, 57, 60, 62, 64 
Friendliness (F)* 
Sum of 1, 10, 22, 27, 39, 51 
Total Mood Disturbance (TMD) 
AH + CB + DD + FI + TA – VA 
*F does not contribute to TMD 
 
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Descriptive statistics (N, mean, median, minimum, and maximum) of the total scores and each 
component scores, as well as the changes from baseline will be summarized at each time point 
during PT phase and follow-up phases. Mean (SE) POMS-2 values, total scores and each 
component scores, will be presented graphically for PT phase and follow-up phases. 
6. 
Pharmacokinetics/Pharmacodynamics Analysis 
All plasma concentrations below quantification limit (BQL) or missing data will be labeled as 
such in the concentration data presentation. All subjects and samples excluded from the analysis 
will be clearly documented in the Clinical Study Report. 
6.1. 
Pharmacokinetics (Plasma concentrations) 
6.1.1. 
Statistical Analysis of Pharmacokinetics: (Descriptive Statistics) 
Descriptive statistics (N, mean, standard deviation, %CV, median, minimum and maximum) will 
be calculated to summarize plasma esketamine and noresketamine concentrations at each 
sampling time point by esketamine treatment and study day (Day 4[DB], Day 25[DB] and Day 
25[OL]).  Subjects will be excluded from the PK analysis if their data did not allow for accurate 
assessment (eg, incomplete administration of the study drug; missing information of dosing and 
sampling times).  
For descriptive statistics of the plasma esketamine and noresketamine, following data handing 
rules will be applied: 
 
Data from samples outside Visit window rule and Time window rule specified in Section 2.3 
Table 1 and Table 10 will be excluded in the calculation. 
 
BQL will be substituted with “0 (zero)”.  
 
Number of plasma concentration data will be calculated based on the number of subjects 
with measurable value including BQL. 
 
When more than half (>50%) of plasma concentration are BQL at each scheduled time point, 
mean, median, and minimum will be shown as ‘BQL’’, and SD, and %CV will be shown as 
“NC” (not-calculated), respectively. If all plasma concentrations are BQL, maximum will 
also be shown as “BQL”.  
 
When number of plasma concentration data is equal to or less than 2, only N and mean will 
be calculated and SD, %CV, median, minimum and maximum will be shown as “NC” 
regardless of the proportion of BQL, respectively. 
 
If the dose level is modified from the initially planned dose on blood sampling day, plasma 
concentration data for that day will be excluded from the descriptive statistics. 
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Table 10: Pharmacokinetic sampling time per Protocol and for analysis 
Nominal time (Analysis time point)
Time window 
(h) 
(min)
 
(min) 
Postdose 
0.67
40
 
32 - 
48 
1
60
 
48 a - 
72 
2
120
 
96 - 
144 
a: If PK sample for 40 min post dose is collected at 48 min, 48 min is not included in the time window for PK 
sampling at 1 h post dose. 
 
The plasma esketamine and noresketamine concentrations will be tabulated and summarized by 
esketamine treatment, respectively. Individual concentrations will be listed. 
Population PK analysis of plasma concentration-time data of esketamine (and noresketamine or 
other metabolites, if needed) will be performed with non-linear mixed-effects modeling 
(NONMEM) approach. If deemed necessary, data will be combined with data from other studies. 
Details will be given in a population PK analysis plan will be presented in a separate report 
6.1.2. 
Generating Pharmacokinetic Profiles 
The following graphs will be produced: 
 
Boxplot of the esketamine exposure at 40 minutes, 1 and 2 hours postdose (DB induction 
phase, Study Day 4 and Study Day 25). 
 
Boxplot of the noresketamine exposure at 40 minutes, 1 and 2 hours postdose (DB induction 
phase, Study Day 4 and Study Day 25). 
6.2. 
Pharmacokinetic/Pharmacodynamic Relationships 
The PK/PD analysis will be based on the PK/PD analysis set (defined in Section 2.4.6) for 
nominal time-matched plasma concentrations and safety parameters. 
Safety parameter: blood pressure (DBP and SBP), QTcF and CADSS total score 
 
DBP and SBP: 40 minutes and 1 hour postdose, Day 4(DB), 25(DB) and Day 25(OL) 
 
QTcF: 1 hour postdose, Day 25(DB) and Day 25(OL) 
 
CADSS total score: 40 minutes, Day 4(DB), 25(DB) and Day 25(OL) 
The following plots will be generated to evaluate the relationship between safety parameter 
(absolute value and change [change from predose for SBP, DBP and CADSS total score, change 
from baseline for QTcF]) and plasma concentrations of esketamine by phases: 
 
DBP at each time-matched point of measurement from each dose will be plotted against the 
corresponding plasma concentration of esketamine.  
 
SBP at each time-matched point of measurement from each dose will be plotted against the 
corresponding plasma concentration of esketamine.  
 
QTcF at each time-matched point of measurement from each dose will be plotted against the 
corresponding plasma concentration of esketamine. 
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 
CADSS total score at each time-matched point of measurement from each dose will be 
plotted against the corresponding plasma concentration of esketamine. 
 
Additional plots will be produced, if deemed necessary. 
Pearson product moment correlations (R2) will be calculated for nominal time-matched plasma 
concentrations and safety parameter. 
The above analyses will be repeated for noresketamine. 
Population PK/PD (MADRS total score and possibly selected AEs as additional PD parameters) 
analysis may be evaluated. If there is any visual trend in graphical analysis, suitable models will 
be applied to describe the PK/PD relationships. Details will be given in a PK/PD analysis plan 
will be presented in a separate report. 
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REFERENCES 
1. 
Bornkamp, B., Pinheiro, J.C., and Bretz, F. (2009) MCPMod - An R Package for the Design and Analysis of 
Dose-Finding Studies. Journal of Statistical Software, 29(7), 1–23. 
2. 
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. 
3. 
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. 
4. 
Juvia PH, Douglas MM. Profile of Mood States. 2nd ed. Canada: Multi-Health Systems Inc., 2012. 
5. 
Juvia PH, Douglas MM, Kazuhito Y (eds.). Profile of Mood States. 2nd ed. Japanese manual. Japan: 
Kanekoshobo, 2015. 
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. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: the PHQ 
primary care study. JAMA. 1999; 282:1737-1744. 
12. 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 (U/L) 
N/A 
990 
Creatinine [µmol/L] 
N/A 
265.2 
Gamma glutamyl transferase [U/L] 
N/A 
300 
Glucose [mmol/L] 
2.2 
16.7 
Phosphate [mmol/L] 
0.7 
2.6 
Potassium [mmol/L] 
3.0 
5.8 
Sodium [mmol/L] 
125 
155 
Bilirubin, total [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 [%] 
30 
90 
Monocytes [%] 
N/A 
20 
Eosinophils [%] 
N/A 
10 
Basophils [%] 
N/A 
6 
Lymphocytes [%] 
10 
60 
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] 
 
> 3X ULN 
AND 
 
 
Bilirubin, total [µmol/L] 
 
>2X ULN 
Note: The same limits apply to both males and females unless sex is indicated; N/A = Not applicable. 
 
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