Conditions: Depressive Disorder, Treatment-Resistant
Keywords: Depressive Disorder, Treatment-Resistant Esketamine Oral Antidepressant Elderly Participants
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 139
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of switching elderly participants with treatment-resistant depression (TRD) from a prior antidepressant treatment (to which they have not responded) to either intranasal esketamine plus a new oral antidepressant or switching to a new oral antidepressant plus intranasal placebo.

Detailed description:
This is a randomized, double-blind (neither the researchers nor the participants know what treatment the participant is receiving), active-controlled, multicenter study (more than 1 study site) in elderly participants with TRD to assess the efficacy, safety, and tolerability of flexible doses of intranasal esketamine plus a newly initiated oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus intranasal placebo. The study will consist of 3 phases: Screening/Prospective Observational Phase (4 to 7 weeks), Double-blind induction Phase (4 weeks), Follow up Phase (2 weeks). Participants who rollover into a long-term open-label safety study will not participate in the Follow-up Phase. At the start of the Screening/Prospective observational Phase, participant must have had documented nonresponse to at least one antidepressant treatment (based on Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire \[MGH-ATRQ\] criteria) in the current episode of depression, and the participant is taking a different oral antidepressant treatment on the MGH-ATRQ for at least the previous 2 weeks at or above the minimum therapeutic dose. This antidepressant treatment will be discontinued prior to the double-blind induction Phase. Participants taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of lorazepam) and/or permitted non-benzodiazepine sleep medications (example, zolpidem, zaleplon) during the screening/prospective observational phase can continue these medications. All participants will start with first dose (Day 1 as 28 milligram \[mg\]); second dose (Day 4) is either 28 or 56 mg. All subsequent doses may be 28, 56 or 84 mg. After the first dose, all dosing decisions are determined by the investigator based on efficacy and tolerability. In addition, each participant will be assigned to receive 1 of 4 oral antidepressant medications from 2 different classes of antidepressant treatments, a Selective Serotonin Reuptake Inhibitor (SSRI) (escitalopram or sertraline) or a Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) \[duloxetine or venlafaxine extended release (XR)\], initiated on Day 1 and continued through the double-blind induction Phase. Participants will be primarily evaluated for improvement in depressive symptoms as assessed by change in Montgomery Asberg Depression Rating Scale (MADRS) total score at Week 4. Participants' safety will be monitored throughout the study.

Arms:
arm 1: Participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen in the Double-Blind Induction Phase. All participants will start with first dose (Day 1 as 28 milligram \[mg\]); second dose (Day 4) is either 28 or 56 mg. All subsequent doses may be 28, 56 or 84 mg. After the first dose, all dosing decisions are determined by the investigator based on efficacy and tolerability. In addition participants will simultaneously initiate a new, open-label oral antidepressant (Duloxetine, Escitalopram, Sertraline, or Venlafaxine extended release \[XR\]) on Day 1 that will be continued for the duration of Double-Blind Induction Phase. arm 2: Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a flexible dose regimen in Double-Blind Induction Phase using the same titration as Esketamine. In addition participants will simultaneously initiate a new, open-label oral antidepressant (Duloxetine, Escitalopram, Sertraline, or Venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.

Interventions: intervention 1: Esketamine intervention 2: Placebo intervention 3: Duloxetine (Oral Antidepressant) intervention 4: Escitalopram (Oral Antidepressant) intervention 5: Sertraline (Oral Antidepressant) intervention 6: Venlafaxine Extended Release (XR) (New Antidepressant)
Intervention descriptions: intervention 1: All participants will start with first dose (Day 1 as 28 milligram \[mg\]); second dose (Day 4) is either 28 or 56 mg. All subsequent doses may be 28, 56 or 84 mg. After the first dose, all dosing decisions are determined by the investigator based on efficacy and tolerability. intervention 2: Participants will self-administer matching placebo, intranasally, twice per week for 4-weeks as a flexible dose regimen in the Double-Blind Induction Phase. intervention 3: Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital -Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day). intervention 4: Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be given at a dose of 10 mg/day throughout the Double-Blind Induction Phase. This dose (10 mg/day) is the also the minimum therapeutic dose. intervention 5: Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline may be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day. intervention 6: Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release may be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 75 mg/day.

Protocol document:
Prot_000.pdf: 
Status: Approved, Date: 18 July 2016
1
Janssen Research & Development*
Clinical Protocol
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 Treatment-resistant Depression
Trial of Rapid-acting Intranasal Esketamine for Treatment-resistant Major Depressive Disorder 
(TRANSFORM-3)
Protocol ESKETINTRD3005; Phase 3
AMENDMENT 3
JNJ-54135419 (esketamine)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Janssen Sciences Ireland UC; or Janssen 
Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent these 
various legal entities; the sponsor is identified on the Contact Information page that accompanies the 
protocol.
This compound is being investigated in Phase 3 clinical studies.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2014-004588-19
Status:
Approved
Date:
18 July 2016
Prepared by:
Janssen Research & Development, LLC
EDMS number and version:
EDMS-ERI-93094734, 4.0
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.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 32
TIME AND EVENTS SCHEDULE (Screening/Prospective Observational Phase and Double-
blind Induction Phase).............................................................................................................................. 44
TIME AND EVENTS SCHEDULE (Follow-up Phase) .............................................................................. 49
ABBREVIATIONS ...................................................................................................................................... 51
1.
INTRODUCTION................................................................................................................................ 53
1.1.
Background .................................................................................................................................... 54
1.1.1.
Summary of Nonclinical Findings ............................................................................................... 54
1.1.2.
Clinical Studies ........................................................................................................................... 57
1.1.2.1.
Pharmacokinetics and Product Metabolism ............................................................................ 57
1.1.2.2.
Pharmacodynamics and Efficacy ............................................................................................ 59
1.1.2.3.
Safety and Tolerability............................................................................................................. 61
1.1.3.
Marketing Experience................................................................................................................. 66
1.2.
Active Comparators in Double-blind Induction Phase ................................................................... 66
1.2.1.
Selective Serotonin Reuptake Inhibitors..................................................................................... 67
1.2.1.1.
Escitalopram............................................................................................................................ 67
1.2.1.2.
Sertraline ................................................................................................................................. 67
1.2.2.
Serotonin and Norepinephrine Reuptake Inhibitors ................................................................... 68
1.2.2.1.
Duloxetine................................................................................................................................ 68
1.2.2.2.
Venlafaxine Extended-release................................................................................................. 69
1.3.
Overall Rationale for the Study...................................................................................................... 70
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 70
2.1.
Objectives ...................................................................................................................................... 70
2.2.
Hypothesis ..................................................................................................................................... 71
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 71
3.1.
Overview of Study Design.............................................................................................................. 71
3.2.
Study Design Rationale.................................................................................................................. 74
3.2.1.
Study Population......................................................................................................................... 74
3.2.2.
Study Phases.............................................................................................................................. 75
3.2.3.
Blinding and Randomization....................................................................................................... 77
3.2.4.
Treatment Groups and Dose Selection ...................................................................................... 77
3.2.5.
Efficacy Measures ...................................................................................................................... 79
3.2.6.
Safety Evaluations...................................................................................................................... 79
3.2.7.
Other Assessments .................................................................................................................... 81
3.2.8.
Pharmacokinetic Assessments................................................................................................... 81
3.2.9.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations .............................. 81
4.
STUDY POPULATION ...................................................................................................................... 82
4.1.
Inclusion Criteria ............................................................................................................................ 82
4.2.
Exclusion Criteria ........................................................................................................................... 84
4.3.
Prohibitions and Restrictions ......................................................................................................... 90
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 91
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JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
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6.
DOSAGE AND ADMINISTRATION .................................................................................................. 92
6.1.
Screening/Prospective Observational Phase ................................................................................ 92
6.2.
Double-Blind Induction Phase........................................................................................................ 93
6.2.1.
Guidance for Blood Pressure Monitoring on Intranasal Treatment Session Days..................... 95
6.3.
Follow-up Phase ............................................................................................................................ 96
7.
TREATMENT COMPLIANCE............................................................................................................ 96
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 97
9.
STUDY EVALUATIONS .................................................................................................................... 98
9.1.
Study Procedures........................................................................................................................... 98
9.1.1.
Overview..................................................................................................................................... 98
9.1.2.
Screening/Prospective Observational Phase ............................................................................. 99
9.1.3.
Double-Blind Induction Phase .................................................................................................. 101
9.1.4.
Follow-up Phase....................................................................................................................... 102
9.2.
Efficacy......................................................................................................................................... 103
9.2.1.
Evaluations ............................................................................................................................... 103
9.2.1.1.
Primary Efficacy Evaluation................................................................................................... 103
9.2.1.2.
Secondary Efficacy Evaluations (Clinician-completed) ......................................................... 103
9.2.1.2.1.
CGI-S ................................................................................................................................. 103
9.2.1.3.
Other Secondary Efficacy Evaluations (Patient-reported Outcomes) ................................... 104
9.2.1.3.1.
EQ-5D-5L ........................................................................................................................... 104
9.2.2.
Endpoints.................................................................................................................................. 104
9.2.2.1.
Primary Endpoint ................................................................................................................... 104
9.2.2.2.
Secondary Endpoints ............................................................................................................ 104
9.3.
Pharmacokinetics......................................................................................................................... 104
9.3.1.
Evaluations ............................................................................................................................... 105
9.3.2.
Analytical Procedures............................................................................................................... 105
9.3.3.
Pharmacokinetic Parameters ................................................................................................... 105
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations........................................................................ 105
9.5.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations................................ 105
9.6.
Safety Evaluations ....................................................................................................................... 106
9.7.
Other Evaluations......................................................................................................................... 114
9.8.
Sample Collection and Handling.................................................................................................. 115
10.
SUBJECT COMPLETION/WITHDRAWAL..................................................................................... 116
10.1.
Completion ................................................................................................................................... 116
10.2.
Withdrawal From the Study.......................................................................................................... 116
10.3.
Withdrawal From the Use of Samples in Future Research.......................................................... 117
11.
STATISTICAL METHODS............................................................................................................... 117
11.1.
Subject Information ...................................................................................................................... 117
11.2.
Sample Size Determination ......................................................................................................... 118
11.3.
Interim Analysis for Sample Size Re-estimation or Stopping for Futility...................................... 118
11.4.
Efficacy Analyses ......................................................................................................................... 119
11.5.
Pharmacokinetic Analyses........................................................................................................... 119
11.6.
Pharmacokinetic/Pharmacodynamic Analyses............................................................................ 120
11.7.
Biomarker and Pharmacogenomic Analyses............................................................................... 120
11.8.
Safety Analyses ........................................................................................................................... 120
11.9.
Independent Data Monitoring Committee .................................................................................... 122
12.
ADVERSE EVENT REPORTING .................................................................................................... 122
12.1.
Definitions .................................................................................................................................... 123
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 123
12.1.2.
Attribution Definitions................................................................................................................ 124
12.1.3.
Severity Criteria ........................................................................................................................ 124
12.2.
Special Reporting Situations........................................................................................................ 125
12.3.
Procedures................................................................................................................................... 125
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Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
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12.3.1.
All Adverse Events.................................................................................................................... 125
12.3.2.
Serious Adverse Events ........................................................................................................... 126
12.3.3.
Pregnancy................................................................................................................................. 127
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 127
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 127
13.1.
Procedures................................................................................................................................... 128
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 128
14.
STUDY DRUG INFORMATION....................................................................................................... 128
14.1.
Physical Description of Study Drug(s) ......................................................................................... 128
14.2.
Packaging .................................................................................................................................... 129
14.3.
Labeling........................................................................................................................................ 130
14.4.
Preparation, Handling, and Storage............................................................................................. 130
14.5.
Drug Accountability ...................................................................................................................... 130
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 131
16.
ETHICAL ASPECTS ....................................................................................................................... 131
16.1.
Study-specific Design Considerations ......................................................................................... 131
16.2.
Regulatory Ethics Compliance..................................................................................................... 134
16.2.1.
Investigator Responsibilities ..................................................................................................... 134
16.2.2.
Independent Ethics Committee or Institutional Review Board (IEC/IRB)................................. 134
16.2.3.
Informed Consent ..................................................................................................................... 135
16.2.4.
Privacy of Personal Data .......................................................................................................... 136
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 137
16.2.6.
Country Selection ..................................................................................................................... 137
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 137
17.1.
Protocol Amendments.................................................................................................................. 137
17.2.
Regulatory Documentation .......................................................................................................... 138
17.2.1.
Regulatory Approval/Notification .............................................................................................. 138
17.2.2.
Required Prestudy Documentation........................................................................................... 138
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 139
17.4.
Source Documentation................................................................................................................. 139
17.5.
Case Report Form Completion .................................................................................................... 140
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 140
17.7.
Record Retention ......................................................................................................................... 141
17.8.
Monitoring .................................................................................................................................... 141
17.9.
Study Completion/Termination..................................................................................................... 142
17.9.1.
Study Completion ..................................................................................................................... 142
17.9.2.
Study Termination..................................................................................................................... 142
17.10.
On-site Audits............................................................................................................................... 142
17.11.
Use of Information and Publication.............................................................................................. 143
REFERENCES.......................................................................................................................................... 145
INVESTIGATOR AGREEMENT ............................................................................................................... 157
LIST OF ATTACHMENTS
Attachment 1: 
Prohibited Concomitant Medications with Intranasal Study Medication 
(Esketamine or Placebo) .......................................................................................... 150
Attachment 2:
New York Heart Association Classification of Cardiac Disease............................... 153
Attachment 3:
Oral Antidepressant Titration Schedule for Double-Blind Induction Phase.............. 154
Attachment 4:
Anticipated Events.................................................................................................... 155
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
5
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 ........................................... 62
Table 2: 
Mean Supine Blood Pressure and Heart Rate - Cohort 1 (ESKETINTRD1012)...................... 63
Table 3:
Intranasal Treatment Sessions Administration During the Double-blind Induction 
Phase........................................................................................................................................ 93
Table 4
Dose Titration of Intranasal Esketamine* ................................................................................. 94
Table 5:
Volume of Blood to Be Collected From Each Subject .............................................................. 99
FIGURES
Figure 1:
Study Design for ESKETINTRD3005 ....................................................................................... 74
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
6
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
10 March 2015
Amendment 1
08 June 2015
Amendment 2
10 January 2016
Amendment 3
18 July 2016
Amendments below are listed beginning with the most recent amendment.
Amendment 3 (18 July 2016) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is to improve recruitment while 
maintaining the integrity of the study. Changes are made that relate to the elderly population specifically (which 
differ in some aspects from younger patients) not included in the original protocol.
Applicable Section(s)
Description of Change(s)
Rationale: Montgomery-Asberg Depression Rating Scale (MADRS) scores in the elderly, per multiple expert 
opinions are lower than in younger patients. This difference is attributed to the tendency of the elderly to minimize 
symptoms. Therefore, a lower MADRS total cut-off score of 24 will be used for the elderly to align with a MADRS 
total score of 28 used in younger subjects.
Synopsis Overview of Study 
Design;
Synopsis Study Population;
3.1. Overview of Study Design;
3.2.1. Study Population;
4.1. Inclusion Criterion;
6.1. Screening/Prospective
Observational Phase;
9.1.2. Screening/Prospective
Observational Phase
MADRS total score changed from ≥28 to ≥24, wherever the original value 
of 28 occurs.
Rationale: The Inventory of Depressive Symptomatology-Clinician rated, 30-item scale (IDS-C30) scores in the 
elderly, as per multiple expert opinions, are lower than in younger subjects, because of the tendency to minimize 
symptoms (as with the MADRS scores). Therefore, a lower IDS-C30 cut-off score of 31 for the elderly will be more 
aligned with the MADRS total score of ≥24 that will be used in the elderly.
Synopsis Study Population;
3.2.1. Study Population;
4.1. Inclusion Criterion;
9.1.2. Screening/Prospective
Observational Phase
IDS-C30 score changed from ≥34 to ≥31, wherever the original value of 34 
occurs.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
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Applicable Section(s)
Description of Change(s)
Rationale: Criteria for the minimum number of oral antidepressant treatments in the current episode of depression 
with non-response at the start of the Screening/Prospective Observational Phase, has been revised from ≥2 to ≥1. 
The elderly are more likely to have longer episodes of depression, and to have been on more oral antidepressants
during the episode, than younger subjects. Therefore, the criteria for the maximum number of oral antidepressant 
treatments in the current episode of depression with non-response at the start of the Screening/Prospective 
Observational Phase, has been revised from ≤5 to ≤8. This change is supported by discussions with multiple experts 
in geriatric psychiatry. 
Synopsis Study Population;
3.2.1. Study Population;
4.1. Inclusion Criterion;
9.1.2. Screening/Prospective
Observational Phase
Change in the number of oral antidepressants allowed during the current 
episode from ≥2 to ≤5 to ≥1 to ≤8. 
Rationale: Patients with Parkinson’s disease were previously excluded as some have cognitive impairment. 
However, many patients with Parkinson’s disease who suffer from depression do not have cognitive impairment, 
and the exclusion criteria has therefore, been revised to allow these patients to be included in the study.
Synopsis Study Population;
4.2. Exclusion Criteria
Exclusion Criterion no. 12 has been modified:
The text previously stated that subjects with Parkinson’s will be excluded.
The text has been revised (new text in bold): ‘Subjects with Parkinson’s 
disease with clinical evidence of cognitive impairment will be excluded’.
Rationale: Medical stabilization, allowed during the Screening/Prospective Observation period, may take longer in 
the elderly where changes are slower. 
Synopsis Overview of Study 
Design;
Time & Events Table footnote (a);
3.1. Overview of Study Design;
3.2.2. Study Phases;
9.1.2 Screening/Prospective 
Observational Phase
The text has been revised to indicate that the 3 week period during the 
screening/prospective observational phase may be used for optimization of 
medical management if needed to facilitate subject participation: 
If clinically indicated, a subject’s current antidepressant treatment(s) may be 
tapered and discontinued over an additional, optional period of up to 
3 weeks, per the local prescribing information or per clinical judgment.
The following text has been added: “This 3-week period may also be used to 
optimize medical management if needed to facilitate subject participation 
(eg, treatment of blood pressure or diabetes, wean from other medications, 
etc,). In such cases, if there is no planned taper, the oral regimen should be
continued in the interim and then discontinued by Day 1 of the double-blind 
induction phase. ”
Rationale: Testing is significantly slower in the elderly population and subjects frequently complain of fatigue. 
Cognition testing, in particular, takes longer in the elderly than in the younger subject population. It is considered 
that a baseline may still be established, if values for cognition testing are obtained just prior to the initial date for the 
Double-Blind Induction Phase (Visit 2.1), rather than on the actual date itself.  
Time & Events Schedule,
Screening/Prospective Observational 
Phase
Changes to the text added to allow for some of the assessments (eg, 
cognition) 
to 
take 
place 
either 
during 
the 
last 
visit 
in 
the 
Screening/Prospective Observational Phase (Visit 1.3) or prior to the initial 
visit for the Double-Bind Phase (Visit 2.1). 
Legend s)
Addition of a footnote (s) by cognition testing to indicate that these tests can 
precede Visit 2.1.
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Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
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Applicable Section(s)
Description of Change(s)
Rationale: Following discussions with a leading expert within the disease area, a decision has made to remove the 
Smell Threshold test, as this is operationally burdensome to perform and not required for the elderly population. 
Synopsis Safety Evaluations;
Synopsis Statistical Methods;
Time & Events Schedule;
3.2.6. Safety Evaluations;
9.6. Safety Evaluations;
11.8. Safety Analyses
Removal of Smell Threshold test throughout the study
Rationale: To decrease the patient burden, the UPSIT will be assessed prior to and post treatment, only.
Time & Events Schedule
The UPSIT will be assessed on Visit 1.2. of the 
Screening/Prospective/Observational Phase (prior to treatment), and on 
either Visit 2.9 at the end of the Double-Blind Treatment Phase or at the 
Early Withdrawal (EW) visit
Change:
The UPSIT will not be assessed on Visit 2.5. Double-Blind Induction Phase.
Rationale: Following discussions with a leading expert within the disease area, it was decided that 3 booklets 
instead of the original 4 booklets were sufficient to generate UPSIT data for the elderly population, while removal of 
one of the booklets will reduce the operational burden for the elderly subjects. 
9.6. Safety Evaluations 
The description of the UPSIT test has been changed to consist of 3 booklets 
instead of the original 4 booklets.
Rationale: Following discussions with a leading expert within the disease area, it was decided that data from the 
UPSIT was only required from 25% of subjects in the study, and that this would be sufficient to assess any potential 
change in smell in this population. This was based on the expectation that at least 50% of elderly subjects will have 
some diminution of smell (not actual anosmia). Therefore, even if half of the subjects have anosmia (fewer 
expected) at least 25% of the subjects will be able to be evaluated.
4.2. Exclusion Criteria
Exclusion criterion no. 7 has been deleted.
An UPSIT score is not exclusionary 
Rationale: Analysis of data from elderly subjects in the Phase 3 clinical trial ESKETIN3004, and the Phase 1 
clinical trials ESKETINTRD1003 and ESKETINTRD1012, did not show an effect of esketamine on the PR interval, 
as assessed by electrocardiography.  
4.2. Exclusion Criteria
Exclusion criterion no. 13.2 has been modified:
The following text indicated has been deleted: ‘Evidence of 2nd and 3rd
degree AV block, or 1st degree AV block with PR interval ˃200 msec (if the 
initial PR interval is <240 msec, may repeat the ECG once and use average 
of both readings), complete left bundle branch block (LBBB) or complete 
right bundle branch block (RBBB). 
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
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Applicable Section(s)
Description of Change(s)
Rationale: The Patient Health Questionaire-9 item (PHQ-9) and the Sheehan Disability Scale (SDS), will not be 
used to evaluate efficacy. This will reduce patient burden, without having a marked impact on the data generated 
from this study. 
Synopsis Efficacy 
Evaluations/Endpoints;
Synopsis Statistical Methods;
Time & Events Schedule;
3.2.5. Efficacy Measures;
9.2.1. Evaluations;
9.2.1.2. Key Secondary Efficacy 
Evaluations (Patient-Reported)
9.2.2.2. Secondary Endpoints;
11.4. Efficacy Analyses;
Reference to the Patient Health Questionaire-9 item (PHQ-9) scale and the 
Sheehan Disability Scale (SDS) was removed throughout. 
Rationale: To improve recruitment, the antidepressant treatment requirements at study entry (ie, time of signing the 
ICF) in inclusion criterion no. 3 were changed. In addition, the definition of nonresponse at the end of the 
screening/prospective observational phase was revised.
4.1. Inclusion Criteria
Inclusion criteria no.3 has been revised as follows (bold text added, 
strikethrough text deleted):
At the start of the screening/prospective/observational phase, subject must 
have had nonresponse (≤25% improvement) to ≥1 but ≤8 (if current episode 
is ˃2 years, upper limit applicable to only the last 2 years) oral 
antidepressant treatments in the current episode of depression, assessed 
using the MGH-ATRQ and confirmed by documented records (eg, 
medical/pharmacy/prescription records or a letter from a treating physician, 
etc). In addition, subject is taking a different oral antidepressant treatment 
(on the MGH-ATRQ) for at least the previous 2 weeks at or above the 
minimum therapeutic dose.
-
For specific tricyclic antidepressants which are ongoing and being 
taken at a dose below the MGH-ATRQ minimum therapeutic dose, 
a blood level that is within the therapeutic (antidepressant) range, is 
acceptable to establish the adequacy of the antidepressant 
treatment.
-
Subjects must be adherent to the continued oral antidepressant 
treatment 
medication(s) 
through 
the 
screening/prospective 
observational phase, as documented on the PAQ. Missing ≥4 days 
of antidepressant medication in the prior 2 week period will be 
considered as inadequate adherence.
-
Subjects who are nonresponders to their current oral antidepressant 
medication(s) from the screening/prospective observational phase 
(as assessed by independent, remote raters) may be eligible for 
randomization if all other entry criteria are met. Non-response at 
the end of the screening/prospective observational phase is defined 
as ≤25% improvement in the MADRS total score from Week 1 to 
Week 4 and a MADRS total score of ≥24 on Week 2 and 
Week 4.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
10
Applicable Section(s)
Description of Change(s)
Synopsis Overview of Study 
Design;
Synopsis Study Population;
Synopsis Dosage and 
Administration;
3.1. Overview of Study Design;
3.2.1. Study Population;
6.1. Screening/Prospective 
Observational Phase;
9.1.2. Screening/Prospective 
Observational Phase;
Attachment 1
Synopsis Overview of Study 
Design;
Synopsis Study Population;
3.1. Overview of Study Design;
3.2.1. Study Population;
6.1. Screening/Prospective 
Observational Phase;
9.1.2. Screening/Prospective 
Observational Phase
16.1. Study-specific Design 
Considerations
Text regarding antidepressant treatment during the screening/prospective 
observational phase was revised as follows (bold text added):
At the start of the screening/prospective observational phase, the subject 
must have had documented nonresponse to at least one antidepressant 
treatment (based on MGH-ATRQ criteria) in the current episode of 
depression, and the subject is taking a different oral antidepressant 
treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or 
above the minimum therapeutic dose. This antidepressant treatment, as well 
as any other ongoing medications being taken for depression at screening 
(including adjunctive/augmentation therapies) will continue from the start of 
Week 1 through the end of Week 4 of the screening/prospective 
observational phase. Dose adjustment is permitted per clinical judgment, 
but the oral antidepressant treatment is to remain at or above the 
minimum therapeutic dose (per the MGH-ATRQ) through the end of 
Week 4.
Text regarding nonresponse to oral antidepressant at end of the 
screening/prospective observational phase (strikethrough deleted text):
Non-response at the end of the screening/prospective observational phase is 
defined as ≤25% improvement in the MADRS total score from Week 1 to 
Week 4 for 2 consecutive visits and a MADRS total score of ≥24 for 2 
consecutive visits on Week 2 and Week 4. 
Text regarding subject eligibility was revised as follows (bold text added):
For eligibility, subjects must have had nonresponse to at least one prior 
antidepressant treatment and be currently taking an antidepressant 
treatment at the start of the screening/prospective observational phase 
that will be continued as prospective treatment in the screening/prospective 
observational phase. Only subjects with nonresponse to their current 
antidepressant treatment after 4 weeks of prospectively observed treatment 
(for a total duration of antidepressant treatment of at least 6 weeks by the 
end of the screening/prospective observational phase) will be eligible to 
proceed to the double-blind induction phase, when all subjects will receive a 
new oral antidepressant in addition to intranasal esketamine or placebo.
Rationale: The list of key secondary objectives has been revised to exclude several analyses in order to reduce 
patient burden.
Synopsis Objectives and 
Hypothesis;
2.1. Objectives and Hypothesis
The following text have been deleted as indicated and the parameters listed 
below will not be assessed:
Key Secondary Objectives:
The key secondary objectives are to assess the effect of intranasal 
esketamine plus a newly initiated oral antidepressant compared with a newly
initiated oral antidepressant (active comparator) plus intranasal placebo in 
the following parameters in elderly subjects with TRD.
Functioning and associated disability
Depressive symptoms (subject-reported)
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
11
Applicable Section(s)
Description of Change(s)
Rationale: Inclusion criterion no. 9 was revised to specify the same requirements for contraception for female 
partners of male subjects as specified for female subjects.
4.1. Inclusion Criteria
The text of inclusion criterion no. 9 was revised as follows (bold text 
added):
During the study (ie, from Day 1 of the double-blind induction phase, prior 
to randomization) and for a minimum of 1 spermatogenesis cycle (defined as 
approximately 90 days) after receiving the last dose of intranasal study 
medication, a man who is sexually active with a woman of childbearing 
potential
-
must be practicing a highly effective method of contraception 
with his female partner from those listed above (see examples of 
highly effective methods of contraception provided for female 
subjects). 
-
must use a condom if his partner is pregnant.
-
must agree not to donate sperm.
The following text has been deleted: ‘Alternatively female partners of 
childbearing potential may be practicing a highly effective method of birth 
control: eg, established use of oral, injected, or implanted hormonal methods 
of contraception; placement of an intrauterine device (IUD) or intrauterine 
system (IUS); or male partner sterilization.’
Rationale: The level of education is known to have an impact on the results of the MMSE, with those subjects 
without a high school education having lower results. The exclusion criterion has been modified to allow for this.
Synopsis Study Population;
4.2. Exclusion Criteria;
9.7. Other Evaluations
Exclusion criterion no. 11 has been modified as follows (bold text added):
Subject has a Mini Mental State Examination (MMSE) <25 or <22 for 
those subjects with less than an equivalent of a high school education.
Rationale: Exclusion criterion no. 16 was revised to allow prescription use of psychostimulants with dosing 
restrictions on intranasal treatment session days to allow subjects to safely use at other permitted times during study 
participation.
4.2. Exclusion Criteria
Text in exclusion criterion no. 16 was  revised as follows (bold text added):
Subject has positive test result(s) for drugs of abuse (including barbiturates, 
methadone, opiates, cocaine, phencyclidine, and 
amphetamine/methamphetamine) at the start of the screening/prospective 
observational phase or Day 1 of the double-blind induction phase prior to 
randomization.
-
Subjects who have a positive test result at screening due to 
prescribed 
psychostimulants 
(eg, 
amphetamine, 
methylphenidate, etc.) taken for an indication other than MDD,
are permitted to continue to take this medication during the 
study in accordance with Attachment 1.
-
Otherwise, subjects who have a positive test result at screening 
due to prescribed/over-the-counter opiates, or barbiturates may be 
permitted to continue in the screening/prospective observational 
phase if the medication is discontinued at least 1 week or 5 half-
lives, whichever is longer, before Day 1 of the double-blind 
induction phase (prior to randomization) in accordance with 
Attachment 1 restrictions. The result of the Day 1 (prior to 
randomization) test for drugs of abuse must be negative for the 
subject to be randomized.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
12
Applicable Section(s)
Description of Change(s)
Rationale: Clarifications made regarding the usage of antidepressant treatments for indications other than 
depression during the screening/prospective observational phase, and the use of corticosteroids, psychostimulants, 
and ADHD medications.
8. Prestudy and Concomitant 
Therapy
Attachment 1
The following text was added:
Any medication that is listed on the MGH-ATRQ and is being taken at the 
start of the screening/prospective observational phase for an indication other 
than depression (eg, insomnia) should be continued during the 
screening/prospective observational phase but must be discontinued before 
the start of the double-blind induction phase.
Prohibited Concomitant Medications with Intranasal Study Medication
Changes to the text:
Antidepressants: “Even if used for other indications 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).
Psychostimulants: continuous use permitted (previously prohibited); text 
added “prescribed psychostimulants taken for indications other than MDD 
can be continued but must not be taken within 12 hours prior to the 
intranasal treatment session or for 2 hours after the intranasal treatment 
session”. 
ADHD medications: continuous use permitted (previously prohibited); text 
added “Can be continued but must not be taken within 12 hours prior to the 
intranasal treatment session or for 2 hours after the intranasal treatment 
session).
The following text in the preceeding paragraph on prohibited concomitant 
medications has been revised (text added in bold; strikethrough text 
deleted):
Except where specifically noted, the prohibited medications listed in the 
following table are prohibited from 1 week (or 5 half-lives, whichever is 
longer) prior to the first dose of intranasal study medication until after the 
last dose of intranasal study medication. Note: If a medication is part of the 
antidepressant treatment regimen being taken at the time of signing the ICF 
(ie, start of screening/prospective observational phase), dose adjustment is 
permitted per clinical judgment, but the oral antidepressant treatment 
is to remain at or above the minimum therapeutic dose (per the MGH-
ATRQ) through the end of Week 4. .it must be continued unchanged until 
the end of week 4 of the screening/prospective observational phase. 
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
13
Applicable Section(s)
Description of Change(s)
Rationale: In the previous Amendment, inclusion of subjects who have thyroid-stimulating hormone (TSH) outside 
the normal ranges was permitted, however, the text indicating that a subject must have a normal TSH at screening 
was not removed. This has been corrected in the current Amendment.
4.1 Inclusion Criteria
Inclusion criterion no. 7 revised as follows (bold text added):
Delete following text: subject “must have thyroid stimulating hormone 
(TSH) within normal range in the screening/prospective observational 
phase” and “if the free thyroxine (fT4) is normal, the subject can be 
enrolled”.
-
Subjects with a pre-existing history of thyroid disease/disorder who 
are treated with thyroid hormones must be on a stable dosage for 3 
months prior to the start of the screening/prospective observational 
phase.
-
For any subject (regardless of thyroid history), if the thyroid-
stimulating hormone (TSH) value is out of range, a free thyroxine 
(fT4) will be conducted. If the fT4 value is abnormal and 
considered to be clinically significant (after discussion with the 
medical monitor), the subject is not eligible. 
Rationale: Provide clarification in the footnotes on antidepressant treatment in the screening/prospective 
observational phase, and guidance on repetition of the MADRS assessment.
Time and Events Schedule;
Screening/Prospective Observational 
Phase; Double-blind Induction 
Phase;
Footnote a)
Double-blind Induction Phase;
Footnote c)
Screening/prospective Observational 
Phase;
Double-blind Induction Phase;
Footnote q)
Footnote a) revised as follows (bold text added): 
This 3 week period may also be used to optimize medical management if 
needed to facilitate subject participation. Subjects who do not require a 
taper and are thus eligible to immediately proceed to the double-blind 
induction phase can have Visit 1.3 and Visit 2.1 occur on the same day or 
within 1 week of each other. (If not occurring on the same day, the 
antidepressant treatment regimen should be continued after Visit 1.3 
and then discontinued prior to Visit 2.1).
Delete “only” from footnote c) that refers to MADRS Visit 2.1 Efficacy 
Assessment.
Footnote q) revised as follows (bold text added, strike through deleted text): 
The MADRS should be administered no more than 2 days prior to the 
subject’s targeted (not actual) scheduled clinic visit date (except Visit 2.9, 
which is within 1 day prior). If performed on the day of the scheduled 
clinic visit for an intranasal treatment session, the MADRS must be 
performed prior to the intranasal treatment session.
Rationale: Revise the visit window for Day 28 (Visit 2.9) of the Double-blind Induction Phase to allow more 
flexibility for conducting the visit.  
Time and Events Schedule, 
Double-blind Induction Phase
For Visit 2.9 (Day 28) during the Double-blind Induction Phase, the visit 
window has been revised to ±1 day (rather than -1 day). 
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
14
Applicable Section(s)
Description of Change(s)
Rationale: Addition of footnote to Time & Events Schedule stating that information on adverse events and 
concomitant therapies will be requested by site staff during the Follow-up Phase by remote assessment.
Time and Events Schedule, Follow-
up Phase
The following statement was added as a footnote (e) to the remote 
assessment (Visit 3.1) of the follow-up phase:
For the Remote Assessment (RA) Visit 3.1, site staff will contact the subject 
by telephone to obtain information regarding adverse events and 
concomitant therapies
Rationale: Removal of requirement to report arterial oxygen saturation <93% and any treatment-emergent change 
in the nasal examination as adverse events because adverse event reporting in these instances should be at the 
discretion of the PI.
9.6. Safety Evaluations
Text revised as follows (bold text added):
The following statement was deleted from reporting arterial oxygen 
saturation:
Any arterial oxygen saturation <93% “and lasting for more than 
2 minutes“…”will be reported as an adverse event”
Text now states: “Any arterial oxygen saturation <93% should be confirmed 
by an additional measurement on another part of the body”.
The following statement was deleted from the description of nasal 
examinations: 
“Any treatment-emergent change or worsening from the baseline 
examination will be recorded as an adverse event”.
Rationale: Removal of LSD and MDMA from urine drug screen results that will lead to discontinuation as LSD is 
not measured in the current urine drug screen and prescribed psychostimulants are now permitted.
4.3. Prohibitions and Restrictions
Lysergic acid diethylamide (LSD) and MDMA were deleted from the list of 
drugs that will lead to discontinuation if detected in the urine drug screen 
during the study.
Rationale: Clarification of procedure to follow if subjects wish to withdraw from the study.
10.2 Withdrawal from the Study
Withdrawal of Consent: the following text has been revised  (bold text 
added): 
Subjects who wish to withdraw from the study should be asked if they are 
agreeable to continue to an early withdrawal visit (if withdrawing from 
the double-blind induction phase) and the follow up phase, or to be 
contacted to collect follow-up information.
Rationale: Added definition of treatment-resistant depression (TRD) to the synopsis.
Synopsis Study Population
Definition of TRD from Section 3.2.1 also added to the synopsis under 
Study Population.
‘Treatment-resistant depression (TRD) 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.’
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
15
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of adverse event reporting procedures in the instance of pregnancy. In addition, 
clarification that all SAEs must be reported using the SAE form.
12.3.1. All Adverse Events
Text revised as follows (bold text added):
-
The text stipulating 30 days for reporting serious adverse events has 
been deleted.
All adverse events and special reporting situations, whether serious or non-
serious, will be reported from the time a signed and dated ICF is obtained 
until completion of the subject's last study-related procedure (which may 
include contact for follow-up of safety), with the exception of pregnancy 
which will be reported up to 6 weeks after the last dose of study 
medication (females) or 90 days after the last dose of study medication 
(partners of male participants). Serious adverse events, including those 
spontaneously reported to the investigator, to within 30 days after the last 
dose of study drug must be reported using the Serious Adverse Event Form. 
The sponsor will evaluate any safety information that is spontaneously 
reported by an investigator beyond the time frame specified in the protocol.
Rationale: Minor changes were made throughout the protocol for compliance with updated protocol template text 
and to correct errors.
9.3. Pharmacokinetics
To correct an error, the text was revised to change “serum” to “plasma”:
Plasma collected for PK may additionally be used to evaluate safety or 
efficacy aspects that address concerns arising during or after the study 
period.
17.5 Case Report Form Completion
Delete text stating “All data relating to the study must be recorded in CRF.”
References 
Removed edition number and date from reference 42.
Removed original reference number49 and 86 from the list and updated the 
reference list. 
Investigator Agreement Page
Removed the “LAST PAGE” designation.
Amendment INT-2 (10 January 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: The overall reason for the amendment is to update and/or clarify protocol 
content based on ongoing feedback received during study initiation activities.
Applicable Section(s)
Description of Change(s)
Rationale: Indicate that a subject will be excluded if the subject’s depressive symptoms have previously 
demonstrated nonresponse to esketamine or ketamine in the current major depressive episode.
Synopsis, Study 
Population; 
4.2. Exclusion Criteria
Exclusion criterion no.1 has been revised to state that potential subjects will be excluded 
if the subject’s depressive symptoms have previously demonstrated nonresponse to 
“esketamine or ketamine in the current major depressive episode, per clinical judgment”. 
The following criterion for exclusion has been deleted: “Any subjects who have 
previously received esketamine or ketamine for depression.”
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
16
Applicable Section(s)
Description of Change(s)
Rationale: Clarify that “at least 7 treatments with unilateral ECT” (electroconvulsive therapy) encompasses bilateral 
as well as unilateral ECT treatments.
Synopsis, Study 
Population; 
4.2. Exclusion Criteria
Exclusion criterion no.1 now states “unilateral/bilateral” rather than only “unilateral.”
Rationale: Indicate that subjects who received vagal nerve stimulation in the current depressive episode are 
excluded.
Synopsis, Study 
Population; 
4.2. Exclusion Criteria 
Exclusion criterion no. 2 was revised to now exclude a subject who has received vagal 
nerve stimulation (VNS) in the current depressive episode. It previously stated subjects 
with a vagal nerve implant were excluded.
Rationale: Clarification of the description of major depressive disorder (MDD) and obsessive compulsive disorder 
in the exclusion criteria.
Synopsis, Study 
Population; 
4.2. Exclusion Criteria
The text of exclusion criterion no.3. was modified: 

“MDD with psychosis” was revised to “MDD with psychotic features” 

Only Subjects with “current” obsessive compulsive disorder will be excluded.
Rationale: Clarification of the conditions for exclusion of subjects with coronary artery disease.
4.2. Exclusion Criteria
The text of exclusion criterion no.8. was modified such that the following cardiovascular 
conditions will now be excluded:

Coronary artery disease with myocardial infarction, unstable angina, or 
revascularization procedure (eg, coronary angioplasty or bypass graft surgery) 
within 12 months before the start of the screening/prospective observational phase. 
Subjects who have had a revascularization performed >12 months prior to 
screening and are clinically stable and symptom-free, per investigator’s clinical 
judgment, can be included.
Rationale: Clarification of the wording used for describing a subject’s antihypertensive medication.
4.2. Exclusion Criteria
The text of exclusion criterion no. 9 was revised to now state “antihypertensive 
medication(s)” rather than “antihypertensive medication regimen.”
Rationale: Clarification of definition of clinically significant ECG abnormalities as defined by QT interval 
corrected according to Fridericia’s formula (QTcF).
4.2. Exclusion Criteria
Exclusion criterion no.13 has been revised as follows. The first subbullet in exclusion 
criterion no. 13 was separated into two subbullets (bold text was added):

During screening, a QT interval corrected according to Fridericia's formula 
(QTcF) (ms): ≥450 ms; if the QTcF is prolonged on the initial ECG, the 
average QTcF of three ECGs, recorded at least 4 minutes apart, must not be 
≥450 ms.

On Day 1 (predose), a QT interval corrected according to Fridericia's formula 
(QTcF): ≥450 ms based on the site-evaluated ECG; if the QTcF is prolonged 
on the initial ECG, the average QTcF of three ECGs, recorded at least 4 
minutes apart, must not be ≥450 ms.
In the second subbullet, the bold text was added as shown below:

Evidence of 2nd and 3rd degree AV block, or 1st degree AV block with PR 
interval >200 ms (if the initial PR interval is <240 ms, may repeat the ECG 
once and use average of both readings), complete left bundle branch block 
(LBBB), or complete right bundle branch block (RBBB).
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
17
Applicable Section(s)
Description of Change(s)
Rationale: The use of concomitant medications that prolong the QT interval/corrected QT (QTc) are no longer 
excluded as there is no known QTc increase signal known with esketamine and extensive ECG monitoring is in 
place and precautions in case of increase in QTc are added.
4.2. Exclusion Criteria
Exclusion criterion no. 14 has been revised as follows: 
Subject has a history of additional risk factors for Torsades des Pointes (eg, heart failure, 
hypokalemia, family history of Long QT Syndrome), or the use of concomitant 
medications that prolong the QT/QTc interval.
Rationale: Indicate that the screening test for abnormal ALT and AST may be repeated once during screening if 
there is an explanation for a transient out of range value.
4.2. Exclusion Criteria
Text was added to exclusion criterion no. 15 to specify that a repeat of the screening test  
for abnormal ALT and AST is permitted once during the screening period, per 
investigator discretion, provided there is an explanation for a transient out of range 
value.
Rationale: Clarification that a positive test for cannabinoids on Day 1 is exclusionary, but not at screening.
4.2. Exclusion Criteria
Text of exclusion criterion no. 16 was revised to clarify that a positive test for 
cannabinoids at the start of the screening/prospective phase is not exclusionary; 
however, a positive test for cannabinoids on Day 1 (predose) of the double-blind-
treatment phase is exclusionary.
Rationale: The term “secondary diabetes” was removed from exclusion criterion no. 18 because the criterion states 
that any uncontrolled diabetes mellitus is exclusionary.
4.2. Exclusion Criteria
The text of exclusion criterion no. 18 was modified to delete the phrase “or secondary 
diabetes”.
Rationale: Provide clarification that the investigator’s clinical judgment based on assessment will be used to 
determine eligibility of subjects who have any anatomical or medical condition that may impede delivery or 
absorption of intranasal study drug.
4.2. Exclusion Criteria
The text of exclusion criterion no. 20 was modified to indicate that the “investigator’s 
clinical judgment based on assessment” will be used to determine eligibility.
Redundant text (ie, examples of structural or functional abnormalities) has been deleted.
Rationale: Exclusion criterion no. 21 is no longer required as it is covered as part of exclusion criterion no. 20.
4.2. Exclusion Criteria
The text of exclusion criterion no. 21 has been deleted.
Rationale: Clarify that a subject with obstructive sleep apnea can be included if the subject receives effective 
treatment/therapy, which results in an apnea-hypopnea index of <30.
Synopsis, Study 
Population; 
4.2. Exclusion Criteria

The text of exclusion criterion no. 25 has been modified as follows (bold text 
added):
“Subject has a score of 5 on the STOP-Bang questionnaire, in which case 
obstructive sleep apnea must be ruled out (eg, apnea-hypopnea index [AHI] <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.”

In the list of exclusion criteria in the synopsis (Study Population), the text “STOP-
Bang questionnaire score of ≥5” has been deleted as this is not necessarily an 
exclusion per exclusion criterion no. 25.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
18
Applicable Section(s)
Description of Change(s)
Rationale: Clarify that a subject is excluded if the subject has participated in 2 or more interventional studies (for a 
psychiatric condition) with different investigational drugs, or the subject is enrolled in an investigational study, 
which is interventional.
4.2. Exclusion Criteria
The text of exclusion criterion no. 26 has been modified as follows (bold text added):
“Subject has received an investigational drug (including investigational vaccines) or 
used an invasive investigational medical device within 60 days before the start of the 
screening/prospective observational phase, or has participated in 2 or more MDD or 
other psychiatric condition clinical interventional studies (with different 
investigational drugs including investigational vaccines or investigational medical 
devices for each study) in the previous 1 year before the start of the 
screening/prospective observational phase, or is currently enrolled in an investigational 
interventional study.”
Rationale: Subjects with severe renal impairment (creatinine clearance <30 ml/min) are being excluded (exclusion 
criterion no. 31) as a safety precaution, since the effect of impaired renal clearance on the pharmacokinetics of 
intranasal esketamine is not fully known and subjects may be more vulnerable to blood pressure increases.
4.2. Exclusion Criteria
Exclusion criterion no. 31 for all subjects was added: “Severe renal impairment 
(creatinine clearance <30 ml/min).”
Rationale: Clarification added to inclusion criterion regarding nonresponse to oral antidepressant treatments in 
current episode of depression. 
Synopsis, Overview of 
Study Design, Study 
Population, Dosage and 
Administration; 
3.1. Overview of Study 
Design; 3.2.1. Study 
Population;
4.1. Inclusion Criteria; 
6.1. 
Screening/Prospective 
Observational Phase; 
9.1.2. 
Screening/Prospective 
Observational Phase
The text of inclusion criterion no. 3 was modified to state that the subject must:

Have had nonresponse (≤25% improvement) to ≥2 but ≤5 (if current episode is >2 
years, upper limit applicable to only the last 2 years) oral antidepressant treatments 
in current episode of depression.

Have 
had 
nonresponse 
confirmed 
by 
documented 
records 
(eg, 
medical/pharmacy/prescription records, a letter from treating physician, etc.).

Be taking one of the oral antidepressant treatment(s) with nonresponse that is 
documented on the MGH-ATRQ (ie, oral antidepressant treatment must be taken 
for at least 6 weeks at the minimum therapeutic dose with a lack of clinically 
meaningful improvement) at the start of the screening/prospective observational 
phase.
The following text was added to specify the criteria for non-response at the end of the 
screening/observational phase: “Non-response at the end of the screening/prospective 
observational phase is defined as ≤25% improvement in the MADRS total score for 2 
consecutive visits and a MADRS total score of ≥28 for 2 consecutive visits.”
Other sections of the text were revised to correspond to the changes in the inclusion 
criterion. 
Rationale: Indicate that the severity of a subject’s depressive symptoms in the current major depressive episode 
must also be confirmed using a Site Independent Qualification Assessment.
Synopsis, Study 
Population; 3.2.1. Study 
Population;
4.1. Inclusion Criteria; 
9.1.2. 
Screening/Prospective 
Observational Phase
The text of inclusion criterion no. 5 was modified as follows (bold text added): “The 
subject’s current major depressive episode, depression symptom severity (Week 1 
MADRS total score ≥28 required), and antidepressant treatment response in the 
current depressive episode, must be confirmed using the Site Independent Qualification 
Assessment.”
Other sections of the text were revised to correspond to the changes in the inclusion 
criterion.
Text was added in Section 3.2.1 (Study Population) indicate that the severity of a 
subject’s depressive symptoms must be confirmed using a Site Independent 
Qualification Assessment.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
19
Applicable Section(s)
Description of Change(s)
Rationale: Clarify text in inclusion criterion regarding additional lab test for assessing levels of free thyroxine.
4.1. Inclusion Criteria; 
9.1.1 Overview, Table 5; 
9.6 Safety Evaluations
Text was added to inclusion criterion no. 7 to clarify that for any subject (regardless of 
thyroid history), if the TSH value is out of range, a free thyroxine (fT4) will be 
conducted. If the fT4 is normal, the subject can be enrolled. If the fT4 value is out of 
range, the subject is not eligible.
The following statements were deleted from inclusion criterion no. 7:

For those without a pre-existing history of hypothyroidism, a normal thyroid-
stimulating hormone [TSH] is required at screening.

If the TSH is below the normal range, free thyroxine (fT4) levels will be measured 
and if fT4 is within the normal range the subject can be enrolled.
Other sections of the text were revised to correspond to the changes in the inclusion 
criterion.
Row was added to Table 5 in Section 9.1.1 (Overview) to specify the volume of blood 
per sample used to assess levels of fT4, and footnote ‘e’ was added to this table to 
specify that for any subject (regardless of thyroid history), if the TSH value is out of 
range, a free thyroxine will be conducted.
Rationale: The text in inclusion criterion no. 9 was revised to clarify the description of methods of birth control for 
a man who is sexually active with a woman of childbearing potential or a woman who is pregnant.
4.1. Inclusion Criteria
The text of inclusion criterion no. 9 was modified as follows (bold text was added):
A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy must agree to use a barrier method of birth control eg, either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository from Day 1 of 
the double-blind induction phase (prior to randomization) through 3 months after the last 
dose of intranasal study medication. During the study (ie, from Day 1 of the double-
blind induction phase, prior to randomization) and for a minimum of 1 
spermatogenesis cycle (defined as approximately 90 days) after receiving the last 
dose of intranasal study medication, in addition to the user independent highly 
effective method of contraception, a man 

who is sexually active with a woman of childbearing potential must agree to 
use a double-barrier method of contraception (eg, diaphragm or cervical/vault 
caps plus condom with spermicidal foam/gel/film/cream/suppository)

who is sexually active with a woman who is pregnant must use a condom

must agree not to donate sperm.
Alternatively female partners of childbearing potential may be practicing a highly 
effective method of birth control: eg, established use of oral, injected, or implanted 
hormonal methods of contraception; placement of an intrauterine device (IUD) or 
intrauterine system (IUS); or male partner sterilization.
Note: If the female partner’s childbearing potential changes after start of the study, a
the female partner of a male study subject, must begin a highly effective method of birth 
control, as described above.
Rationale: Correct a statement referring to the US prescribing information for duloxetine.
1.2.2.1. Duloxetine
The phrase “Although not in the US prescribing information” was deleted from the 
statement regarding evaluation of an initial dose of 30 mg/day as the US prescribing 
information for duloxetine does indicate that for some patients, it may be desirable to 
start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before 
increasing to 60 mg once daily. 
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
20
Applicable Section(s)
Description of Change(s)
Rationale: Text added to provide the details of predose procedures to be followed in the event an intranasal 
treatment session is postponed/delayed (within the visit window) due to a predose vital sign assessment.
Time & Events 
Schedule; 9.6. Safety 
Evaluations
Text was added in the description of safety evaluations to indicate that if an intranasal 
treatment session is postponed/delayed (within the visit window) due to a predose vital 
sign assessment, all time points of the following assessments must be repeated on the 
actual intranasal treatment session day: vital signs, 12-lead ECG, C-SSRS, MOAA/S, 
pulse oximetry, BPRS+, and CADSS.
In the Time & Events Schedule (Screening/prospective Observational Phase and 
Double-blind Phase), the text of footnote ‘o’ was revised for consistency with the text 
added in the description of safety evaluations, and footnote ‘o’ was deleted from the row 
for CGADR assessment.
Rationale: MADRS total score is to be recorded at Study Day 22 (Visit 2.7); however, in the Time & Events 
Schedule the MADRS assessment was mistakenly omitted at this timepoint.
Time & Events 
Schedule
The Time & Events Schedule (Screening/prospective Observational Phase and Double-
blind Phase) was revised to indicate that the MADRS total score is to be recorded at 
Study Day 22 (Visit 2.7).
Rationale: The row in the Time and Events Schedule showing assessment windows for the MADRS was removed 
due to misunderstandings it was creating relative to the visit windows.
Time & Events 
Schedule
In the Time & Events Schedule (Screening/prospective Observational Phase and 
Double-blind Phase), the row for “Remote MADRS interview window” was deleted, and 
the following guidance regarding MADRS assessment windows was added to footnote 
‘q’: “The MADRS should be administered no more than 2 days prior to the subject’s 
scheduled clinic visit. If performed on the day of the scheduled clinic visit for an 
intranasal treatment session, the MADRS must be performed prior to the intranasal 
treatment session.”
Rationale: Text revised to clarify the arterial oxygen saturation level that requires further monitoring.
9.6. Safety Evaluations
Text regarding pulse oximetry measurement was corrected to indicate that postdose 
oxygen saturation levels <93% (not ≤93%) require further monitoring.
Rationale: Clarification of intranasal esketamine dose adjustments which are permitted after Day 15 for 
consistency.
3.2.4 Treatment Groups 
and Dose Selection
The text in the Intranasal Study Drug section has been revised to clarify that the 
intranasal esketamine dose may be decreased by 28 mg after Day 15, while increases in 
esketamine dose are not permitted after Day 15 (for consistency with Section 6.2, 
Table 4).
Rationale: Remove restriction regarding up-titration in dose during the double-blind induction phase for subjects 
who had a previous down-titration in dose due to elevated blood pressure.
Synopsis, Dosage and 
Administration; 6.2 
Double-blind Induction 
Phase
The following sentence has been deleted from the text “No up-titration in dose is 
permitted during the double-blind induction phase if there was a prior down titration due 
to elevated blood pressure.”
Rationale: Clarification of the description for the Hopkins Verbal Learning Test-Revised (HVLT-R) recall test.
Time & Events 
Schedule; 9.6. Safety 
Evaluations
Text regarding cognition testing has been revised to clarify the description of the HVLT-
R recall text and to add text indicating that subjects will complete a practice session for 
the computerized cognitive battery, but not the HVLT-R, during the 
screening/prospective observational phase.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
21
Applicable Section(s)
Description of Change(s)
Rationale: Indicate that biomarkers will be assessed at the protein and RNA level and provide the rationale for 
recommendation of subject adherence to a low fat diet on the day of sample collection.
Synopsis, Biomarker, 
Pharmacogenomic 
(DNA), and Expression 
(RNA) Evaluations; 
3.2.9. Biomarker, 
Pharmacogenomic 
(DNA), and Expression 
(RNA) Evaluations
Text was added to specify that biomarkers will be assessed at both the protein and RNA 
level.
In addition, the following sentence was added: “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.”
Rationale: Blood volume table updated to include changes in blood volumes for biomarker (protein/DNA) 
assessment.
9.1.1. Overview, Table 5
Table 5 was revised as follows:

Volume of blood sample for Biomarker: protein was changed from 13 mL to 10 mL.

Volume of blood sample for Biomarker: DNA was changed from 8.5 mL to 6 mL 

Total Volume of Blood to be collected per subject was changed from 125.5 mL to 
112.0 mL.

Deleted footnote ‘d’ Blood volume listed under protein biomarkers represents the 
combined volume of several different collection tubes. 

In Double-blind Induction Phase section of the table, merged the two rows for 
‘Biomarker: protein visits’ to a single row. Description now states: “Biomarker: 
protein (at Visits 2.1, 2.3, and 2.8). The volume of sample collected at each visit is 
10 mL, and the number of samples per subject was revised to 3.
Rationale: Clarification of guidance on blood pressure monitoring on intranasal treatment session days, including 
clarification that discontinuation is mandatory for subjects who meet blood pressure criteria on intranasal treatment 
session days for discontinuation from further dosing.
6.2.1. Guidance on 
Blood Pressure 
Monitoring on Intranasal 
Treatment Session Days
In the heading for the section, the term “Dosing Days” has been replaced with 
“Intranasal Treatment Session Days”.
The following revisions were made to clarify guidance on blood pressure monitoring on 
intranasal treatment session days (bold text was added):
“Given the potential for treatment emergent transient elevation in systolic and diastolic 
blood pressure, the following guidance should be followed on intranasal dosing days:
If subsequent to fulfilling the inclusion and exclusion criteria on Day 1 (ie, 
applicable for all other intranasal treatment session days after Day 1), a subject’s 
pre-dose SBP is >150 mmHg and/or DBP is >90 mmHg, it is recommended that 
to repeat the blood pressure measurement is repeated after the subject rests for 10 
minutes in sitting or recumbent position. If after rest and repeated measurements,
the pre-dose SBP is >150 mmHg and/or the DBP is >90 mmHg, then dosing 
should be postponed and the subject scheduled to return on the following day or 
within the given visit window. If the blood pressure elevation still persists on the next 
visit, the subject will be scheduled for a consultation by cardiologist, other specialist,
or a primary care physician, prior to further dosing.
If at any postdose time point on the dosing day the SBP is 180 mm Hg but <190 mm 
Hg and/or the DBP is 100 mm Hg but <110 mm Hg, further intranasal dosing 
should be interrupted and the subject should be referred to a cardiologist, other 
specialist, consultation 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 provided considered 
appropriate according to the clinical judgment of the investigator for the 
subject is given approval to continue in the study, the subject may continue 
with intranasal dosing if the pre-dose blood pressure at the next scheduled 
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
22
Applicable Section(s)
Description of Change(s)
visit is within the acceptable range (see bullet above).
If at any postdose time point on the a dosing day the SBP is 190 mm Hg and/or the 
DBP is 110 mm Hg, the subject should must discontinue from further dosing and 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 and/or the DBP 100 mm Hg, assessments should continue every 30 minutes 
until:

the 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

until the subject is referred for appropriate medical care if clinically indicated.
If the blood pressure remains ≥180 SBP and/or  ≥110 mmHg DBP 2 hours after 
dosing, the subject should be referred for immediate medical treatment.
Synopsis, Dosage and 
Administration; 6.2. 
Double-blind Induction 
Phase
For consistency with exclusion criterion no. 9, the blood pressure requirements in the 
instructions for intranasal dosing were revised to state “Prior to intranasal dosing, 
subjects must not have a blood pressure >150 mm Hg systolic and/or >90 mm Hg 
diastolic” instead of “Prior to intranasal dosing, subjects must have a blood pressure 
≤150/90 mm Hg.”
Rationale: Alert site staff to ECG readings that would raise safety concerns and necessitate subject withdrawal and 
study discontinuation.
9.6. Safety Evaluations
The following text was added in the Single, 12-lead ECG section:
The subject must be discontinued at any time point after baseline (Day 1, predose) if:

QTcF change from baseline is ≥60 ms AND QTcF >480 ms, or

QTcF >500 ms.
10.2. Withdrawal from 
the Study
The following bullet was added to the list of reasons for withdrawal from the study:

At any time point after baseline (Day 1, predose), the subject has a:

QTcF change from baseline ≥60 ms AND QTcF >480 ms, or

QTcF >500 ms
Rationale: Provide further clarification regarding how the current regimen should remain unchanged for the 
duration of the screening/prospective observational phase and provide the criterion for non-response at the end of 
the screening/prospective observational phase (ie, site investigators are no longer blinded ).
Synopsis, Overview of 
Study Design, Study 
Population, Dosage and 
Administration; 
3.1. Overview of Study 
Design; 3.2.1. Study 
Population; 6.1. 
Screening/Prospective 
Observational Phase; 
9.1.2. 
Screening/Prospective 
Observational Phase
Text was revised to clarify that:

At the start of the screening/prospective observational phase the subject’s 
antidepressant treatment, as well as any ongoing medications for depression 
(including adjunctive and augmentation therapies), will continue unchanged at the 
same dosage from the start of Week 1 through the end of Week 4 of the 
screening/prospective observational phase.

During 
the 
screening/prospective 
observational 
phase, 
subjects 
taking 
benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of 
lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, 
zaleplon) during the screening/prospective observational phase can continue these 
medications, but no dose increases beyond the equivalent of 6 mg/day of 
lorazepam or new benzodiazepine medications are permitted during the 
screening/prospective observational phase.

Eligible subjects who do not require a tapered discontinuation of their 
antidepressant treatment(s) can proceed immediately into the double-blind 
induction phase.

Non-response at the end of the screening/prospective observational phase is 
defined as ≤25% improvement in the MADRS total score for 2consecutive visits 
and a MADRS total score of ≥28 for 2 consecutive visits.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
23
Applicable Section(s)
Description of Change(s)
Rationale: Provide clarification that all medication(s) being used for depression must be discontinued after 
completion of the 4-week prospective observational phase.
Synopsis, Overview of 
Study Design, Dosage 
and Administration; 
3.1. Overview of Study 
Design; 3.2.2. Study 
Phases; 6.1.
Screening/Prospective 
Observational Phase; 
9.1.2. 
Screening/Prospective 
Observational Phase
Text was revised to clarify that eligible subjects who enter the double-blind phase will 
discontinue all of their current medication(s) being used for antidepressant treatment, 
including adjunctive/augmentation therapies.
Rationale: Indicate that during the double-blind induction phase dosing of the oral antidepressant is to follow the 
mandatory titration schedule and doses of oral antidepressant study medication are not to exceed the maximum dose 
defined in the titration schedule.
Synopsis, Dosage and 
Administration; 
3.2.4. Treatment Groups 
and Dose Selection; 
6.2 Double-blind 
Induction Phase; 
9.1.3. Double-blind 
Induction Phase

Deleted text stating that dosing of the oral antidepressant during the double-blind 
induction phase will follow the local prescribing information, with a forced titration 
to the maximum tolerated dose.

Added text stating that dosing of the oral antidepressant during the double-blind 
induction phase will follow a mandatory titration schedule (provided in Attachment 3).

Statement added to indicate that during the double-blind induction phase, doses of 
oral antidepressant study medication are not to exceed the maximum dose defined in 
the titration schedule.
Attachment 3
The following statement was deleted from the first paragraph: “Adjustments to the 
titration schedule may be required in other countries in order to conform to local 
prescribing information.”
Rationale: Update and clarification to prohibited medications and substances and restrictions during the double-
blind induction phase.
Synopsis, Overview of 
Study Design; 3.1. 
Overview of Study 
Design; 4.3. 
Prohibitions and 
Restrictions
The following text was added to the list of Prohibitions and Restrictions:
“Subjects taking benzodiazepines (at dosages equal to or less than the equivalent of 6 
mg/day of lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, 
zolpidem, zaleplon) during the screening/prospective observational phase can continue 
these medications during the induction phase. No dose increases beyond the equivalent 
of 6 mg/day of lorazepam or new benzodiazepine medications are permitted during the 
induction phase, with the exception of the use of permitted benzodiazepine rescue 
medication. Benzodiazepines and non-benzodiazepine sleeping medication (eg, 
zolpidem, zaleplon, eszopiclone, and ramelteon) are prohibited within 12 hours prior to 
the start of each intranasal treatment session or cognition testing.”
4.3. Prohibitions and 
Restrictions
Lysergic acid diethylamide (LSD) was added to the list of drugs that will lead to 
discontinuation if detected in the urine drug screen from Day 1 of the induction phase 
through the final visit in the double-blind induction phase.
4.3. Prohibitions and 
Restrictions
Removed restriction stating that subjects should not ingest grapefruit juice, Seville 
oranges, or quinine for 24 hours before intranasal dosing.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
24
Applicable Section(s)
Description of Change(s)
Rationale: Clarifications for the use of prestudy and concomitant therapies.
4.3. Prohibitions and 
Restrictions; 8. Prestudy 
and Concomitant 
Therapy
Clarified that psychotherapy includes cognitive behavioral therapy (CBT); subjects 
receiving CBT must have had therapy ongoing for the last 3 months prior to the 
screening/prospective observation phase; new CBT is prohibited, but new psychotherapy 
is allowed; and any change in existing therapy or new therapy must be documented on 
the concomitant therapies form.
8. Prestudy and 
Concomitant Therapy
Added that antidepressant treatments which are not listed on the MGH-ATRQ but were 
used or are currently being used as antidepressant treatment in the current depressive 
episode must be recorded on the ‘Concomitant Therapy’ eCRF.
8. Prestudy and 
Concomitant Therapy
Clarified note regarding the timing of oral antihypertensive medications relative to 
administration of intranasal study drug.
8. Prestudy and 
Concomitant Therapy
Clarified that unless clinically indicated, it is recommended that transient increases in 
blood pressure not be treated.
Rationale: Clarifications to Attachment 1 regarding prohibited concomitant medications.
Attachment 1
The following changes were made in Attachment 1 describing prohibited concomitant 
medications with intranasal study medication (esketamine or placebo):

Included the following statement proceeding the table listing prohibited 
medications: “Note:  If a medication is part of the antidepressant treatment regimen 
being taken at the time of signing the ICF (ie, start of screening/prospective 
observational phase), it must be continued unchanged until the end of Week 4 of 
the screening/prospective observational phase. If the investigator determines it is 
clinically appropriate, the antidepressant medication may be tapered during the 
optional, up to 3-week, taper period”.

Deleted row referring to CYP3A4 inhibitors as prohibited concomitant medication.

Added a new row for prohibited non-stimulant ADHD medications (eg, 
atomoxetine, guanfacine).

Added new text to comments on the use of antidepressants in this study, stating 
that “Even if used primarily for sleep, trazodone or low dose tricyclic 
antidepressants are not permitted during the treatment phase”.
Attachment 1

Deleted text in comments on the use of non-benzodiazepine sleeping medication.

Added phrase“(at dosages less than or equal to the equivalent of 6 mg/day of 
lorazepam)” to describe benzodiazepines in the “Drug Class” column for 
consistency with the text in other sections.

Provided additional examples of anorexiants (phendimetrazine) that are prohibited 
as concomitant medication for reasons of safety, anticonvulsants (pregabalin) that 
are permitted when used for indications other that seizures, and psychostimulants 
(methylphenidate, modafinil, armodafinil) that are prohibited due to cardiovascular 
safety.

Added row for non-vitamin K antagonist oral anticoagulant agents (eg, dabigatran, 
rivaroxaban, apixaban).

Added statement indicating that pseudoephedrine-containing products should not 
be used within 12 hours prior to an intranasal treatment session.

Added “Safety and PD interaction” as reason for prohibitions listed for cough/cold 
preparations/nasal solutions containing vasoconstrictors, decongestants.

The comment regarding thyroid hormone supplements was deleted as it was not 
consistent with the text in inclusion criterion no. 7. 
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
25
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of criteria for subject withdrawal.
10.2 Withdrawal from 
the Study
Text pertaining to subject withdrawal from the study was clarified as follows:

Added the following text to the “Withdrawal of Consent” bullet: “(Note: See 
“Withdraw of Consent” section below; this should only be selected as a reason for 
withdrawal if the subject does not agree to any further study assessments or 
procedures. If the subject is agreeable to participating in the Early Withdrawal visit 
and the follow-up phase, another reason for withdrawal should be selected.)”

Added text to specify that if the subject withdraws from the study before the end of 
the double-blind induction phase, an Early Withdrawal visit is to be performed.

Added text to detail efforts study personnel must make to contact subjects to 
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 including 
phone numbers of relatives), as well as other contact information (eg, e-mail 
addresses) from subjects before randomization. In addition, the study site should 
emphasize the importance of follow-up information to the subject before 
randomization.”

Added text to indicate that subjects who withdraw will not be replaced.

The following text was deleted: “Study drug assigned to the withdrawn subject 
may not be assigned to another subject. If a subject withdraws from the study 
before the end of the double-blind induction phase for reasons other than 
withdrawal of consent, an early withdrawal visit should be conducted within 1 
week of the date of discontinuation, followed by the follow-up phase.”
10.2 Withdrawal from 
the Study

Added the following text under a separate heading (“Withdrawal of Consent”) to 
specify the conditions and procedures for withdrawal due to “withdrawal of 
consent”: 
“Every effort will be made in the study to ensure withdrawal of consent is not 
selected as a reason for discontinuation when in fact the subject withdrew for an 
identifiable reason (eg, due to an adverse event or lack of efficacy).
Subjects who wish to withdraw from the study should be asked if they are 
agreeable to 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 subject’s source records.
The investigator will be responsible for making all required notifications to the 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC).”
10. Subject 
Completion/Withdrawal; 
16.2.5. Long-Term 
Retention of Samples 
for Additional Future 
Research
Added a separate heading (10.3 Withdrawal From the Use of Samples in Future 
Research) for description of withdrawal from the use of research samples. The text in 
this section has not been changed.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
26
Applicable Section(s)
Description of Change(s)
Rationale: A diary has been added to record oral antidepressant use, and information regarding oral antidepressant 
use and accountability has been clarified.
Synopsis, Dosage and 
Administration;
Time & Events 
Schedule;
6.2. Double-Blind 
Induction Phase;
7. Treatment 
Compliance;
15. Study-Specific 
Materials
The following changes were made:

Text added to indicate that a diary will be provided for subjects to keep a record of 
oral antidepressant study medication use, to be reviewed and updated (if 
applicable), and returned at the end of the double-blind induction phase, in the 
event of an early withdrawal, or at the end of the follow-up phase.

Text regarding the timing of oral antidepressant medication administration has 
been revised to now state: “On intranasal dosing days, it is recommended the oral 
antidepressant medication not be taken until at least 3 hours after the intranasal 
treatment session.”

Row in the Time & Events Schedule (Screening/prospective Observational Phase 
and Double-blind Phase) for “Additional supply of oral antidepressant” has been 
deleted and the information has been added to the row “Dispensing of new oral 
antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine XR)”.

Text revised to indicate that antidepressant treatment adherence will be assessed by 
performing pill counts (ie, compliance check) and drug accountability during the 
follow-up phase as well as the double-blind induction phase.
Rationale: Provide further clarification regarding site staff training requirements for intranasal treatment sessions.
Synopsis, Dosage and 
Administration;
6.2. Double-blind 
Induction Phase
Text revised to state that a site staff member with training in cardiopulmonary 
resuscitation (eg, Basic Life Support course or equivalent courses) that is up to date per 
local regulations must be present with the subject during the intranasal treatment 
sessions and the postdose observation period.
Rationale: Update list of study-specific materials
15. Study-Specific 
Materials
Guidance document for the use of the MGH-ATRQ has been added.
Rationale: Clarification of study site personnel availability for on-site monitoring visits.
17.8. Monitoring
Text revised to now state: “It is expected that study-site personnel will be available to 
provide an update on the progress of the study at the study site.”
Minor revisions were also made to clarify the description of source documents and the 
comparison of recorded data with source data.
Rationale: Clarification of the content of data in the electronic case report form (eCRF)
17.11. Use of 
Information and
Publication
Text revised to now stipulate that the Clinical Study Report generated by the sponsor 
will contain eCRF data from all study sites that participated in the study and will 
represent uploaded data transferred from external service providers into the sponsor’s 
database.
Rationale: Include published data relating to adverse events associated with use of esketamine.
1.1.2.3. Safety and 
Tolerability
Additional text added to include published data relating to adverse events associated 
with short-term use of esketamine.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
27
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of text regarding oral antidepressant medication use in the follow-up phase
Synopsis, Overview of 
Study Design; Dosage 
and Administration; 
Time & Events 
Schedule; 3.1. Overview 
of Study Design; 6.3. 
Follow-up Phase; 9.1.3. 
Double-blind Induction 
Phase; 9.1.4. Follow-up 
Phase
Text revised to now state that following the 4-week double blind treatment phase, the 
oral antidepressant medication should be continued for the 2 weeks of the follow-up 
phase unless determined as not clinically appropriate.
Rationale: Clarification of the language regarding subjects who develop treatment emergent ulcerative cystitis to 
indicate the discontinuation of such subjects is mandatory.
3.2.6 Safety 
Evaluations; 9.6. Safety 
Evaluations
Updated/ added text in these sections describing the BPIC-SS and instructions for 
discontinuing due to ulcerative cystitis, to read as follows,: “If a subject is determined to 
have a diagnosis of ulcerative cystitis the subject must be discontinued from the study 
and followed up with appropriate medical care.”
Rationale: Minor clarifications to the text were made.
Synopsis, Overview of 
Study Design
For consistency with the information in Section 9.1.2 (Screening/Prospective 
Observation Phase), text in the synopsis regarding the study criteria for nonresponse has 
been revised to now state “The site investigators will be blinded to the study criteria for 
nonresponse; therefore, this information is maintained in a separate document.”
Time & Events 
Schedule
Added footnote “r” to Visit 2.1 C-SSRS (Since Last Visit) assessment to indicate this is 
only performed for subjects who do not have Visit 1.3 and 2.1 occur on the same day.
1. Introduction
The abbreviation TRD is now defined as “treatment-resistant depression”.
Text updated to indicate that the description of the mechanism of action of ketamine 
applies to esketamine as well.
1.1.2.2. 
Pharmcodynamics and 
Efficacy
The following text was added: “In Study ESKETINTRD2003, Panel A was conducted in 
the United States and Belgium and Panel B in Japan.”
4. Study Population
Text revised to now state: “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.”
6.1. 
Screening/Prospective 
Observational Phase
For consistency with other sections, a sentence was added to state that the sponsor will 
not supply antidepressant medication(s) during the screening/prospective observational 
phase.
9.2.1.1. Primary 
Efficacy Evaluation
The MADRS item previously described as “interest level” was changed to “inability to 
feel (interest level)”.
9.3. Pharmacokinetics
The following text was added: “Whole blood samples will be used to evaluate the PK of 
esketamine. Serum 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 serum samples. Subject confidentiality will be 
maintained”.
9.6. Safety Evaluations
The statement in the section regarding vital signs now reads: “Blood pressure and 
pulse/heart rate measurements will be assessed in a supine position with a completely 
automated device or using manual techniques”.
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JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
28
Applicable Section(s)
Description of Change(s)
12.3.2. Serious Adverse 
Events
With regard reporting serious adverse events, the following exception to reporting 
hospitalization of a subject has been modified to start: “For convenience the investigator 
may choose to hospitalize the subject during a treatment period”.
16.2.2.Independent 
Ethics Committee or 
Institutional Review 
Board (IEC/IRB)
The phrase “where required” has been added to the following statement: “At least once a 
year, the IEC/IRB will be asked to review and reapprove this study”.
17.4. Source 
Documentation
Text has been revised to reflect current requirements for source documents.
17.5. Case Report Form 
Completion
Text has been revised to reflect current requirements for completion of CRFs.
Throughout the protocol
Minor corrections have been made to the abbreviations and definitions of abbreviations. 
Minor edits have been made that do not change the meaning of the text.
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment INT-1 (08 June 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: The overall reason for the amendment is to allow for a 28 mg dose 
throughout the study, based on pharmacokinetic data from study ESKETINTRD1012 in elderly subjects.
Applicable Section(s)
Description of Change(s)
Rationale: Based on pharmacokinetic data from study ESKETINTRD1012 a change was made to allow a 28 mg 
dose of esketamine throughout the study which could potentially improve safety and tolerability
1.1.2.1. 
Pharmacokinetics and 
Product Metabolism; 
1.1.2.3. Safety and 
Tolerability
Description of preliminary pharmacokinetic results for study ESKETINTRD1012 was 
added in addition to a safety overview from the study.
1.1.2.2. 
Pharmacodynamics 
and Efficacy
Justification statement for including the 28 mg dose beyond Day 1 was added.
Synopsis Dosing and 
Administration;
3.1. Overview of 
Study Design;
3.2.4. Treatment 
Groups and Dose 
Selection
Change made to allow 28 mg dose of esketamine throughout the study, not just on Day 1. 
New table added to describe dose titration guidance.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
29
Applicable Section(s)
Description of Change(s)
Synopsis;
1.2. Active 
Comparators in 
Double-blind 
Induction Phase; 
1.3. Overall Rationale 
for the Study;
2.1. Objectives;
3.1. Overview of 
Study Design;
3.2.4. Treatment 
Groups and Dose 
Selection;
6.2. Double-Blind 
Induction Phase;
9.1.3. Double-Blind 
Induction Phase
Added 28 mg to the list of intranasal doses of esketamine used in this study. Removed 
references of 28 mg only being allowed on Day 1.
Rationale: More conservative blood pressure parameters related to patient dosing were incorporated to improve 
subject safety
Synopsis Dosing and 
Administration; 
6.2. Double-blind 
Induction Phase; 
6.2.1. Guidance for 
Blood Pressure 
Monitoring on Dosing 
Days
Added that prior to intranasal dosing, subjects must have a pre-dose blood pressure ≤ 
150/90 mm Hg and prior to dose escalation, subjects must have had  a post-dose blood 
pressure, on the prior intranasal dosing day, of  < 180 mm Hg for systolic and  <100 mm 
Hg for diastolic blood pressure.
Rationale: Correction to Day 28 study window
Time & Events 
Schedule
The study window for Day 28 of the induction phase was incorrectly listed as ±2 days. 
This window has been corrected to be -1 day.
Rationale: Collection of blood sample for Biomarker, Pharmacogenomic (DNA), and Expression (RNA) 
Evaluations was moved to Study Day 28 so that it corresponds with the hematology sample collection
Time & Events 
Schedule
Collection of blood sample for Biomarker, Pharmacogenomic (DNA), and Expression 
(RNA) Evaluations was moved to Study Day 28 from the original Study Day 25.
Rationale: The frequency of assessments of the Sheehan Disability Scale was increased following feedback from 
the FDA
Time & Events 
Schedule
An additional assessment for the SDS was added on Day 15 of the Induction Phase.
Rationale: Footnote for predose procedures to be followed in case dosing is delayed (within visit windows).
Time & Events 
Schedule
A footnote ‘o’ was added to Study Drug - Intranasal esketamine or placebo.
Rationale: Footnote for rescheduling smell test assessments in case the subject has significant nasal congestion
Time & Events 
Schedule;
9.6 UPSIT and Smell 
Threshold Test
A footnote ‘p’ was added to UPSIT and Smell Threshold Test.
A note for rescheduling UPSIT and Smell Threshold Test in case of nasal congestion was 
added.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
30
Applicable Section(s)
Description of Change(s)
Rationale: Study drug accountability was added at two weeks after the last intranasal dose
Time & Events 
Schedule
An assessment for study drug accountability was added at Visit 3.2 of the follow-up phase.
Rationale: Inclusion criteria modified to enroll subjects with a normal thyroid-stimulating hormone function or free 
thyroxine levels in case of subjects with no pre-existing history of hypothyroidism to ensure that the subject is 
medically stable
4.1. Inclusion Criteria 
Direct-entry Subjects;

Inclusion criterion for direct-entry subjects was modified to ensure a normal 
thyroid-stimulating hormone [TSH] function in case of subjects without a 
pre-existing history of hypothyroidism. If the TSH is below the normal 
range, free thyroxine (fT4) levels will be measured and if fT4 is within the 
normal range the subject can be enrolled.
Rationale: Inclusion criterion was expanded to include subjects using specific tricyclic antidepressants at a dose 
below the MGH-ATRQ minimum therapeutic dose.
4.1. Inclusion Criteria 
Direct-entry Subjects
Inclusion criteria for direct-entry subjects was modified for accepting specific tricyclic 
antidepressants which are being taken at a dose below the MGH-ATRQ minimum 
therapeutic dose but achieve a blood level that is within the therapeutic range.
Rationale: Exclusion criteria expanded to include additional DSM-5 diagnostic codes for intellectual disability and 
autism spectrum disorder
Synopsis Study 
Population;
4.2. Exclusion 
Criteria Direct-entry 
Subjects
Exclusion criterion for direct-entry subjects was expanded to include additional DSM-5 
diagnostic codes for intellectual disability as well as autism spectrum disorder.
Rationale: Exclusion criteria modified to exclude all subjects who have previously received esketamine or ketamine 
regardless of the type of response based on PMDA feedback
Synopsis Study 
Population;
4.2. Exclusion 
Criteria Direct-entry 
Subjects
Exclusion criterion was modified to exclude subjects who have previously received 
esketamine or ketamine.
Rationale: Clarification of dosing for subjects using an intranasal decongestant
6.2 Double-blind 
Induction Phase
Text describing the guidance for use of an intranasal decongestant to reduce congestion 
before administering esketamine.
Rationale: Accounting for blood volume to match inclusion criteria
9.1.1 Overview
Six mL blood accounting for determining tricyclic antidepressant blood levels of specific 
tricyclic antidepressants which are being taken at a dose below the MGH-ATRQ minimum
therapeutic dose.
Rationale: Correction to match T&E Schedule
9.1.1 Overview
Volume of blood to be collected from each user was modified to include 2.5 mL for 
biomarker RNA in the screening/prospective observational phase thereby increasing total 
volume collected to 125.5 mL.
Rationale: Correction to description of MMSE
9.7. Other Evaluations
The description of the MMSE was incorrect. The statement “attention (total score, 5), 
calculation (total score, 5)” was changed to “attention and calculation (total score, 5)”.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
31
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of  scoring of the PAQ assessments
9.7. Other Evaluations
Text describing scoring of the PAQ was revised to indicate it is based on Question 1 (not 
1c through 1f). 
Rationale: Clarification that SIGMA is the structured interview guide of the MADRS
9.2.1.1 Primary 
Efficacy Evaluation
The following sentence was added to describe the MADRS “The structured interview 
guide for the MADRS (SIGMA) will be used for each administration”.
Rationale: List of clinical laboratory tests revised to align with other protocols in the program
9.6. Safety 
Evaluations
Total bilirubin was added to the serum chemistry panel.
Rationale: Correction to Site Independent Qualification Assessment
9.7. Other Evaluations
Reference to telephone contact was removed from the description of the Site Independent 
Qualification Assessment.
Rationale: Update to include new template text for reporting abnormal pregnancy outcomes
12.3.3. Pregnancy
Instructions for the reporting of abnormal pregnancy outcomes (eg, spontaneous abortion, 
fetal death, stillbirth, congenital anomalies, ectopic pregnancy) were added.
Rationale: Clarification of the supply of oral antidepressant that will be provided to subjects entering the follow-up 
phase
Time & Events 
Schedule
Footnote “n” was added to the Induction Phase T&E stating that subjects entering the 
follow-up phase will be provided with a 2 week supply of oral antidepressant.
Synopsis Overview of 
Study Design and 
Dosage and 
Administration; 
16.1. Study-specific 
Design 
Considerations; 
6.2 Double-blind 
Induction Phase;
9.1.4 Follow-up Phase
Change the supply of oral antidepressant given during the follow-up phase from 4 weeks to 
2 weeks.
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Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
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SYNOPSIS
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 
Treatment-resistant Depression
Study Acronym: TRANSFORM-3
Major depressive disorder (MDD), a serious, recurrent, and disabling psychiatric illness, is the second 
leading cause of years lost to disability worldwide. MDD is associated with excess mortality and with 
years of potential life lost. About 30% of patients fail to achieve remission despite treatment with multiple 
antidepressant medications, and are considered to have treatment-resistant depression (TRD). There is a 
significant need to develop novel treatments based upon relevant pathophysiologic pathways underlying 
MDD for the rapid relief of symptoms of depression, especially in patients with TRD.
Depression in later life, traditionally defined as age older than 65 years, is associated with disability, 
increased mortality, and poorer outcomes from physical illness. In addition, the condition is often under-
recognized and under-treated. In the PRISM-E study, a large study of older patients with MDD, 71% of 
the patients did not remit even after 6 months of standard of care treatment in specialty or integrated care 
treatment centers. Factors associated with non-remission included severity of depression at baseline, a 
family history of depression, comorbid anxiety, and general medical comorbidity. According to the World 
Health Organization (WHO) data, proportionately more people aged over 65 years commit suicide than 
any other age group, and most have major depression. Older people who attempt suicide, are more likely 
to die than younger people, while in those who survive, their prognosis is worse.
Ketamine and esketamine (S-ketamine, the S enantiomer of ketamine) are approved and widely used for 
the induction and maintenance of anesthesia via intramuscular (IM) or intravenous (IV) administration. 
The desired analgesic-anesthetic effects of ketamine and esketamine are attributed to the blockade of 
ionotropic N-methyl-D-aspartate (NMDA) glutamate receptors. The mechanism of action of ketamine and 
esketamine is distinct from conventional monoaminergic antidepressant treatments. Ketamine and 
esketamine profoundly affect fast excitatory glutamate transmission, increase brain-derived neurotrophic 
factor (BDNF) release, and stimulate synaptogenesis.
Janssen Research & Development (JRD) is developing intranasal esketamine as an antidepressant 
therapy. A higher NMDA receptor affinity of esketamine, as compared with ketamine, allows a lower 
volume of medication to be administered via the non-invasive and rapidly-absorbed intranasal route.
The current study is being conducted to evaluate the efficacy, safety, and tolerability of flexibly-dosed 
intranasal esketamine, plus a newly initiated oral antidepressant, in elderly subjects with TRD. The study 
will serve as a pivotal Phase 3 short-term efficacy and safety study in support of regulatory agency 
requirements for registration of intranasal esketamine for the treatment of TRD.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective of this study is to evaluate the efficacy of switching elderly subjects with TRD 
from a prior antidepressant treatment (to which they have not responded) to flexibly dosed intranasal 
esketamine (28 mg, 56 mg or 84 mg) plus a newly initiated oral antidepressant, compared with switching 
to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in improving 
depressive symptoms, as assessed by the change from baseline in the Montgomery-Asberg Depression 
Rating Scale (MADRS) total score from Day 1 (pre-randomization) to the end of the 4-week double-blind 
induction phase. 
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Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
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Secondary Objectives

To assess the effect of intranasal esketamine plus a newly initiated oral antidepressant compared with
a newly initiated oral antidepressant (active comparator) plus intranasal placebo on the following
parameters in elderly subjects with TRD:
o
Depression response rates
o
Depression remission rates
o
Overall severity of depressive illness
o
Health-related quality of life and health status

To investigate the safety and tolerability of intranasal esketamine plus a newly initiated oral 
antidepressant compared with a newly initiated oral antidepressant (active comparator) plus intranasal 
placebo in elderly subjects with TRD, including the following:
o
Treatment-emergent adverse events (TEAEs), including AEs of special interest
o
Local nasal tolerability
o
Effects on heart rate, blood pressure, respiratory rate, and blood oxygen saturation
o
Effects on alertness and sedation
o
Potential psychosis-like effects
o
Dissociative symptoms 
o
Potential effects on cognitive function 
o
Potential effects on suicidal ideation/behavior 
o
Potential treatment-emergent symptoms of cystitis and/or lower urinary tract symptoms 
o
Potential withdrawal and/or rebound symptoms following cessation of intranasal 
esketamine treatment
o
Potential effects on sense of smell 

To assess the pharmacokinetics (PK) of intranasal esketamine in elderly subjects with TRD receiving 
intranasal esketamine plus a newly- initiated oral antidepressant
Exploratory Objectives

To assess the PK/pharmacodynamic (PK/PD) relationship of intranasal esketamine and MADRS 
total score in elderly subjects with TRD.

To assess the potential relationship of biomarkers with response/nonresponse to intranasal 
esketamine or oral antidepressants in elderly subjects with TRD.
Hypothesis
The hypothesis for this study is that, in elderly subjects with TRD, switching from a failed antidepressant 
treatment to intranasal esketamine plus a newly initiated oral antidepressant is superior to switching to a 
newly initiated oral antidepressant treatment (active comparator) plus intranasal placebo in improving 
depressive symptoms.
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, active-controlled, multicenter study in male and female elderly 
subjects with TRD to assess the efficacy, safety, and tolerability of flexibly dosed intranasal esketamine 
(28 mg, 56 mg or 84 mg) plus a newly initiated oral antidepressant, compared with a newly initiated oral 
antidepressant (active comparator) plus intranasal placebo.
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The study has 3 phases which are briefly described below.
Screening/prospective observational phase (4-week duration + optional 3-week taper period)
This phase will prospectively assess treatment response to the subject’s current oral antidepressant
treatment regimen. 
At the start of the screening/prospective observational phase, the subject must have had documented 
nonresponse to at least one antidepressant treatment (based on MGH-ATRQ criteria) in the current 
episode of depression, and the subject is taking a different oral antidepressant treatment(s) (on the MGH-
ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose. This antidepressant 
treatment, as well as any other ongoing medications being taken for depression at screening (including 
adjunctive and augmentation therapies), will continue from the start of Week 1 through the end of Week 4 
of the screening/prospective observational phase. Dose adjustment is permitted per clinical judgment, but 
the oral antidepressant treatment is to remain at or above the minimum therapeutic dose (per the MGH-
ATRQ) through the end of Week 4.
After 4 weeks, subjects who are nonresponders to their current oral antidepressant treatment may be 
eligible to proceed to the double-blind induction phase. Non-response at the end of the 
screening/prospective observational phase is defined as ≤25% improvement in the MADRS total score 
from Week 1 to Week 4 and a MADRS total score of ≥24 on Week 2 and Week 4. 
Eligible subjects who are entering the double-blind induction phase will discontinue all of their current 
medication(s) being used for antidepressant treatment, including adjunctive/augmentation therapies. Of 
note, subjects taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of 
lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, zaleplon) during the 
screening/prospective observational phase can continue these medications, but no dose increases beyond 
the equivalent of 6 mg/day of lorazepam or new benzodiazepine medications are permitted during the 
screening/prospective observational phase. If clinically indicated, a subject’s current antidepressant 
treatment(s) may be tapered and discontinued over an additional, optional period of up to 3 weeks per the 
local prescribing information or per clinical judgment. This 3 week period may also be used to optimize 
medical management if needed to facilitate subject participation (eg, treatment of blood pressure or 
diabetes, wean from other medications, etc,). In such cases, if there is no planned taper, the oral regimen 
should be continued in the interim and then discontinued by Day 1 of the double-blind induction phase.
As a new oral antidepressant will be initiated on Day 1 of the double-blind induction phase, eligible 
subjects who do not require a tapered discontinuation of their antidepressant treatment(s) can proceed 
immediately into the double-blind induction phase.
Double-blind induction phase (4-week duration)
Approximately 148 eligible subjects will be randomly assigned at a 1:1 ratio (n=74 per treatment arm) to 
receive double-blind intranasal treatment with either esketamine [28 mg, 56 mg or 84 mg], or placebo, 
starting with an initial dose of 28 mg on Day 1. The intranasal treatment sessions (esketamine or placebo) 
will occur twice weekly. In addition, all subjects will initiate a new, open-label oral antidepressant on Day 
1 that will be taken daily for the duration of this phase. The assigned oral antidepressant will be 1 of 4 
oral antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine extended release 
[XR]) that the subject has not previously had a nonresponse to in the current depressive episode, has not 
been previously intolerant to (lifetime), and is available in the participating country.
Subjects taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of 
lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, zaleplon) during the 
screening/prospective observational phase can continue these medications during the induction phase. No 
dose increases beyond the equivalent of 6 mg/day of lorazepam or new benzodiazepine medications are 
permitted during the induction phase, with the exception of the use of permitted benzodiazepine rescue 
medication.
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Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
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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. Subjects who do not 
complete the double-blind induction phase of this study will not be eligible to participate in the 
ESKETINTRD3004 study. ESKETINTRD3004 is a long-term open-label safety study involving repeated 
open-label treatment sessions of intranasal esketamine.
If a subject withdraws from the study before the end of the double-blind induction phase for reasons other 
than withdrawal of consent, an Early Withdrawal visit should be conducted within 1 week of the date of 
discontinuation, followed by the follow-up phase.
Follow-up phase (2-week duration)
This phase will include all subjects who withdraw early before the end of the double-blind induction 
phase, or choose not to participate, in the subsequent ESKETINTRD3004 safety study, and have received 
at least 1 dose of intranasal study medication in the double-blind induction phase. There will be no 
intranasal treatment sessions administered during this phase.
At the start of the follow-up phase, further clinical/standard of care for the treatment of depression will be 
arranged by the study investigator and/or the subject’s treating physician. All subjects will be provided 
with an additional 2-week supply of the oral antidepressant medication to ensure that there is no 
interruption of oral antidepressant therapy during the transition to further clinical/standard of care. The 
decision to continue the oral antidepressant in this phase will be at the discretion of the investigator.
However, in order to better assess potential withdrawal symptoms from intranasal study medication and 
facilitate maintenance of clinical benefit following cessation of intranasal dosing, the oral antidepressant 
medication should be continued for the 2 weeks of the follow-up phase unless determined as not clinically 
appropriate.
Taking into consideration the up to 3-week optional taper period, the maximum duration of an individual 
subject’s study participation will be up to 13 weeks (for subjects completing the follow-up phase).
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study.
STUDY POPULATION
The study population will include elderly men and women, 65 years (inclusive) and older, who meet the 
Diagnostic and Statistical Manual of Mental Disorders (5th Edition; DSM-5) diagnostic criteria for 
single-episode MDD (if a single episode MDD, the duration of the episode must be 2 years) or recurrent 
MDD, without psychotic features, based upon clinical assessment, and confirmed by the 
Mini-International Neuropsychiatric Interview (MINI). In addition, the subject must have an Inventory of 
Depressive Symptomatology-Clinician rated, 30-item (IDS-C30) total score of 31, which corresponds to 
moderate to severe depression.
At the start of the screening/prospective observational phase, subjects must have had a nonresponse (ie, 
lack of clinically meaningful improvement, defined as ≤25% improvement) to 1 but 8 (if current
episode is >2 years, upper limit is only applicable to the last 2 years) oral antidepressant treatments taken 
at an adequate dosage and for an adequate duration, as assessed using the Massachusetts General 
Hospital–Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and documented by records 
(eg, medical/pharmacy/prescription records, a letter from the treating physician, etc.) for the current 
episode of depression. 
In addition, the subject must currently be taking a different oral antidepressant treatment (on the MGH-
ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose. This antidepressant 
treatment, as well as any other medications being used for depression treatment (including 
adjunctive/augmentation therapies), will continue from the start of Week 1 through the end of Week 4 of 
the screening/prospective observational phase. Dose adjustments are permitted per clinical judgment, but 
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Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
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the oral antidepressant treatment is to remain at or above the minimum therapeutic dose (per the MGH-
ATRQ) through to the end of Week 4.
Non-response at the end of the screening/prospective observational phase is defined as ≤25% 
improvement in the MADRS total score and a MADRS total score of ≥24 on Week 2 and Week 4.
Treatment-resistant depression (TRD) 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.
The subject’s current major depressive episode, depression symptom severity (Week 1 MADRS total 
score ≥24 required), and antidepressant treatment response in the current depressive episode
(retrospectively assessed) must be deemed valid for participation in the clinical study based on a Site
Independent Qualification Assessment. The Site Independent Qualification Assessment is a tool to 
facilitate subject selection for MDD clinical studies, with a goal to ensure enrollment of subjects who 
have symptoms that reflect the current state of illness and that these symptoms can be reliably measured 
with appropriate measurement tools.
Potential subjects will be excluded from participating in the study if they have previously demonstrated 
nonresponse of depressive symptoms to esketamine or ketamine in the current major depressive episode, 
to all 4 of the oral antidepressant treatment options available for the double-blind induction phase (ie, 
duloxetine, escitalopram, sertraline, and venlafaxine XR) in the current major depressive episode (based 
on MGH-ATRQ), or to an adequate course of treatment with electroconvulsive therapy (ECT) in the 
current major depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT. Subjects 
who received vagal nerve stimulation (VNS) or who received deep brain stimulation (DBS) in the current 
major depressive episode will be excluded. Subjects will also be excluded if they have a current or prior 
DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders 
(confirmed by the MINI), obsessive compulsive disorder (current only), neurodegenerative disorder (eg, 
Alzheimer’s Disease, Vascular dementia, Parkinson’s disease with clinical evidence of cognitive 
impairment) or evidence of mild cognitive impairment (MCI), a Mini Mental State Examination (MMSE) 
score <25 or <22 for those subjects with less than an equivalent of high school education, intellectual
disability (only DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), autism spectrum 
disorder, borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or 
narcissistic personality disorder; if they have homicidal ideation/intent or suicidal ideation with some 
intent to act within 6 months prior to the start of the screening/prospective observational phase per the 
investigator’s clinical judgment and/or based on the Columbia Suicide Severity Rating Scale (C-SSRS); 
or if they have a history of moderate or severe substance or alcohol use disorder according to DSM-5 
criteria.
DOSAGE AND ADMINISTRATION
Screening/prospective observational phase
At the start of the screening/prospective observational phase, the subjects must have had documented 
nonresponse to at least one antidepressant treatment (based on MGH-ATRQ criteria) in the current 
episode of depression, and the subject is taking a different oral antidepressant treatment (on the MGH-
ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose. This antidepressant 
treatment, as well as any other medications being taken for depression at screening (including 
adjunctive/augmentation therapies), will continue from the start of Week 1 through the end of Week 4 of 
the screening/prospective observational phase for the prospective observation of a response or a 
nonresponse. Dose adjustment is permitted per clinical judgment, but the oral antidepressant treatment is 
to remain at or above the minimum therapeutic dose (per the MGH-ATRQ) through the end of Week 4.
The sponsor will not supply these antidepressant medications. Antidepressant treatment adherence during 
this phase will be assessed using the Patient Adherence Questionnaire (PAQ).
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Status: Approved, Date: 18 July 2016
37
Subjects who are eligible to enter the double-blind induction phase: After the completion of 4 weeks of 
prospective antidepressant treatment and assessment of the antidepressant treatment response, all 
antidepressant treatment(s) will be discontinued, including adjunctive/augmentation therapies. If 
clinically indicated (eg, antidepressant treatments with short half-lives, such as paroxetine and
venlafaxine XR, or tolerability concerns), the antidepressant treatment(s) may be tapered off and stopped 
over a period of up to 3 weeks per the local prescribing information or clinical judgment.
As a new oral antidepressant will be initiated on Day 1 of the double-blind induction phase, eligible 
subjects who do not require a tapered discontinuation of their antidepressant treatment(s) can proceed 
immediately into the double-blind induction phase.
Double-blind induction phase
During this phase, subjects will receive double-blind intranasal treatment with esketamine or placebo. In 
addition, subjects will simultaneously initiate a new, open-label oral antidepressant on Day 1 that will be 
continued for the duration of this phase.
Intranasal Study Medication
All subjects will self-administer the intranasal study drug (esketamine or placebo) at treatment sessions 
twice a week for 4 weeks at the study site. The first treatment session will be on Day 1. Intranasal 
treatment sessions should not take place on consecutive days.

Prior to the first intranasal dose on Day 1, subjects will practice spraying (into the air, not 
intranasally) a demonstration intranasal device that is filled with placebo solution.

Instructions for intranasal dosing:

After Day 1 (dose 28 mg), all dosing decisions are to be determined by the investigator based on 
efficacy and tolerability.

Prior to intranasal dosing, subjects must not have a blood pressure >150 mm Hg systolic and/or 
>90 mm Hg diastolic.

Prior to any dose escalation, subjects must have had a post-dose blood pressure, on the prior 
intranasal dosing day, of <180 mm Hg for systolic and <100 mm Hg for diastolic blood 
pressure.

Dose titration of intranasal esketamine will be performed as outlined in the table below:
Dose Titration of Intranasal Esketamine*
Day 
Dose
Dose Titration Guidance
Day 1
28 mg
Day 4
28 or 56 mg
The dose may remain at 28mg or be increased to 56mg, as 
determined by the investigator based on efficacy and tolerability
Days 8, 11, 15
28, 56 or 84 mg
The dose may be maintained, increased or reduced by 28mg from 
the previous dosing session, as determined by the investigator 
based on efficacy and tolerability. No dose increase is permitted 
beyond Day 15.
Days 18, 22 and 25
28, 56 or 84 mg
No dose increase is permitted beyond Day 15. If needed for 
tolerability, dose reduction by 28mg from the previous dose is 
permitted on Days 18, 22 and 25.
* Dose changes are determined by the investigator based on efficacy and tolerability and in accordance with blood 
pressure guidelines.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
38
From Day 8 to Day 15, inclusive, for those who have had a prior down titration from a higher dose, a 
dose increase by 28 mg is allowed based on clinical judgment. 
On all intranasal treatment session days, a site staff member with training in cardiopulmonary 
resuscitation (eg, Basic Life Support course or equivalent courses) that is up to date per local regulations 
must be present with the subject during the intranasal treatment sessions and the postdose observation 
period. In addition, equipment for supportive ventilation and resuscitation needs to be present. Subjects 
must remain at the site until study procedures have been completed and the subject is ready for discharge.
At the time of discharge, subjects should be accompanied by a responsible adult when released from the 
clinical site. Subjects must not drive a car or work with machines for 24 hours after receiving intranasal 
study drug. 
Oral Antidepressant Study Medication
Starting on Day 1, a new, open-label oral antidepressant treatment will be initiated in all subjects. The 
oral antidepressant will be 1 of 4 oral antidepressant medications (duloxetine, escitalopram, sertraline, or 
venlafaxine XR). The antidepressant medication will be assigned by the investigator based on review of 
MGH-ATRQ and relevant prior antidepressant medication information, and will be one that the subject 
has not previously had a nonresponse to in the current depressive episode, has not been previously 
intolerant to (lifetime), and is available in the participating country. 
Dosing of the oral antidepressant will begin on Day 1. A mandatory titration schedule is provided in the 
protocol. Doses are not to exceed the maximum dose defined in the titration schedule. If higher doses are 
not tolerated, a down-titration is permitted based on clinical judgment.
All subjects will be provided with an additional 2-week supply of the oral antidepressant medication, to 
ensure that there is no interruption of oral antidepressant therapy during the transition to further 
clinical/standard of care in the follow-up phase.
Study-site personnel will instruct subjects on how to store and take the oral antidepressant treatment
supplied during this study for at-home use. A subject diary will be provided to capture oral antidepressant 
study medication use.
On intranasal dosing days, it is recommended that the oral antidepressant medication not be taken until at 
least 3 hours after the intranasal treatment session.
Follow-up phase
At the start of the follow-up phase, further clinical/standard of care for the treatment of depression will be 
arranged by the study investigator and/or the subject’s treating physician.
No intranasal study medication will be administered during this phase.
The decision to continue the oral antidepressant medication in this phase will be at the discretion of the 
investigator, however, in order to better assess potential withdrawal symptoms from intranasal study 
medication, the oral antidepressant medication should be continued for the follow-up phase unless 
determined as not clinically appropriate.
Subjects entering the follow-up phase will have 2 follow-up visits conducted at 1 and 2 weeks after the 
last dose of study medication. The follow-up visits at 1 and 2 weeks after the last dose of study 
medication will be a telephone contact and a clinical visit, respectively.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
39
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. The MADRS is a clinician-rated scale designed to measure 
depression severity and detects changes due to antidepressant treatment.
The primary efficacy endpoint will be the change from baseline in MADRS total score from Day 1 
pre-randomization, to the end of the 4-week double-blind induction phase.
Secondary Efficacy Evaluations and Endpoints
Secondary efficacy evaluation endpoints include the change from baseline (Day 1 prior to randomization) 
to the end of the 4-week double-blind induction phase in:

Proportion of responders (50% reduction from baseline in MADRS total score) at the end of the 
4-week double-blind induction phase

Proportion of subjects in remission (MADRS 12) at the end of the 4-week double-blind induction 
phase

Change from baseline (Day 1 prior to randomization) to the end of the 4-week double-blind induction 
phase in:
o
Severity of depressive illness, using the Clinical Global Impression – Severity (CGI-S)
o
Health-related quality of life and health status, as assessed by the EuroQol-5 dimension-5 
level (EQ-5D-5L).
PHARMACOKINETIC EVALUATIONS
Plasma samples will be analyzed to determine concentrations of esketamine (and noresketamine, 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. Plasma samples may be 
analyzed to document the presence of circulating metabolites using a qualified research method. In 
addition, plasma PK samples may be stored for future analysis of the metabolite profile.
BIOMARKER, PHARMACOGENOMIC (DNA), AND EXPRESSION (RNA) EVALUATIONS
Assessment of biomarkers (protein and RNA) and their potential relationship to intranasal esketamine 
plus a newly initiated oral antidepressant 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 markers). Samples of deoxyribonucleic acid 
(DNA) and biomarkers (protein and RNA) may be used to help address emerging issues and to enable the 
development of safer, more effective, and ultimately individualized therapies.
SAFETY EVALUATIONS
Safety evaluations will include:

Monitoring of TEAEs, including TEAEs of special interest, clinical laboratory tests (including 
hematology, serum chemistry, and urinalysis), urine drug screen, 12-lead electrocardiogram, vital 
signs, pulse oximetry, physical examination, and body weight measurements

Nasal examinations and nasal symptom questionnaire

Columbia Suicide Severity Rating Scale (C-SSRS), to assess potential suicidal ideation and behavior
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
40

Clinician Administered Dissociative States Scale (CADSS), to assess the treatment-emergent 
dissociative symptoms

Four-item positive symptom subscale of the Brief Psychiatric Rating Scale (BPRS+), to assess 
potential treatment-emergent psychotic symptoms

Modified Observer’s Assessment of Alertness/Sedation (MOAA/S), to measure treatment-emergent 
sedation

Clinical Global Assessment of Discharge Readiness (CGADR), to document the subject’s current 
clinical status and is the clinician’s assessment of the readiness to be discharged from the study site

Physician Withdrawal Checklist (20 items; PWC-20) to assess potential withdrawal symptoms 
following cessation of intranasal esketamine treatment

Bladder Pain/ Interstitial Cystitis Symptom Score (BPIC-SS), to monitor subjects for potential 
symptoms of cystitis, bladder pain, and interstitial cystitis

Computerized cognitive battery and Hopkins Verbal Learning Test-Revised (HVLT-R), to assess the 
effect of intranasal esketamine on cognition

University of Pennsylvania Smell Identification Test (UPSIT), to assess any potential treatment-
emergent effects on the sense of smell.
STATISTICAL METHODS
Subject Information
The primary efficacy and safety analysis sets are defined below.

Full Analysis Set: All randomized subjects who receive at least 1 dose of intranasal study 
medication and 1 dose of oral antidepressant medication in the double-blind induction phase.

Safety Analysis Set: All randomized subjects who receive at least 1 dose of intranasal study 
medication or 1 dose of oral antidepressant medication in the double-blind induction phase.
Sample Size Determination
The maximum sample size planned for this study was calculated assuming a treatment difference at the 
end of the double-blind induction phase of 6.5 points in MADRS total score between esketamine and the 
active comparator, a standard deviation of 12, a 1-sided significance level of 0.025, and a drop-out rate of 
25%. A maximum of about 74 subjects will need to be randomized to each treatment group to achieve 
80% power using a fixed design with no interim analysis. The treatment difference and standard deviation 
used in this calculation were based on results of Panel A from the ESKETINTRD2003 study and on 
clinical judgment.
Interim Analysis for Sample Size Re-Estimation or Stopping for Futility
One unblinded interim analysis will be performed 4 weeks after randomizing 50 subjects in the study 
(approximately 25 per treatment group). It is projected that at that time approximately 36 subjects in the 
full analysis set would have completed the double-blind induction phase of the study (approximately 
18 subjects per treatment group). The dropout rate will be monitored to ensure a sufficient number of 
subjects are included in the interim analysis. As the assumptions of the expected treatment difference and 
variability may or may not be upheld, the purpose of the interim analysis is to either re-estimate sample 
size or to stop the study due to futility. The sample size may be adjusted to achieve the desired power 
while maintaining control of the overall Type I error. The maximum sample size planned for this study is 
74 per treatment group. The study team will be blinded to the results of the interim analysis and any 
adjustments that will be made to the sample size. However, the clinical supplies group will be informed 
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
41
of the decision made at the interim analysis so that only the required amount of study medication will be 
packaged.
Primary and Secondary Efficacy Analyses
With the exception of the European Union (EU) dossier, the primary efficacy variable, 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 (MMRM). The model will include baseline MADRS total 
score as a covariate, and treatment, country, class of antidepressant (Serotonin and Norepinephrine 
Reuptake Inhibitors [SNRI] or Selective Serotonin Reuptake Inhibitors [SSRI]),
day, and 
day-by-treatment interaction as fixed effects, and a random subject effect. Comparison of the intranasal 
esketamine plus oral antidepressant arm versus oral antidepressant plus intranasal placebo will be 
performed using the appropriate contrast.
For the EU dossier, the primary efficacy analysis will be based on an analysis of covariance (ANCOVA) 
model using last observation carried forward (LOCF) data. The model will include factors for treatment, 
country, and class of oral antidepressant (SNRI or SSRI) and baseline MADRS total score as a covariate. 
Comparison of the intranasal esketamine plus oral antidepressant arm versus intranasal placebo plus oral 
antidepressant will be performed using the appropriate contrast.
Response and remission rates will be summarized at each visit
The ranks of change from baseline in CGI-S scores at the end of the double-blind induction phase will be 
analyzed based on LOCF data using an ANCOVA model, with country and class of antidepressant (SNRI 
or SSRI) as factors, and the baseline score (unranked) as the covariate. 
Dimension scores of the EQ-5D-5L, descriptive system, the health status index, and the EQ visual analog 
scale (EQ-VAS) scores will be summarized over time.
Additionally, scores of all efficacy endpoints will be summarized for all visits in the double-blind 
induction phase. Summaries will be provided to show consistency of effect among relevant subgroups 
(eg, antidepressant class SNRI and SSRI).
PK Analyses
Plasma esketamine (and noresketamine, if warranted) concentrations will be listed for all subjects. The 
plasma concentration-time data of esketamine (and noresketamine, if warranted) will be analyzed using 
population PK modeling. Data may be combined with those of other selected studies to support a relevant 
structural model. Typical population values of basic PK parameters will be estimated together with the 
inter-individual variability. 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.
PK/PD Analyses
The relationship between the MADRS total score (and possibly selected adverse events as additional PD
parameters), and PK metrics of esketamine, may be evaluated. If there is any visual trend in graphical 
analysis, suitable models will be applied to describe the exposure-effect relationships. The results of the 
PK/PD analyses may be reported separately.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Analyses
Baseline biomarker values and changes from baseline biomarker values to the time points specified in the 
Time and Events Schedule will be summarized. Exploratory biomarker analyses may include 
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
42
comparisons of biomarker measures between the treatment groups, correlation with efficacy and other 
measures, and relationships with clinical response, relapse, and nonresponse.
The analysis plan and summarized results from both biomarker and pharmacogenomics analyses will be 
reported separately.
Safety Analyses
All safety data will be analyzed separately for the double-blind induction phase and the follow-up phase.
The verbatim terms used in the electronic case report form (eCRF) by investigators to identify adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). All reported 
adverse events with onset during the double-blind induction phase (ie, TEAEs, and adverse events that 
have worsened since baseline) will be included in the analysis. For each adverse event, the percentage of 
subjects who experience at least 1 occurrence of the given event will be summarized by treatment group.
Adverse events occurring during the follow-up phase will be summarized separately.
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. Adverse events of special 
interest will be further listed in the SAP.
Subjects who die, who discontinue treatment due to an adverse event, or who experience a severe or a 
serious adverse event will be summarized separately.
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly abnormal 
results (specified in the SAP) will be used in the summary of laboratory data. Descriptive statistics will be 
calculated for each laboratory analyte at baseline and at each scheduled time point in each phase of the 
study. Changes from baseline results will be presented. Frequency tabulations of the abnormalities will be 
provided. Listings of subjects with laboratory results outside the reference ranges and markedly abnormal 
results will also be provided.
Electrocardiogram (ECG) data will be summarized by ECG parameter. Descriptive statistics will be 
calculated at baseline and for observed values and changes from baseline at each scheduled time point. 
Frequency tabulations of the abnormalities will be made. The ECG variables that will be analyzed are 
heart rate, PR interval, QRS interval, QT interval, and corrected QT (QTc) interval using the following 
correction methods: QT corrected according to Fridericia’s formula (QTcF), which will be the primary 
correction factor, and QT corrected according to Bazett's formula (QTcB).
Descriptive statistics of QTc intervals and changes from double-blind baseline will be summarized at each 
scheduled time point. The percentage of subjects with QTc interval >450 msec, >480 msec, or >500 msec 
will be summarized, as will the percentage of subjects with QTc interval increases from baseline 
<30 msec, 30-60 msec, or >60 msec.
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, pulse oximetry, and blood pressure 
(systolic and diastolic) (supine) values and changes from baseline will be summarized at each scheduled 
time point. The percentage of subjects with values beyond clinically important limits will be summarized.
Changes in findings from the baseline nasal examination (including the upper respiratory tract/throat) will 
be listed by treatment group. Examinations will provide ratings (absent, mild, moderate, or severe) that 
are based on a visual inspection of the nostrils, nasal mucosa, and throat for nasal erythema, rhinorrhea, 
rhinitis, capillary/blood vessel disruption and epistaxis. A shift table for changes from double-blind 
baseline in ratings for each examination will be presented by treatment group.
Scoring from the nasal symptom questionnaire will be summarized descriptively for each scheduled time 
point by treatment group.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
43
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.
Descriptive statistics of the CADSS, BPRS+, and MOAA/S scores and changes from predose will be 
summarized at each scheduled time point.
Descriptive statistics of the CGADR, PWC-20, BPIC-SS, UPSIT scores and changes and/or percent 
changes from baseline will be summarized at each scheduled time point.
Descriptive statistics of each cognitive domain score and changes from baseline will be summarized at 
each scheduled time point.
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
44
TIME AND EVENTS SCHEDULE (Screening/Prospective Observational Phase and Double-blind Induction Phase)
Phase
Screening/
Prospective Observational Phase
Double-blind Induction Phase
Visit number
1.1
1.2
1.3a
2.1a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
EWb
Week
Week 1
End of 
Week 2
End of
Week 4
1
2
3
4
Study day
-
-
-
1
(baseline)
4
8
11
15
18
22
25
28
EW
Clinical visit window (in days)
-
±2
±2
-
±1
±1
±1
±1
±1
±1
±1
±1
-
Clinical visit (C)
C
C
C
C
C
C
C
C
C
C
C
C
C
Screening/Administrative
Informed consent (ICF)
X
Medical history, psychiatric history, 
demographics, and employment status
X
MINI
X
MMSE
X
MGH-ATRQ
X
Site Independent Qualification 
Assessment
X
Height 
X
Inclusion/exclusion criteria
X
X
Prestudy therapy
X
Preplanned surgery/procedures
X
STOP Bang questionnaire 
(including assessment of BMI and 
neck circumference)
X
IDS-C30
X
Study Drug
Randomization
X
Dispensing of new oral antidepressant 
(duloxetine, escitalopram, sertraline, 
or venlafaxine XR)
X
Xn
X
Practice session for use of intranasal 
deviced
X
Intranasal esketamine or placeboo
X
X
X
X
X
X
X
X
Drug accountability (intranasal study 
medication)
X
X
X
X
X
X
X
X
X
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
45
Phase
Screening/
Prospective Observational Phase
Double-blind Induction Phase
Visit number
1.1
1.2
1.3a
2.1a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
EWb
Week
Week 1
End of 
Week 2
End of
Week 4
1
2
3
4
Study day
-
-
-
1
(baseline)
4
8
11
15
18
22
25
28
EW
Clinical visit window (in days)
-
±2
±2
-
±1
±1
±1
±1
±1
±1
±1
±1
-
Clinical visit (C)
C
C
C
C
C
C
C
C
C
C
C
C
C
Drug accountability (oral 
antidepressant study medication)
X
X
X
Dispense subject diary for oral 
antidepressant
X
Review subject diary and update (if 
applicable)
X
X
X
X
X
X
X
X
X
Oral antidepressant compliance check
X
X
X
X
X
Return of subject diary if not entering 
follow up phase
X
Safety Assessments (Clinician)
Physical examination
X
X
X
X
Nasal examinationd
X
X
X
X
Vital signs: blood pressure, pulse, 
respiratory rate, temperatured,o
X
X
X
X
X
X
X
X
X
X
Vital signs (postdose): blood pressure, 
pulse, respiratory ratee,o
X
X
X
X
X
X
X
X
Weight
X
X
X
X
12-lead ECGf,o
X
X
X
X
X
X
X
X
X
X
C-SSRS: Baseline/Screening version
X
C-SSRS: Since last visit versiond,o
X
X
Xr
X
X
X
X
X
X
X
X
X
MOAA/Sg,o
X
X
X
X
X
X
X
X
Pulse oximetryg,o
X
X
X
X
X
X
X
X
X
BPRS+h,o
X
X
X
X
X
X
X
X
CADSSh,o
X
X
X
X
X
X
X
X
CGADRi
X
X
X
X
X
X
X
X
PWC-20
Xj
X
Safety Assessments (Subject-completed)
Nasal symptom questionnairek
X
X
X
X
X
BPIC-SSd
X
X
X
X
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
46
Phase
Screening/
Prospective Observational Phase
Double-blind Induction Phase
Visit number
1.1
1.2
1.3a
2.1a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
EWb
Week
Week 1
End of 
Week 2
End of
Week 4
1
2
3
4
Study day
-
-
-
1
(baseline)
4
8
11
15
18
22
25
28
EW
Clinical visit window (in days)
-
±2
±2
-
±1
±1
±1
±1
±1
±1
±1
±1
-
Clinical visit (C)
C
C
C
C
C
C
C
C
C
C
C
C
C
Assessment of Sense of Smell
UPSITd,p
X
X
X
Efficacy Assessments (Clinician)
MADRS (performed by independent, 
remote raters)
X
Xq
Xq
Xc,q
Xd,q
Xd,q
Xd,q
Xq
X
CGI-Sd
X
X
X
X
X
X
X
X
X
X
X
Efficacy Assessments (Subject-completed)
PAQ
X
X
X
EQ-5D-5Ld
X
X
X
X
X
Cognition Testings
Practice sessions for computerized 
test battery
X
Computerized test battery and HVLT-
R
Xd
X
X
Clinical Laboratory Assessments
TSH, HbA1c
X
Lipid panel (fasting) 
X
Hematology, chemistryd
X
X
X
X
Urine drug screend
X
X
X
X
Alcohol breath test
X
X
Urinalysisd
X
X
X
X
X
Pharmacokinetics
Blood collectionl
X
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations
Blood sample collection (protein)m,d
X
X
X
X
X
Blood sample collection (DNA) m,d
X
X
X
Blood sample collection (RNA) m,d
X
X
X
X
X
NCT02422186


JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3005 Amendment 3
Status: Approved, Date: 18 July 2016
47
Phase
Screening/
Prospective Observational Phase
Double-blind Induction Phase
Visit number
1.1
1.2
1.3a
2.1a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
EWb
Week
Week 1
End of 
Week 2
End of
Week 4
1
2
3
4
Study day
-
-
-
1
(baseline)
4
8
11
15
18
22
25
28
EW
Clinical visit window (in days)
-
±2
±2
-
±1
±1
±1
±1
±1
±1
±1
±1
-
Clinical visit (C)
C
C
C
C
C
C
C
C
C
C
C
C
C
Ongoing Subject Review
Concomitant Therapy
Ongoing
Adverse Events
Ongoing
Footnotes:
Abbreviations: BMI=body mass index; BPIC-SS=Bladder Pain/Interstitial Cystitis Symptom Score; 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; C-SSRS=Columbia Suicide Severity Rating Scale; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; EQ-5D-5L=EuroQol-5 dimension, 5-level; EW=early withdrawal; HbA1C=glycosylated hemoglobin; HVLT-R=Hopkins 
Verbal Learning Test-Revised; IDS-C30=Inventory of Depressive Symptomatology Clinician-rated 30-item scale; MADRS=Montgomery-Asberg 
Depression Rating Scale; MGH-ATRQ=Massachusetts General Hospital Antidepressant Treatment History Questionnaire; MINI=Mini International 
Neuropsychiatric Interview; MMSE=Mini Mental State Examination; MOAAS=Modified Observer's Assessment of Alertness/Sedation; PAQ=Patient 
Adherence Questionnaire; PWC-20=20-item Physician Withdrawal Checklist; RNA=ribonucleic acid; STOP-Bang=Snoring, Tired, Observed Apnea, 
High Blood Pressure, Body mass index, Age, Neck Size, Gender (a questionnaire); TSH=thyroid-stimulating hormone; UPSIT= University of 
Pennsylvania Smell Identification Test
Note: On intranasal dosing days, time 0 is defined as the time of the first intranasal spray. Therefore postdose time points are referenced from this.
a)
An additional, optional period of up to 3 weeks is permitted to taper and discontinue current antidepressant treatment(s) after completion of the 
Week 4 (Visit 1.3) assessments, per the local prescribing information or clinical judgment. This 3 week period may also be used to optimize 
medical management if needed to facilitate subject participation. Subjects who do not require a taper and are thus eligible to immediately 
proceed to the double-blind induction phase can have Visits 1.3 and 2.1 occur on the same day or within 1 week of each other (if not occurring 
on the same day, the antidepressant treatment regimen should be continued after visit 1.3. and then discontinued prior to Visit 2.1).
b) If a subject withdraws before the end of the double-blind induction phase (ie, before completing Visit 2.9/Day 28) for reasons other than withdrawal 
of consent, and an early withdrawal visit should be conducted within 1 week of the date of discontinuation, followed by the follow-up phase. If the 
early withdrawal visit is conducted on the same day as a scheduled visit, duplicate assessments are not required.
c) Performed for subjects requiring a taper period during the screening/prospective observational phase; the result will be the subject’s baseline MADRS 
for the double-blind induction phase. For all other subjects, the baseline MADRS for the double-blind induction phase will be the MADRS performed 
at the end of Week 4 of the screening/prospective observational phase.
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d) Predose (if/when performed on intranasal dosing days). Predose subject-reported outcome assessments should be administered before all other study-
related procedures during a clinic visit.
e) Postdose vital signs will be measured at 40 minutes, 1 hour, and 1.5 hours postdose. Please refer to Section 6.2.1 for guidance on blood pressure 
monitoring on dosing days.
f) Twelve-lead ECG will be performed predose and at t=1 hour postdose at Visit 2.1. Twelve-lead ECG will be performed at t=1 hour postdose (no 
predose) at Visits 2.2 through 2.8. A time window of ±15 minutes is permitted.
g) The MOAA/S will not be performed at Visit 1 (pulse oximetry only). The MOAA/S will be performed every 15 minutes from predose to t=+1.5 hours 
postdose (please refer to Section 9.6 for further guidance on MOAA/S assessments). Pulse oximetry will be performed every 15 minutes from predose 
to t=1.5 hours postdose (please refer to Section 9.6 for further guidance regarding on timing of pulse oximetry assessments).
h) The BPRS+ and CADSS to be performed predose and at 40 minutes and 1.5 hours postdose. 
i) CGADR to 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.
j) PWC-20 to be performed predose on all subjects.
k) Nasal symptom questionnaire will be performed predose and at 1 hour postdose.
l) PK blood collection will be performed at t=40 minutes and t=2 hours postdose (where time=0 is defined as the time of the first intranasal spray).
m) Blood samples should be collected prior to dosing. It is preferred that subjects adhere to a low fat diet on the day of sample collection.
n) Only subjects entering the follow-up phase will be provided with a 2-week supply of oral antidepressant.
o) If intranasal dosing is postponed (but occurs within visit window) due to vital sign results (eg, blood pressure elevation), all assessment time points 
(including predose) must be performedon the actual intranasal dosing day.
p) If on the day of the scheduled smell test assessments the subject has significant nasal congestion, the site should consider postponing to the next 
scheduled visit.
q) The MADRS should be administered no more than 2 days prior to the subject’s targeted (not actual) clinic visit date (except Visit 2.9, which is within 
1 day prior). If performed on the day of the scheduled clinic visit for an intranasal treatment session, the MADRS must be performed prior to the 
intranasal treatment session.
r) Performed only if Visit 1.3 and Visit 2.1 do not occur on the same day.
s) Testing can precede Visit 2.1. 
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TIME AND EVENTS SCHEDULE (Follow-up Phase)
Visit Number
Follow-up Phase
3.1
3.2
Weeks after last intranasal dose
1
2
Visit window for clinic visit or remote assessments only (days)
±3
±3
Clinical visit (C) or remote assessments only (RA)
RAe
C
Oral antidepressant compliancea
Oral antidepressant compliance check
X
Return of subject diary
X
Safety assessments (Clinician-completed)
Physical examination
X
Nasal examination
X
Vital signs: Blood pressure, pulse, respiratory rate, temperature
X
12-lead ECG 
X
C-SSRS: Since last visit version
X
PWC-20
Xb
X
Safety assessments (Subject-completed)
BPIC-SS
X
Efficacy assessments (Clinician-completed)
MADRS (performed by independent, remote raters)c
X
X
CGI-S 
X
Efficacy assessments (Subject-completed)
EQ-5D-5L
X
Cognition testing
Computerized test battery and HVLT-R
X
Clinical laboratory assessments
Hematology, chemistry 
X
Urinalysis
X
Biomarker and Expression (RNA) evaluations
Blood sample collection (protein)d
X
Blood sample collection (RNA) d
X
Study Drug
Drug Accountability
X
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Visit Number
Follow-up Phase
3.1
3.2
Weeks after last intranasal dose
1
2
Visit window for clinic visit or remote assessments only (days)
±3
±3
Clinical visit (C) or remote assessments only (RA)
RAe
C
Ongoing subject review
Concomitant therapy
Ongoing
Adverse events
Ongoing
Footnotes:
Abbreviations: BPIC-SS=Bladder Pain/Interstitial Cystitis Symptom Score; CGI-S=Clinical Global Impression – Severity; C-SSRS=Columbia Suicide 
Severity Rating Scale; ECG=electrocardiogram; EQ-5D-5L=EuroQol-5D, 5-level; HVLT-R=Hopkins Verbal Learning Test-Revised; PWC-20=20-item 
Physician Withdrawal Checklist; RNA=ribonucleic acid.
Note: No intranasal study medication will be administered during this phase.
a) In order to better assess potential withdrawal symptoms from intranasal study medication, the oral antidepressant medication should be continued for 
the 2 weeks of the follow-up phase, unless determined to be not clinically appropriate.
b) Performed by telephone by qualified site staff.
c) MADRS will be performed by an independent remote rater. At Visit 3.1 (Week-1 of follow-up) the subject will have the MADRS assessment with a 
remote rater visit, in addition to a follow-up call from the site.
d) It is preferred that subjects adhere to a low fat diet on the day of sample collection.
e) For the Remote Assessment (RA) Visit 3.1, site staff will contact the subject by telephone to obtain information regarding adverse events and 
concomitant therapies.
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ABBREVIATIONS
AHI
apnea-hypopnea index
ANCOVA
analysis of covariance
ASA
American Society of Anesthesiologists
AUC
area under the plasma concentration-time curve
BDNF
brain-derived neurotrophic factor
BMI
body mass index
BPIC-SS
Bladder Pain/ Interstitial Cystitis Symptom Score 
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
C
clinic visit
Cmax
maximum plasma concentration
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
cytochrome P450, with appended letters (eg, 2B6, 3A4) indicating subtype
DBP
diastolic blood pressure
DBS
deep brain stimulation
DNA
deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders (5th Edition)
ECG
electrocardiogram
eCRF
electronic case report form
ECT
electroconvulsive therapy
eDC
Electronic Data Capture
EQ-5D-5L
EuroQol; 5 dimension; 5 level
EQ-VAS
EuroQol group: Visual Analogue Scale
EU
European Union
EW
Early Withdrawal
FAS
full analysis set
FDA
Food and Drug Administration
fT4
free thyroxine
GCP
Good Clinical Practice
HbA1c
glycated hemoglobin 
HDRS
Hamilton Depression Rating Scale
HIV
human immunodeficiency virus
HPA
hypothalamic pituitary adrenal
HVLT-R
Hopkins Verbal Learning Test-Revised
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IDS-C30
Inventory of Depressive Symptomatology-Clinician rated, 30-item scale
IEC
Independent Ethics Committee
IM
intramuscular
IRB
Institutional Review Board
IV
intravenous
IWRS
interactive web response system
LC-MS/MS
liquid chromatography-tandem mass spectrometry
LOCF
last observation carried forward
MADRS
Montgomery Asberg Depression Rating Scale
MAOI
monoamine oxidase inhibitor
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MGH-ATRQ
Massachusetts General Hospital – Antidepressant Treatment Response Questionnaire
MINI
Mini International Neuropsychiatric Interview (mental status questionnaire)
MOAA/S
Modified Observer’s Assessment of Alertness/Sedation
MMRM
mixed-effects model for repeated measures
NMDA
N-Methyl-D-Aspartate
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PAQ
Patient Adherence Questionnaire
PCP
phencyclidine
PD
pharmacodynamics
PK
pharmacokinetics
PQC
product quality complaint
PRISM-E
Primary Care Research in Substance Abuse and Mental Health for the Elderly
PWC-20
Physician Withdrawal Checklist; 20-item
QIDS-SR16
Quick Inventory of Depressive Symptomatology – Self Report 
QTc
QT interval corrected
QTcB
QT interval corrected according to Bazett's formula
QTcF
QT interval corrected according to Fridericia's formula
RA
remote assessments only
RNA
ribonucleic acid
SAP
statistical analysis plan
SBP
systolic blood pressure
SmPC
Summary of Product Characteristics
SMQ
standard Medical Dictionary for Regulatory Activities query
SNRI
Serotonin and Norepinephrine Reuptake Inhibitors
SSRI
Selective Serotonin Reuptake Inhibitors
STOP-Bang
snoring, tired, observed apnea, high blood pressure, body mass index, age, neck size, gender 
(questionnaire)
SUSAR
suspected unexpected serious adverse reaction
Tmax
time to reach the maximum plasma concentration
TEAE
treatment-emergent adverse event
TRD
treatment-resistant depression
TSH
thyroid-stimulating hormone
UPSIT
University of Pennsylvania Smell Identification Test
US
United States
US FDA
United States Food and Drug Administration
VNS
vagal nerve stimulation
XR
extended release
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1.
INTRODUCTION
Major depressive disorder (MDD) is a serious, recurrent, and disabling psychiatric illness.90 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.91,95 About 30% of 
patients fail to achieve remission despite treatment with multiple antidepressant medications, and 
are considered to have treatment-resistant depression (TRD).32,77 In patients who respond to 
antidepressant treatments, the time to onset of effect is typically 4 to 7 weeks, during which time 
patients continue to suffer from their symptoms and continue to be at risk of self-harm, as well as 
being impacted by the associated harm to their personal and professional lives.77,80 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 patients 
with TRD.19,25
Depression in later life, traditionally defined as age older than 65 years, is associated with 
disability, increased mortality, and poorer outcomes from physical illness and in addition, the 
condition is often under-recognized and under-treated.73 In the Primary Care Research in 
Substance Abuse and Mental Health for the Elderly (PRISM-E) study, a large study of older 
patients with major depressive disorder, 71% of the patients did not remit even after 6 months of 
standard of care treatment in specialty or integrated care treatment centers.2 Factors associated 
with non-remission included severity of depression at baseline, a family history of depression, 
comorbid anxiety, and general medical comorbidity. According to the World Health 
Organization (WHO) data, proportionately more people aged over 65 years commit suicide than 
any other age group; most have major depression. Older people who attempt suicide, are more 
likely to die than younger people, while in those who survive, prognosis is worse for older 
adults.49
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.45 The desired analgesic-anesthetic effects of ketamine and esketamine are 
attributed to the blockade of ionotropic N-methyl-D-aspartate (NMDA) glutamate 
receptors.52,66,98
Monoamines (serotonin, norepinephrine, and/or dopamine) are only modulatory transmitters; 
therefore, conventional monoaminergic antidepressant treatments would not be expected to 
robustly affect synaptic transmission, activity-dependent release of brain-derived neurotrophic 
factor (BDNF), or synaptogenesis.25 In contrast, the mechanism of action of ketamine and 
esketamine is distinct from conventional antidepressant treatments because both ketamine and 
esketamine profoundly affect fast excitatory glutamate transmission, increase BDNF release, and 
stimulate synaptogenesis.25
Most literature reports of the antidepressant effects of ketamine describe studies using IV 
administration of the racemate.16,60 Janssen Research & Development (JRD) is developing 
intranasal esketamine as an antidepressant therapy because it has higher NMDA receptor affinity 
which allows a lower volume of medication to be administered via the intranasal route.51,62,67
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For the most comprehensive nonclinical and clinical information regarding esketamine 
(JNJ-54135419), please refer to the latest edition of the Investigator’s Brochure.42
The term “sponsor” used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
1.1.1.
Summary of Nonclinical Findings
Safety Pharmacology
The following text is quoted from the US prescribing information for anesthetic Ketalar®
(ketamine hydrochloride [HCl] injection).45 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.42
Toxicology
Repeat-Dose Toxicity Studies
In repeat-dose toxicity studies with intranasally administered esketamine in rats up to 9 mg/day 
for 6 months, and dogs up to 72 mg/day for 3 months of duration, the clinical observations 
mainly related to the central nervous system (eg, changes in activity and gait). No adverse effects 
were noted up to the highest dose tested, ie, 9 mg/day in rats and 72 mg/day in dogs. These 
observations reflected the (exaggerated) pharmacology of the test compound. Minor histologic 
findings were noted in the nasal cavity. These tissue changes were not considered adverse.
In 3- and 9-month repeat-dose toxicity studies with intranasally administered esketamine in dogs, 
no relevant electrocardiogram (ECG) changes were noted up 72 mg/day. Heart rate was slightly 
increased. 
Further details can be found in the Investigator’s Brochure.42
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Genetic Toxicity
A series of in vitro and in vivo genotoxicity studies were conducted with ketamine and 
esketamine. The weight of evidence indicates that esketamine poses no genotoxic risk to 
humans.42
Neurotoxicity
Racemic ketamine has been reported to induce neurotoxicity in animal fetuses, and in juvenile, 
adolescent, and adult animals, as evidenced by histopathologic brain lesions and functional 
sequelae. The precise thresholds for dose and duration of exposure causing neurotoxicity in 
animals remain to be established. The relevance to humans of ketamine’s neurotoxic action in 
animals is unknown.
In studies exploring neurotoxic effects of ketamine on juvenile and prenatal monkeys, 
neuroapoptosis was observed to be more widespread in fetal brains than in neonatal brains, after 
administration of ketamine anesthesia IV for 5 hours. In fetal brains, the cerebellum, caudate 
nucleus, putamen, and nucleus accumbens were most severely affected. In neonatal brains, the 
cerebellum was not affected; the strongest neuroapoptotic response was noted in the basal 
ganglia and several thalamic areas.
In juvenile rodents, ketamine induced apoptotic neurodegeneration was observed, that was more 
widespread than in adult rodents, with the developing brain affected in several major regions. 
Neuronal cell death was induced in the dorsolateral thalamus at blood levels of ketamine of 
14 µg/mL (7 times the human anesthetic blood level of approximately 2 µg/mL).
No significant neurotoxic effects occurred in juvenile Rhesus monkeys if the anesthesia was 
administered as IM induction followed by IV maintenance duration was 3 hours. Ketamine 
infusion for 9 or 24 hours increased neuronal cell death in the frontal cortex, but no significant 
changes were noted in the hippocampus, thalamus, striatum, or amygdala. Cognitive 
impairments were observed beginning around 10 months of age, and persisted at 3.5 years of 
age.
The clinical studies will exclude neonates, infants, children, pregnant women, and breastfeeding 
women. Therefore, ketamine’s neurotoxicity in juvenile animals does not represent a safety risk 
to eligible 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 
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adolescent age at initiation of treatment, and in the pre- and post-natal developmental toxicity 
study in rats, no evidence of neurotoxicity was found. Consequently, the risk of neurotoxicity 
associated with intranasal administration of esketamine to adult and adolescent patients is 
considered low.42
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.42
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.42
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.27 The inhibitory action on membrane 
currents may partly explain the species and tissue differences in inotropic responses to ketamine.
Blood pressure responses to ketamine also vary with the laboratory species and with 
experimental conditions. Blood pressure is increased in normotensive and renal hypertensive rats 
with and without adrenalectomy and under pentobarbital anesthesia. The US prescribing 
information for the anesthetic Ketalar (ketamine HCl for injection) provides the following 
guidance.45
Intravenous Ketalar produces a fall in arterial blood pressure in the Rhesus monkey and a rise in 
arterial blood pressure in the dog. In this respect the dog mimics the cardiovascular effect 
observed in man. The pressor response to Ketalar injected into intact, unanesthetized dogs is 
accompanied by a tachycardia, rise in cardiac output and a fall in total peripheral resistance. It 
causes a fall in perfusion pressure following a large dose. The tachycardia and increase in 
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myocardial contractile force seen in intact animals does not appear in isolated hearts. These 
observations support the hypothesis that the hypertension produced by Ketalar is due to selective 
activation of central cardiac stimulating mechanisms leading to an increase in cardiac output. 
The dog would be considered the most predictive species in terms of ketamine’s cardiovascular 
effects in humans, but the antidepressant effects of ketamine were studied only in rodent models. 
The myocardial contractility effects and blood pressure responses to ketamine vary between 
species.42 Consequently, a margin of safety could not be reliably derived from the available 
animal data.
Overall Conclusion
The currently available nonclinical safety studies support chronic intranasal administration of 
esketamine in human subjects up to a dosage of 84 mg/day.
Further details can be found in the Investigator’s Brochure.42
1.1.2.
Clinical Studies
1.1.2.1.
Pharmacokinetics and Product Metabolism
Metabolism and Excretion
Ketamine and esketamine undergo 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.94 Like ketamine, norketamine is a noncompetitive antagonist at the NMDA 
receptor.26,39 Norketamine has a half-life in plasma of approximately 5 hours.37 The major human 
hepatic CYPs that catalyze ketamine N-demethylation in vitro are CYP2B6 and CYP3A4.38,68,96
The CYP enzymes responsible for the formation of norketamine metabolites include CYP2A6 
and CYP2B6.68 Published results of a clinical pharmacokinetic (PK) study indicate that 
esketamine does not invert to the R-enantiomer.34 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.6 Less than 3% of an administered dose was excreted in urine as parent drug.93
A summary of the PK of esketamine administered by the IV and intranasal routes is provided 
below.
Intravenous Esketamine 
Subjects with TRD received 0.2 mg/kg or 0.4 mg/kg esketamine as a 40-minute IV infusion 
during Study ESKTIVTRD2001.12 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 
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(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.16 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, and the double-blind phase of Panel A of the ESKETINTRD2003 that 
inform dose selection for the Phase 3 program are described below. 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.6 The intranasal esketamine treatments were self-administered under the direct 
supervision of the investigator or designee. Subjects in Cohorts 1 and 3 received esketamine 
doses that ranged from 28 to 112 mg. The regimens were self-administered in the upright 
position. No instructions were given with regard to sniffing after administration. The reported 
median time to reach Cmax (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, while 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 
453 ng*h/mL, respectively) compared with the same esketamine dose self-administered by 
subjects in Cohort 1 (107 ng/mL and 400 ng*h/mL, respectively). The semi-reclined position of 
the head and the instruction to subjects to sniff gently 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.10
During the Phase 1 study ESKETINTRD1002, healthy Japanese and Caucasian subjects received 
single intranasal doses of esketamine 28 mg, 56 mg, and 84 mg in a crossover manner.10 On 
average, plasma esketamine Cmax and AUC values were up to 48% higher in Japanese subjects as 
compared with Caucasian subjects.
Study ESKETINTRD1003 compared the PK, safety, and tolerability of intranasally administered 
esketamine in healthy elderly (65 years of age) and younger adult subjects (18 to 55 years of 
age, inclusive).11 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 
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approximately 21% and 17% higher, respectively, in the elderly compared with younger adult 
subjects.11
Study ESKETINTRD1012 evaluated the pharmacokinetics and safety of a single intranasal 
84-mg dose, which was self-administered by 8 healthy subjects who were ≥75 years of age and 
8 healthy younger adults (18 to 55 years of age).8 Preliminary data showed the median time to 
reach the maximum plasma concentration (tmax) of esketamine was 0.53 hours and 0.83 hours, in 
healthy elderly subjects ≥75 years of age and younger adults, respectively. The means of the Cmax
and area under the plasma concentration-time curve from time 0 to infinite time (AUC∞), for 
esketamine were approximately 48% and 31% higher, respectively, in the elderly compared with 
younger adult subjects. Differences were greater based on median Cmax and AUC∞values (97% 
and 63% higher in the elderly, respectively).
Study ESKETINTRD2003 is an ongoing
2-panel, doubly randomized, double-blind, 
placebo-controlled, multicenter study.70 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 
(ongoing) is designed to assess the efficacy and safety of 14-mg and 56-mg dose strengths. 
Results of a preliminary analysis of data from the double-blind phase of Panel A indicate mean 
(standard deviation) esketamine concentrations at 40 minutes postdose were 36.4 ng/mL (16.4), 
58.1 ng/mL (24.5), and 72.5 ng/mL (34.2), respectively, for the 3 doses. The mean esketamine 
concentrations in plasma samples collected on Days 1 and 11 were similar, suggesting that the 
PK results are consistent after repeated administration.
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 in 2 
studies in bipolar depressed subjects (meta-analyses).33 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 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).12 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-value=0.001 in both dose groups) compared with the 
placebo group. The mean (standard deviation) change from baseline Day 1 to Day 2 in MADRS 
total score was -4.9 (4.72) in the placebo group, -16.8 (10.12) in the esketamine 0.20-mg/kg 
group, and -17.8 (9.45) in the esketamine 0.40-mg/kg group. 
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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 study demonstrated that the response to the first dose 
could be maintained by multiple infusions 3 times a week over 2 weeks. The duration of 
response lasted for approximately 19 days.1
The KETIVTRD2002 study assessed whether multiple doses of 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.13
As noted above, Study ESKETINTRD2003 is a 2-panel, doubly randomized, double-blind, 
placebo-controlled, multicenter study.70 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 
(ongoing) 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 
>11 at the end of Period 1. 
The improvement (with respect to change in MADRS total score from baseline Day 1 to Day 8) 
in all 3 esketamine dose groups reached statistical significance (p=0.021, p=0.001, and p<0.001 
for esketamine 28 mg, 56 mg, and 84 mg, respectively) compared with placebo. The results of 
the 2 periods were consistent. The mean differences from placebo on Day 8 (after 1 week of 
treatment), estimated using data from the combined periods, were: 

Esketamine 28 mg:
-4.2 (SE 2.09)

Esketamine 56 mg: 
-6.3 (SE 2.07)

Esketamine 84 mg:
-9.0 (SE 2.13)
The Cohen’s D effect sizes in Period 1 for esketamine compared with placebo were:

Esketamine 28 mg:
low, 0.43 (CI -0.259-1.118)

Esketamine 56 mg:
high, 0.92 (CI 0.201-1.621)

Esketamine 84 mg:
high, 1.19 (CI 0.473-1.883)
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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.
These data with intranasal esketamine support the hypotheses that intranasal esketamine is 
effective as a treatment for depressive symptoms, that it has rapid onset of effect (typically
within 2 hours), and that multiple repeated sessions dose-dependently show sustained response 
throughout the study duration. A clear dose response was seen in the double-blind data in Panel 
A, and the point estimates and confidence intervals suggest a high effect size (Cohen’s D) with 
the 56-mg and 84-mg dose groups, supporting further development. Based on PK data from 
ESKETINTRD1012 it is also possible that the 28-mg dose in the elderly may overlap with the 
56 mg dose in younger patients, so addition of the 28-mg dose in the elderly may provide an 
efficacious dose while improving safety.
1.1.2.3.
Safety and Tolerability
Ketamine is a rapidly acting general anesthetic that is approved and widely used intravenously or 
intramuscularly for the induction and maintenance of anesthesia in children and adults at a dose 
of 1 to 3 mg/kg given as a bolus. Ketamine is marketed as a racemic mixture and in Europe also 
as the S-enantiomer, esketamine. Ketamine was first introduced as an anesthetic in 1963 and is 
considered to have an excellent medical safety profile (Ketalar® USPI 2012; Ketanest®S 
Summary of Product Characteristics [SmPC] 2011).36,45,46,71,84
In the US prescribing information for ketamine HCl for injection and the SmPC for esketamine 
HCl for injection, the following adverse reactions were listed as very common, common, or 
frequent occurrences: Emergence or recovery reactions, elevated blood pressure and pulse rate, 
stimulation of respiration, nausea, and vomiting. See 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 USPI45,a
"Very Common" or "Common" Reactions
Per Anesthetic Esketamine SmPC89,b
Psychiatric 
disorders
Frequency: Emergence reactions occurred in 
approximately 12% of patients.
Characteristics: Severity varied from pleasant 
dreamlike states, vivid imagery, hallucinations, and 
emergence delirium. Some states were accompanied 
by confusion, excitement, and irrational behavior, 
which some patients recalled as an unpleasant 
experience.
Frequency: Recovery reactions were common. When 
esketamine was the sole anesthetic, up to 30% of 
patients displayed dose-dependent recovery reactions.
Characteristics: Reactions included vivid dreams 
(including nightmares), nausea and vomiting, increased 
salivation, blurred vision, dizziness, and motor 
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.
Gastro-
intestinal 
disorders
No gastrointestinal effects were listed as frequent, 
but the USPI stated that anorexia, nausea, and 
vomiting have been observed.
Common effects included nausea and vomiting.
Abbreviations: SmPC, Summary of Product Characteristics; USPI, United States Prescribing Information
a.
"Frequent" was not defined numerically, except in the case of emergence reactions (12%). The terms "very common" and 
"common" did not appear in the adverse effects section of the USPI.
b.
"Very common" was defined in the SmPC as 1/10 and "common" was defined as 1/100 to <1/10.
c.
The incidence of these events can be greatly reduced by the administration of a benzodiazepine.
Source: Investigator's Brochure for esketamine (JNJ-54135419).42
Adverse Events Associated with Short-term Use of Intranasal Esketamine in Patients with 
MDD
According to the SmPC for the esketamine solution for injection/infusion44, the following are 
reported as common adverse effects: transient tachycardia, vivid dreams (including nightmares), 
nausea and vomiting, increased blood pressure, increased salivation, blurred vision, dizziness, 
motor unrest, increase in vascular resistance in pulmonary circulation and increase in mucus 
secretion, increased oxygen consumption, laryngospasms, and temporary respiratory depression. 
It is reported that the risk of respiratory depression typically depends on the dosage and injection 
speed.44
Administration of esketamine is associated with a number of adverse events, which are transient 
in nature and typically resolve in 2 hours or less from the start of drug administration. The phase 
1 study ESKETINTRD1003 evaluated the pharmacokinetics and safety of a single intranasal 
esketamine 28 mg in 14 healthy elderly subjects (65 years of age, with 3 subjects 75 years of 
age) and 20 healthy younger adult subjects (18 to 55 years of age, inclusive). The incidences of 
the treatment emergent adverse events (TEAEs) were slightly higher in young subjects (100% 
[20 subjects]) as compared with elderly subjects (85.7% [12 subjects]). The most commonly 
reported TEAEs by preferred term (>20%) in elderly subjects were dysgeusia and vertigo 
(9 [64%], of 14 subjects each).11
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Additionally, another recently completed Phase 1 study, ESKETINTRD1012, evaluated the 
pharmacokinetics and safety of a single intranasal 84-mg dose, which was self-administered by 
8 healthy elderly subjects who were ≥ 75 years of age (Cohort 1) and 8 healthy younger adults 
(18 to 55 years of age – Cohort 2). An initial review noted TEAEs occurred in all subjects in 
both cohorts (100% [16 subjects – 8 in each cohort]). The TEAE of illusions was reported in 
5 younger subjects (62.5%) and in none of the elderly subjects. In elderly subjects, the incidence 
of TEAEs of vascular disorders (6 subjects [75%] including hot flush [2 subjects, 25%] and 
hypertension [3 subjects, 37.5%]) was higher than in younger adults (1 subject, 12.5% -
hypertension). Vertigo and vertigo positional were more common in elderly subjects (5 subjects, 
62.8% and 1 subject, 12.5%, respectively) than in younger adults (vertigo – 3 subjects, 37.5%).
In both cohorts, the maximal mean increase in systolic and diastolic blood pressure as well as 
heart rate was observed at 32 minutes post dose measurement time point. The mean increase in 
supine systolic blood pressure and pulse rate was slightly greater in Cohort 1 (Table 2) than in 
Cohort 2, while the mean increase in the supine diastolic blood pressure was greater in Cohort 2. 
In both Cohort 1 and Cohort 2, the mean systolic and diastolic blood pressure returned to 
baseline within 4 hours post dose.
Table 2: 
Mean Supine Blood Pressure and Heart Rate - Cohort 1 (ESKETINTRD1012)
Supine SBP (mm Hg)
Mean
Range
Mean Change 
from Baseline
Range
Day 1, predose
133.5
104; 164
Day 1, 32 min
165.3
141; 194
31.8
16; 44
Day 1, 50 min
154.1
127; 177
20.6
- 5; 38
Day 1, 1.5 h
145.6
123; 177
12.1
-11; 32
Day 1, 4 h
130.4
130; 170
-3.1
-36; 31
Supine DBP (mm Hg)
Day 1, predose
68.0
54; 79
Day 1, 32 min
81.5
64; 93
13.5
3; 20
Day 1, 50 min
77.1
65; 87
9.1
-3; 17
Day 1, 1.5 h
76.5
63; 81
8.5
-6; 14
Day 1, 4 h
68.5
57; 81
0.6
-16; 17
Supine Heart Rate (beats/min)
Day 1, predose
60.0
48; 79
Day 1, 32 min
74.8
53; 102
14.8
3; 38
Day 1, 50 min
70.9
53; 96
10.9
1; 32
Day 1, 1.5 h
62.9
46; 81
2.9
-7; 17
Day 1, 4 h
78.0
55; 97
18.0
-6; 39
Abbreviations: SBP, Systolic Blood Pressure; DBP, Diastolic Blood Pressure
In Panel A of the Phase 2 study with intranasal esketamine (ESKETINTRD2003), the most 
common TEAEs (>10% of subjects in the pooled esketamine treatment groups) during the 
double-blind phase were: dizziness, headache, dissociation, dysgeusia (metallic taste), nausea, 
dissociative disorder, and oral hypoesthesia.78 Dissociative symptoms were the most typical of 
these adverse events observed postdose and were characterized by feeling unreal or detached 
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from reality or by perceptual changes. Transient perceptual changes (dissociation), dizziness, and 
nausea were typically seen immediately after drug administration, resolving by 2 hours.
No deaths were reported in the double-blind or open-label phases of the ESKETINTRD2003 
study. One subject experienced an 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 adverse events. One subject in esketamine 28 mg group experienced a TEAE of 
syncope of severe intensity on Day 2 of Period 1, 1 day after receiving the first dose of study 
medication. The subject discontinued from the study and received no further study medication.  
The event resolved on the same day, and the investigator considered the event to be possibly 
related to the study agent. Another subject in the placebo/esketamine 56 mg group experienced a 
TEAE of headache of moderate intensity on Day 11 of Period 2. Study medication was stopped 
following this event, which resolved on the same day. The investigator considered the event to 
be very likely related to the study agent. A third subject in the esketamine group 
(84 mg/esketamine 84 mg) experienced a TEAE of dissociative disorder (verbatim term: 
Dissociative syndrome) of moderate intensity on Day 8 of Period 2 (day of the third esketamine 
84 mg dose in the study). The subject discontinued from the study due to the event of
dissociative disorder, which resolved on the same day. The investigator considered the event to 
be very likely related to the study agent.78
In Panel A dissociative symptoms measured on the Clinician Administered Dissociative States 
Scale (CADSS) were dose-dependent and were observed to reduce significantly with multiple 
doses over 2 weeks. No psychotic symptoms were seen. Transient increases in mean blood 
pressure (systolic and diastolic) were observed post dose following the intranasal esketamine 
administration.
The mean (standard deviation; SD) peak systolic blood pressure after the first administration in 
each dose group in Panel A was:

Placebo: 124.2 (11.51) mmHg; mean increase of 5.4 (7.84) mmHg

Esketamine 28 mg: 131.8 (15.49) mmHg; mean increase of 10.4 (10.44) mmHg

Esketamine 56 mg: 130.4 (18.64) mmHg; mean increase of 11.2 (15.01) mmHg

Esketamine 84 mg: 146.1 (19.9) mmHg; mean increase of 17.1 (15.5) m Hg
Mean (standard deviation; SD) peak diastolic blood pressure after the first administration in each 
dose group was: 

Placebo: 81.2 (8.36) mmHg; mean increase of 3.8 (7.99) mmHg

Esketamine 28 mg: 85.7 (9.16) mmHg; mean increase of 6.5 (7.00) mmHg

Esketamine 56 mg: 86.5 (11.34) mmHg; mean increase of 7.2 (9.67) mmHg

Esketamine 84 mg: 87.8 (10.62) mmHg; mean increase of 8.1 (9.12) mmHg
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The blood pressure increase typically resolved within 2 hours. Unlike dissociative symptoms, the 
blood pressure changes observed do not appear to attenuate over time with multiple doses. 
Transient increases in heart rate were also observed in parallel with blood pressure change. There 
was no clinically meaningful change in blood oxygen level.
Adverse Events Associated with Chronic Use of Ketamine
There are no controlled studies of long-term use with esketamine/ketamine in patients with 
MDD. Much of the literature on chronic use of ketamine comes from data gathered from 
street/illegal use of the drug, rather than systematically conducted clinical studies. Data therefore 
should be interpreted with caution, as in many cases, no baseline pre-drug data are available and 
drug exposure is poorly documented. 
In a 1-year longitudinal study, 150 subjects were divided into 5 groups of 30 subjects each. 
Frequent ketamine users (more than 4 times per week), infrequent ketamine users (at least once a 
month), abstinent users (abstinent for at least 1 month), polydrug controls, and non-users of illicit 
drugs.57 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.56
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.15,56,57,61 Overall, infrequent or recreational 
ketamine use does not appear to be associated with long-term cognitive impairment.56 The most 
robust findings are that frequent ketamine users (more than 5 times a week) exhibit impairments in 
both short- and long-term memory.54 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. 56,57
Ketamine-induced ulcerative cystitis is a recently identified complication.56 The most common 
symptoms are frequency and urgency of urination, dysuria, urge incontinence, and occasionally 
painful hematuria (blood in urine). Computerized tomography scans of these subjects revealed a 
marked thickening of the bladder wall, a small bladder capacity, and perivesicular stranding 
consistent with severe inflammation. At cystoscopy, all patients had severe ulcerative cystitis. 
Biopsies in 4 of these cases found denuded urothelial mucosa with thin layers of reactive and 
regenerating epithelial cells, and ulcerations with vascular granulation tissue and scattered 
inflammatory cells. Cessation of ketamine use provided some relief of symptoms. Most of the 
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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.41,43,55,56,65 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.59 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.79 There is conflicting evidence 
of the existence of a "withdrawal syndrome" after cessation of ketamine use.56 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.56 The 
same study found that 12 of the 30 daily users reported withdrawal symptoms characterized by 
anxiety, shaking, sweating, and palpitations when they stopped using. A few published case 
studies also show craving and somatic and psychological aspects of anxiety as withdrawal 
symptoms.14 However, a specific ketamine withdrawal syndrome has not yet been described.56
Please refer to the Investigator’s Brochure for a summary of the adverse events reported in 
ketamine and esketamine studies.42
1.1.3.
Marketing Experience
No intranasal formulation of esketamine is currently marketed.
1.2.
Active Comparators in Double-blind Induction Phase
This study will evaluate a flexible dose regimen of intranasal esketamine (28 mg, 56 mg or
84 mg) plus a newly initiated oral antidepressant, compared with a newly initiated oral 
antidepressant (active comparator) plus intranasal placebo.
In the double-blind induction phase, subjects will be assigned to receive 1 of 4 commercially 
available oral antidepressant medications from 2 different classes of antidepressant medications, 
selective serotonin reuptake inhibitors (SSRIs: Escitalopram or sertraline), or serotonin and 
norepinephrine reuptake inhibitors (SNRIs: Duloxetine or venlafaxine extended release [XR]).
The indications and safety information provided below for each oral antidepressant are from the 
USPI.24,28,81,87 For further information, please refer to the appropriate package insert applicable to 
the local country in which the study is being conducted.
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In the US, all of the oral antidepressant options include a black box warning in the prescribing 
information regarding suicidality and antidepressant drugs. The black box warning informs the 
prescriber that antidepressant treatments increased the risk, as compared with placebo, of suicidal 
thinking and behavior (suicidality) in children, adolescents, and young adults in short-term 
studies of MDD and other psychiatric disorders. It states that anyone considering using the 
antidepressant in this population must balance the risk with the clinical need. Refer to the US 
prescribing information for the entire content of the black box warning.24,28,81,87
1.2.1.
Selective Serotonin Reuptake Inhibitors
1.2.1.1.
Escitalopram
Escitalopram is indicated in adults for acute and maintenance treatment of MDD and acute 
treatment of generalized anxiety disorder.28
The starting dosage for MDD in the USPI is 10 mg once daily with a maximum of 20 mg once 
daily. If the dosage is increased to 20 mg, this should occur after a minimum of 1 week. No 
additional benefits have been seen at 20 mg/day dose; 10 mg/day is the recommended dose for 
most elderly patients and this is the maximum dose that will be used in the current study.
In adult MDD subjects treated with escitalopram, the most commonly observed adverse reactions 
with escitalopram (incidence of approximately 5% or greater and approximately twice the 
incidence in placebo subjects) were insomnia, ejaculation disorder (primarily ejaculatory delay), 
nausea, sweating increased, fatigue, and somnolence.
Contraindications to the use of escitalopram include serotonin syndrome and monoamine oxidase 
inhibitor (MAOI) use (concomitant use with MAOIs intended to treat psychiatric disorders, 
linezolid, or IV methylene blue; use within 14 days of stopping treatment with an MAOI 
intended to treat psychiatric disorders [in addition, an MAOI should not be used within 14 days 
of stopping escitalopram]); concomitant use with pimozide; and known hypersensitivity to 
escitalopram or citalopram or any of the inactive ingredients.
As with most SSRIs, a gradual reduction in the dosage rather than abrupt cessation of 
escitalopram treatment is recommended whenever possible.
1.2.1.2.
Sertraline
Sertraline HCl is indicated in adults for the treatment of MDD, obsessions and compulsions in 
patients with obsessive compulsive disorder, panic disorder (with or without agoraphobia), 
post-traumatic stress disorder, premenstrual dysphoric disorder, and social anxiety disorder.81
According to the US prescribing information, sertraline should be administered at a dose of 
50 mg once daily for the treatment of MDD. While a relationship between dose and effect has 
not been established for MDD, obsessive compulsive disorder, panic disorder, post-traumatic 
stress disorder, or social anxiety disorder, patients were dosed in a range of 50-200 mg/day in the 
clinical trials demonstrating the effectiveness of sertraline for the treatment of these indications. 
Consequently, a dose of 50 mg, administered once daily, is recommended as the initial 
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therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose increases up to 
a maximum of 200 mg/day. Dose adjustment is recommended in the elderly.
In the current study, to improve tolerability, an initial starting dose of 25 mg is used based on 
experience in clinical practice with elderly patients. Given the 24 hour elimination half-life of 
sertraline, dose changes should not occur at intervals of less than 1 week. In the current study, 
the highest dose is 150 mg/day and patients not tolerating higher doses of sertraline may have the 
dose reduced to a minimum of 50 mg/day.
Contraindications to the use of sertraline include serotonin syndrome and MAOI use 
(concomitant use with MAOIs intended to treat psychiatric disorders, linezolid, or IV methylene 
blue; use within 14 days of stopping treatment with an MAOI intended to treat psychiatric 
disorders); concomitant use with pimozide; and known hypersensitivity to sertraline or any of the 
inactive ingredients. 
In adult subjects, the most common TEAEs associated with the use of sertraline (incidence of at 
least 5% for sertraline or at least twice that for placebo within at least one of the indications) 
were ejaculation failure, dry mouth, increased sweating, somnolence, tremor, dizziness, fatigue, 
pain, malaise, abdominal pain, anorexia, constipation, diarrhea/loose stools, dyspepsia, nausea, 
agitation, insomnia, and decreased libido.
As with most SSRIs, a gradual reduction in the dosage rather than abrupt cessation treatment is 
recommended whenever possible.
1.2.2.
Serotonin and Norepinephrine Reuptake Inhibitors
1.2.2.1.
Duloxetine
Duloxetine is indicated in adults for MDD, generalized anxiety disorder, diabetic peripheral 
neuropathic pain, fibromyalgia, and chronic musculoskeletal pain.24
The starting dosage for MDD in the USPI is 40 to 60 mg/day. The dosage for acute treatment is 
40 to 60 mg/day, with maintenance treatment at 60 mg/day. A starting dose of 30 mg/day has 
also been evaluated.91 In the current study, for improved tolerability in an elderly patient 
population, the initial starting dose is 30 mg/day.
No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, 
caution should be exercised in treating the elderly. When individualizing the dosage in elderly 
patients, extra care should be taken when increasing the dose. The maximum dosage is 
120 mg/day, although there is no evidence that dosages greater than 60 mg/day confer any 
additional benefits. The maximum dose to be used in this study is 60 mg/day.
For pooled studies for all approved indications, the most commonly observed adverse reactions 
in duloxetine-treated subjects (incidence of at least 5% and at least twice the incidence in 
placebo subjects) were nausea, dry mouth, somnolence, fatigue, constipation, decreased appetite, 
and hyperhidrosis. As observed in diabetic peripheral neuropathy studies, duloxetine treatment 
worsens glycemic control in some subjects with diabetes.
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Contraindications to the use of duloxetine include use of an MAOI concomitantly or within 
2 weeks of MAOI use; and use in patients with uncontrolled narrow-angle glaucoma
A gradual reduction in the dosage rather than abrupt cessation is recommended whenever 
possible.
1.2.2.2.
Venlafaxine Extended-release
Venlafaxine XR is indicated in adults for MDD and social anxiety disorder.87
The starting dosage for MDD in the USPI is 75 mg/day (in some patients, 37.5 mg/day for 4 to 
7 days), with a dosage increase by 75 mg/day at intervals of 4 days or longer, and a maximum 
dosage of 225 mg/day. No dose adjustment is recommended for the elderly on the basis of age 
alone, although other clinical circumstances, some of which may be more common in the elderly, 
such as renal or hepatic impairment.
Dosage reductions are recommended for hepatic impairment (including mild) and renal 
impairment. In the current study, the starting dose of venlafaxine is 37.5 mg and the maximum 
dose attained is 150 mg based on the 4 week double-blind treatment duration. Patients not 
tolerating higher doses of venlafaxine XR may have the dose reduced to a minimum of 
75 mg/day.
Contraindications to the use of venlafaxine XR include serotonin syndrome and MAOI use 
(concomitant use with MAOIs intended to treat psychiatric disorders, linezolid, or IV methylene 
blue; use within 14 days of stopping treatment with an MAOI intended to treat psychiatric 
disorders); concomitant use with pimozide; and known hypersensitivity to venlafaxine XR or any 
of the inactive ingredients.
In adult subjects with MDD, adverse events in short-term studies that occurred in at least 5% of 
the subjects receiving venlafaxine XR capsules and at a rate at least twice that of the placebo 
group were abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), 
central nervous system complaints (dizziness, somnolence, and abnormal dreams), and sweating.
Sustained hypertension is noted within the Warnings and Precautions section. Preexisting 
hypertension should be controlled before treatment with venlafaxine XR. It is recommended that 
patients receiving venlafaxine XR tablets have regular monitoring of blood pressure. For patients 
who experience a sustained increase in blood pressure while receiving venlafaxine XR, either 
dosage reduction or discontinuation should be considered.
Across most indications, a dose-related increase in supine systolic and diastolic blood pressure 
was evident in venlafaxine XR-treated patients. Across all clinical studies, 1.4% of subjects in 
the venlafaxine XR-treated groups experienced a 15 mmHg increase in supine diastolic blood 
pressure, with blood pressure 105 mmHg, compared with 0.9% of subjects in the placebo 
groups. Similarly, 1% of subjects in the venlafaxine XR-treated groups experienced a 
20 mmHg increase in supine systolic blood pressure, with blood pressure 180 mmHg,
compared with 0.3% of subjects in the placebo groups.
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A gradual dosage reduction, individualized as necessary, is recommended to avoid 
discontinuation symptoms.
1.3.
Overall Rationale for the Study
This study is being conducted to evaluate the efficacy, safety, and tolerability of flexibly dosed
intranasal esketamine (28 mg, 56 mg or 84 mg) plus a newly initiated oral antidepressant in 
elderly subjects with TRD. The study will serve as a pivotal Phase 3 short-term efficacy and 
safety study in support of regulatory agency requirements for registration of intranasal 
esketamine for the treatment of TRD.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of switching elderly subjects with 
TRD from a prior antidepressant treatment (to which they have not responded) to flexibly-dosed 
intranasal esketamine (28 mg, 56 mg or 84 mg) plus a newly initiated oral antidepressant 
compared with switching to a newly initiated oral antidepressant (active comparator) plus 
intranasal placebo, in improving depressive symptoms, as assessed by the change from baseline 
in the MADRS total score from Day 1 (pre-randomization) to the end of the 4-week double-blind 
induction phase. 
Secondary Objectives

To assess the effect of intranasal esketamine plus a newly initiated oral antidepressant 
compared with a newly initiated oral antidepressant (active comparator) plus intranasal 
placebo on the following parameters in elderly subjects with TRD:

Depression response rates,

Depression remission rates,

Overall severity of depressive illness,

Health-related quality of life and health status.

To investigate the safety and tolerability of intranasal esketamine plus a newly initiated oral 
antidepressant compared with a newly initiated oral antidepressant (active comparator) plus 
intranasal placebo in elderly subjects with TRD, including the following parameters:

Treatment-emergent adverse events (TEAEs), including TEAEs of special interest

Local nasal tolerability

Effects on heart rate, blood pressure, respiratory rate, and blood oxygen saturation

Effects on alertness and sedation

Potential psychosis-like effects

Dissociative symptoms 
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
Potential effects on cognitive function 

Potential effects on suicidal ideation/behavior 

Potential treatment-emergent symptoms of cystitis and/or lower urinary tract symptoms 

Potential withdrawal and/or rebound symptoms following cessation of intranasal 
esketamine treatment

Potential effects on sense of smell 

To assess the PK of intranasal esketamine in elderly subjects with TRD receiving 
intranasal esketamine plus a newly-initiated oral antidepressant.
Exploratory Objectives

To assess the pharmacokinetic/pharmacodynamic (PK/PD) relationship of intranasal 
esketamine and MADRS total score in elderly subjects with TRD.

To assess the potential relationship of biomarkers with response/nonresponse to intranasal 
esketamine or oral antidepressants in elderly subjects with TRD.
2.2.
Hypothesis
The hypothesis for this study is that, in elderly subjects with TRD, switching from a failed 
antidepressant treatment to intranasal esketamine plus a newly initiated oral antidepressant is 
superior to switching to a newly initiated oral antidepressant treatment (active comparator) plus 
intranasal placebo in improving depressive symptoms.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind, active-controlled, multicenter study in male and female 
elderly subjects with TRD to assess the efficacy, safety, and tolerability of flexibly dosed 
intranasal esketamine (28 mg, 56 mg or 84 mg) plus a newly initiated oral antidepressant, 
compared with a newly initiated oral antidepressant (active comparator) plus intranasal placebo. 
The study has 3 phases which are briefly described below.
Screening/prospective observational phase (4-week duration + optional 3-week taper 
period)

This phase will prospectively assess treatment response to the subject’s current oral 
treatment regimen. At the start of the screening/prospective observational phase, the subject 
must have had documented nonresponse to at least one antidepressant treatment (based on 
MGH-ATRQ criteria) in the current episode of depression , and the subject is taking a 
different oral antidepressant treatment (on the MGH-ATRQ) for at least the previous 
2 weeks at or above the minimum therapeutic dose. This antidepressant treatment, as well as 
any other ongoing medications being taken for depression at screening (including 
adjunctive/augmentation therapies), will continue from the start of Week 1 through the end 
of Week 4 of the screening/prospective observational phase. Dose adjustment is permitted 
per clinical judgment, but the oral antidepressant treatment is to remain at or above the 
minimum therapeutic dose (per the MGH-ATRQ) through the end of Week 4. After 4 
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weeks, subjects who are nonresponders to their current oral antidepressant treatment (as 
assessed by independent, remote raters) may be eligible to proceed to the double-blind 
induction phase. Non-response at the end of the screening/prospective observational phase is 
defined as ≤25% improvement in the MADRS total score from Week 1 to Week 4 and a 
MADRS total score of ≥24 on Week 2 and Week 4.

Eligible subjects who are entering the double-blind induction phase will discontinue all of
their current antidepressant treatment(s), including adjunctive/augmentation therapies. Of 
note, subjects taking benzodiazepines (at dosages equal to or less than the equivalent of 
6 mg/day of lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, 
zolpidem, zaleplon) during the screening/prospective observational phase can continue these 
medications. No dose increases beyond the equivalent of 6 mg/day of lorazepam or new 
benzodiazepines are permitted during the screening/prospective observational phase. If 
clinically indicated, a subject’s current antidepressant treatment(s) may be tapered and 
discontinued over an additional, optional period of up to 3 weeks per the local prescribing 
information or per clinical judgment. This 3 week period may also be used to optimize 
medical management if needed to facilitate subject participation (eg, treatment of blood 
pressure or diabetes, wean from other medications, etc,). In such cases, if there is no planned 
taper, the oral regimen should be continued in the interim and then discontinued by Day 1 of 
the double-blind induction phase.

As a new oral antidepressant will be initiated on Day 1 of the double-blind induction phase, 
eligible subjects who do not require a tapered discontinuation of their antidepressant 
treatment(s) can proceed immediately into the double-blind induction phase.
Double-blind induction phase (4-week duration)

Approximately 148 eligible subjects will be randomly assigned at a 1:1 (n=74 subjects per 
treatment arm) to receive double-blind intranasal treatment with either esketamine (28 mg,
56 mg or 84 mg) or placebo. Starting with a dose of 28 mg on Day 1, the intranasal 
treatment sessions (esketamine or placebo) will occur twice weekly for 4 weeks. In addition, 
all subjects will initiate a new, open-label oral antidepressant on Day 1 that will be taken 
daily for the duration of the induction phase. The assigned oral antidepressant will be 1 of 4 
oral antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine XR) 
that the subject has not previously had a nonresponse to in the current depressive episode, 
has not been previously intolerant to (lifetime), and is available in the participating country.

Subjects taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day 
of lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, 
zaleplon) during the screening/prospective observational phase can continue these 
medications during the induction phase. No dose increases beyond the equivalent of 
6 mg/day of lorazepam or new benzodiazepine medications are permitted during the 
induction phase, with the exception of the use of permitted benzodiazepine rescue 
medication.

At the end of the double-blind induction phase, regardless of response status, subjects may 
be eligible to participate in the subsequent study ESKETINTRD3004 if they meet all other 
study entry criteria. ESKETINTRD3004 is a long-term open-label safety study involving 
repeated treatment sessions of intranasal esketamine.
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
If a subject withdraws from the study before the end of the double-blind induction phase for 
reasons other than withdrawal of consent, an Early Withdrawal visit should be conducted 
within 1 week of his/her discontinuing from the study, followed by the follow-up phase.
Follow-up phase (2-week duration)

This phase will include all subjects who withdraw early before the end of the double-blind 
induction phase, or choose not to participate in the subsequent ESKETINTRD3004 safety 
study, and have received at least 1 dose of intranasal study medication in the double-blind 
induction phase. There will be no intranasal treatment sessions administered during this 
phase.

At the start of the follow-up phase, further clinical/standard of care for the treatment of 
depression will be arranged by the study investigator and/or the subject’s treating physician. 
All subjects will be provided with an additional 2-week supply of the oral antidepressant 
medication to ensure that there is no interruption of oral antidepressant therapy during the 
transition to further clinical/standard of care. The decision to continue the oral 
antidepressant in this phase will be at the discretion of the investigator, however, in order to 
better assess potential withdrawal symptoms from intranasal study medication the oral 
antidepressant medication should be continued for the 2 weeks of the follow-up phase unless 
determined as not clinically appropriate.
Taking into consideration the up to 3-week optional taper period, the duration of a subject’s 
study participation will be 8 to 11 weeks (for subjects continuing into ESKETINTRD3004) or 
13 weeks (for subjects completing the follow-up phase).
A diagram of the study design is provided in Figure 1.
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Figure 1:
Study Design for ESKETINTRD3005
*
followed by optional, up to 3 week Taper  if clinically indicated.
AD=antidepressant. DB=double-blind. D/C=discontinued. Esk=Esketamine. MDD=major depressive disorder. 
OL=open-label. PBO=placebo.
Note: Subjects who withdraw early from the double-blind induction phase and receive at least 1 dose of intranasal 
study medication in the double-blind induction phase will have an Early Withdrawal visit performed and then
proceed into the follow-up phase.
A planned interim analysis is described in Section 11.3.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study. 
Please refer to Section 11.9, Independent Data Monitoring Committee, for details.
3.2.
Study Design Rationale
3.2.1.
Study Population
The study population will include elderly men and women, therefore the lower age limit of 
65 years (inclusive), is appropriate. 
Subjects will meet Diagnostic and Statistical Manual of Mental Disorders (5th Edition; DSM-5)
diagnostic criteria for single-episode MDD (if a single episode, duration of episode must be 
2 years) or recurrent MDD, without psychotic features, based upon clinical assessment, and 
confirmed by the Mini-International Neuropsychiatric Interview (MINI). At the start of the 
screening/prospective observational phase, the subject must have an Inventory of Depressive 
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Symptomatology-Clinician rated, 30-item (IDS-C30) total score of 31, which corresponds to
moderate to severe depression. 
Treatment-resistant depression is defined as a lack of clinically meaningful improvement after 
treatment with at least 2 different antidepressant agents prescribed in adequate dosages for 
adequate duration. At the start of this study, subjects must have had nonresponse (defined as 
≤25% improvement) to 1 but 8 (if current episode is >2 years, upper limit applicable to only
the last 2 years) oral antidepressant treatments taken at adequate dosage and for an adequate 
duration, as assessed on the Massachusetts General Hospital–Antidepressant Treatment 
Response 
Questionnaire 
(MGH-ATRQ)
and 
documented 
by 
records 
(eg, 
medical 
/pharmacy/prescription records, a letter from the treating physician, etc.) for the current episode 
of depression. Subjects who have had some initial response, but then lose the response (eg, 
tolerance effects/bradyphylaxis etc.), to an antidepressant treatment will not be considered to 
have failed that antidepressant treatment. 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 to assess treatment response.
In addition, at the start of the screening/prospective observational phase, the subject must be 
taking a different oral antidepressant treatment (on the MGH-ATRQ) for at least the previous 
2 weeks at or above the minimum therapeutic dose. This antidepressant treatment, as well as any 
other medications being taken for depression at screening (including adjunctive/augmentation 
therapies), will continue from the start of Week 1 through the end of Week 4 of the 
screening/prospective observational phase. Dose adjustment is permitted per clinical judgment, 
but the oral antidepressant treatment is to remain at or above the minimum therapeutic dose (per 
the MGH-ATRQ) through the end of Week 4.
Non-response at the end of the screening/prospective observational phase is defined as ≤25% 
improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total score of 
≥24 on Week 2 and Week 4.
The subject’s current major depressive episode, depression symptom severity (Week 1 MADRS
total score ≥24 required), and antidepressant treatment response in their current depressive
episode (retrospectively assessed) must be deemed valid for participation in the clinical study 
based on a Site Independent Qualification Assessment. The Site Independent Qualification 
Assessment is a tool to facilitate subject selection for MDD clinical studies, with a goal to ensure 
enrollment of subjects who have symptoms that reflect the current state of illness and that these 
symptoms can be reliably measured with appropriate measurement tools, as well as to minimize 
placebo response.
3.2.2.
Study Phases
The 4-week duration of the screening/prospective observational phase will provide adequate time 
to assess subject eligibility according to the study entry criteria, while also allowing for a 
prospective confirmation of nonresponse to the current antidepressant treatment(s) that is 
continued 
for 
the 
duration 
of 
this 
phase. 
The 
dose 
of 
all 
antidepressant 
medication(s)/treatment(s) should remain unchanged throughout the screening/prospective 
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observational phase. This method of recruitment allows subjects to enter the study on a variety of 
different antidepressant medications that they had been taking, which mimics clinical practice 
and yet allows for prospective demonstration of treatment resistance to the current antidepressant 
treatment. Even though there is no depression rating score available at the start of the 
antidepressant treatment, the subjects at screening will have to meet criteria for moderate to 
severe depression.
After 4 weeks of prospective observation of continuation of the current antidepressant treatment 
and assessment of treatment response, subjects who meet the predefined nonresponse criteria and 
are eligible to enter the double-blind induction phase will discontinue all of the current 
antidepressant treatments, including adjunctive/augmentation therapies, prior to starting the next 
phase.
Nonresponders who are eligible to enter the double-blind induction phase are permitted to have 
up to 3 additional weeks to taper and discontinue their current antidepressant treatment prior to 
entry into the double-blind induction phase per the local prescribing information or clinical 
judgment (eg, tolerability concerns). The optional taper of up to 3 weeks is expected to provide 
an adequate amount of time for taper and discontinuation. This 3 week period may also be used 
to optimize medical management if needed to facilitate subject participation (eg, treatment of 
blood pressure or diabetes, wean from other medication, etc,). In such cases, if there is no 
planned taper, the oral regimen should be continued in the interim and then discontinued by 
Day 1 of the double-blind induction phase.
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, with a 4 week 
duration considered to be sufficiently long to show the antidepressant effects of the active 
comparator. Preliminary findings from an analysis of 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.48,97 Similarly, it has been demonstrated that improvement of 
25% on the Hamilton Depression 17-item Rating Scale (HDRS) 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.63 All together, these results 
suggest that a 4-week duration should be adequate to assess antidepressant response.
For subjects entering the follow-up phase, the 2-week duration following the last dose of 
intranasal study medication will allow sufficient time to assess safety and tolerability after 
cessation of intranasal study medication, including potential withdrawal symptoms. During this 
follow-up phase, further clinical/standard of care for the treatment of depression will be arranged 
by the study investigator and/or the subject’s treating physician.
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3.2.3.
Blinding and Randomization
Blinded intranasal treatment will be used to reduce potential bias during data collection and 
evaluation of clinical endpoints.
An intranasal placebo control will be used in the double-blind induction phase to establish the 
frequency and magnitude of changes in clinical endpoints that may occur in the absence of 
intranasal active treatment.
Randomization will be used to minimize bias in the assignment of subjects to intranasal 
treatment groups, to increase the likelihood that known and unknown subject attributes (eg, 
demographic and baseline characteristics) are evenly balanced across treatment groups, and to 
enhance the validity of statistical comparisons across treatment groups. The randomization will 
be stratified by country and class of antidepressant (SNRI or SSRI) with an allocation ratio of 1:1 
to intranasal placebo or intranasal esketamine. The stratification is aimed at balancing treatment 
groups across country and class of antidepressant.
3.2.4.
Treatment Groups and Dose Selection
The 2 treatment groups in the double-blind induction phase are:

Intranasal esketamine (28 mg, 56 mg or 84 mg) 

Intranasal placebo
Of note, to improve tolerability, subjects who are assigned to esketamine will start with 28 mg of 
intranasal esketamine on Day 1.
In all treatment groups, subjects will switch to a new, oral antidepressant, initiated on Day 1 of 
the double-blind induction phase, that will continue for the duration of the phase and longer, if 
applicable.
The treatment groups will allow for an evaluation of the efficacy, safety, and tolerability of 
flexibly dosed intranasal esketamine, plus a newly initiated oral antidepressant as compared with
a newly initiated oral antidepressant treatment plus intranasal placebo as an active comparator in 
elderly subjects with TRD. 
Intranasal Study Drug
The dose selection (28 mg, 56 mg and 84 mg) and administration interval (2 treatment sessions 
per week for 4 weeks) for this study were based on the sponsor’s previous clinical data; in 
particular the results from Studies ESKETIVTRD2001, KETIVTRD2002, ESKETINTRD1001, 
ESKETINTRD1003, ESKETINTRD1012 and Panel A of the ESKETINTRD2003 study, 
described above in Section 1.1.2. 
The data from Study ESKETINTRD2003 Panel A support the hypotheses that both the 56 mg 
and 84 mg doses are effective as a treatment for depression in subjects with TRD, that they have 
a rapid onset of effect, and that 2 treatment sessions per week can sustain the response 
throughout the 4 week duration of the double-blind induction phase. In addition, the 56 mg and 
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84 mg dosages were generally well tolerated by subjects. PK data from study 
ESKETINTRD1003 (CSR ESKETINTRD1003 in preparation) which evaluated intranasally 
administered esketamine in elderly (65 years of age) and younger adult subjects (18 to 55 years 
of age, inclusive), indicated plasma esketamine Cmax and AUC values are relatively comparable 
between the elderly and younger adults.11 More recently, Study ESKETINTRD1012 evaluated 
the pharmacokinetics and safety of a single intranasal 84 mg dose in elderly subjects ≥75 years 
of age. Preliminary data showed the means of the Cmax and AUC∞were approximately 48% and 
31% higher, respectively, in the elderly compared with younger adult subjects. Differences were 
greater based on median Cmax and AUC∞values (97% and 63% higher in the elderly, 
respectively). Based on PK data from ESKETINTRD1012 it is also possible that the 28 mg dose 
in the elderly may overlap with the 56 mg dose in younger patients, so addition of the 28 mg 
dose in the elderly may provide an efficacious dose while improving safety.
In the current study, subjects who are randomly assigned to esketamine will start with 28 mg of 
intranasal esketamine on Day 1. The dose of esketamine may be maintained at 28 mg or 
increased to 56 mg on Day 4. On Day 8, 11 or 15 the dose may be maintained, increased or 
reduced by 28 mg, with no further increases in dose permitted after Day 15. The dose may be 
decreased by 28 mg on subsequent dosing days. The rationale for this approach is that using the 
lower starting dose (28 mg) initially and then adjusting the dose in increments of 28 mg based on 
efficacy and tolerability may allow subjects to adjust to the effects of the lower dose before 
going to higher doses. For example, internal data from the CADSS suggest a dose response, with 
the greatest effect seen initially on the 84 mg dose (ESKETINTRD2003). However, on 
subsequent repeated dosing, dissociative symptoms lessen. Starting with the lower dose may 
therefore limit the number of elderly subjects discontinuing the study treatment because of 
intolerability. 
The use of flexible dosing, rather than using a fixed dose, of intranasal esketamine is considered 
to facilitate improved tolerability by gradually increasing to a higher dose and will also inform 
clinical practice, as many clinicians prefer to gradually increase, and then adjust as clinically 
required, the dose of an antidepressant medication in the elderly population.
Oral Antidepressant
On Day 1 of the double-blind induction phase, a new, open-label oral antidepressant treatment 
will be initiated in all subjects. Each subject will be assigned to receive 1 of 4 oral antidepressant 
medications from 2 different classes of antidepressant treatments, an SSRI (escitalopram or 
sertraline) or an SNRI (duloxetine or venlafaxine XR).
The assignment of the oral antidepressant treatment will be done by the investigator based on 
review of the MGH-ATRQ and relevant prior antidepressant medication treatment information.
These 2 classes were selected because they are the most commonly prescribed antidepressant 
classes in this population and are generally well-tolerated. The oral antidepressant treatment
assigned will be one that the subject has not previously had a nonresponse to in the current 
depressive episode, has not been previously intolerant to (lifetime), and is available in the 
participating country. Dosing of the oral antidepressant will begin on Day 1. A mandatory 
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titration schedule is provided (Attachment 3) to ensure that the oral antidepressant is taken at an 
adequate dosage and duration for efficacy assessment at the end of the double-blind induction 
phase as well as for potential maintenance of effect (in the subsequent ESKETINTRD3004
study). Doses are not to exceed the maximum dose defined in the titration schedule. If higher 
doses are not tolerated, a down-titration is permitted based on clinician’s judgment.
3.2.5.
Efficacy Measures
MADRS
The 10-item clinician-administered MADRS was designed to be used in subjects with MDD to 
measure the overall severity of depressive symptoms.53,54 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 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 this study, subjects in either of the 2 treatment groups who respond to the study medication 
(ie, responders) are defined as subjects who meet the criterion for response defined as 50% 
reduction in the MADRS total score from baseline (Day 1 pre-randomization) to the end of the 
4-week double-blind induction phase.
MADRS will also be used to evaluate a secondary objective assessing proportion of subjects 
with response and those in remission (defined as subjects with a MADRS total score 12) at the 
end of the 4-week double-blind induction phase.50
Clinical Global Impression – Severity (CGI-S)
The CGI-S is included to rate the severity of the subject’s illness at the time of assessment, 
relative to the clinician’s past experience with subjects who have the same diagnosis and 
improvement with treatment.35 Please refer to Section 9.2.1.2.1 for additional information 
regarding CGI-S. 
EuroQol-5 Dimension-5 Level (EQ-5D-5L)
The EQ-5D-5L is included as a standardized patient-completed instrument for use as a measure 
of health-related quality of life and health status.27,31 Please refer to Section 9.2.1.3.1 for 
additional information regarding EQ-5D-5L.
3.2.6.
Safety Evaluations
Physical examination, body weight, vital signs (including blood pressure measurements), 12-lead 
ECG, pulse oximetry, clinical laboratory tests, nasal examinations, and evaluation of TEAEs and 
concomitant therapies will be performed throughout the study to monitor subject safety. 
TEAEs of special interest will be examined separately grouped in the following categories: drug 
abuse, dependence and withdrawal (standardized Medical Dictionary for Regulatory Activities 
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[MedDRA] queries [SMQ]), increased blood pressure, increased heart rate, transient 
dizziness/vertigo, impaired cognition, anxiety, and cystitis.
A subject-completed nasal symptom questionnaire will also be conducted as per the Time and 
Event Schedule to assess for any treatment-emergent nasal tolerability symptoms.
The Columbia Suicide Severity Rating Scale (C-SSRS)69 will be performed to assess suicidal 
ideation and behavior, the CADSS will be administered to assess treatment-emergent 
dissociative symptoms, the 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 adverse events, and the Physician Withdrawal Checklist; 
20-item (PWC-20) will be administered (as applicable) to assess potential withdrawal symptoms 
after cessation of esketamine treatment.
Given the potential for treatment emergent transient elevation in systolic and diastolic blood 
pressure, heart rate and blood pressure will be monitored throughout the study and at multiple 
time points on dosing days. Specific guidance to be followed on intranasal dosing days is 
provided in Section 6.2.1.
Even though it is anticipated that the potential risk for treatment-emergent cystitis is very low 
based upon the doses to be used in this study, subjects will be monitored for symptoms of 
cystitis, bladder pain, and interstitial cystitis using the subject-completed Bladder Pain/Interstitial 
Cystitis Symptom Score (BPIC-SS) at specific time points.40 A score >18 on the BPIC-SS scale 
is considered as probable cystitis, and any subjects that meet this cut-off will have a urinalysis 
and culture conducted at that visit to assess for potential urinary tract infection. Those without 
evidence of an ongoing urinary tract infection will be referred to a specialist for diagnostic 
workup. There are no definitive tests for diagnosing ulcerative cystitis. If a subject is determined 
to have a diagnosis of ulcerative cystitis, the subject must be discontinued from the study and 
followed up with appropriate medical care. 
The effect of intranasal esketamine on cognition over the 4-week double-blind induction phase 
will be assessed using a computerized cognitive battery and Hopkins Verbal Learning 
Test-Revised (HVLT-R). The cognitive battery will provide assessment of multiple cognitive 
domains, including attention, visual learning and memory, and executive function. The HVLT-R 
is a measure of verbal learning and memory.
The University of Pennsylvania Smell Identification Test (UPSIT) will be performed to assess 
any treatment-emergent effects on the sense of smell.
On all intranasal dosing days, subjects must remain at the site until study procedures have been 
completed and the subject is ready for discharge. Subjects should be accompanied by a 
responsible adult when released from the clinical site. Subjects must not drive a car or work with 
machines for 24 hours after receiving intranasal study drug.
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A list of prohibited medications is provided in Attachment 1 as general guidance for the 
investigator (but is not all-inclusive).
3.2.7.
Other Assessments
Patient Adherence Questionnaire
During the screening/prospective observational phase, the patient-reported Patient Adherence 
Questionnaire (PAQ) will be used to assess how often the subject has taken, and whether he or 
she has made any changes to, his or her antidepressant treatment regimen in the last 2 weeks. 
This assessment will provide confirmation of medication adherence
when evaluating 
antidepressant treatment response. Subjects who report missing 4 days of antidepressant 
medication during a 2-week recall period will be discontinued because of inadequate adherence.
3.2.8.
Pharmacokinetic Assessments
Pharmacokinetic samples will be obtained during the study for measurement of the plasma 
concentrations of esketamine, noresketamine, and/or additional metabolites, if warranted.
3.2.9.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) 
Evaluations
Assessment of biomarkers (protein and RNA) and their potential relationship to the different 
treatment groups and to maintenance/stabilization of response, 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.
Genetic variation can be an important contributory factor to inter-individual differences in drug 
distribution and response, and can also serve as a marker for disease susceptibility and prognosis. 
Pharmacogenomic research may help to explain inter-individual variability in clinical outcomes 
and may help to identify population subgroups that respond differently to a drug or subgroups 
that are more susceptible to relapse. In addition, pharmacogenomics research may allow for the 
identification of genetic factors that influence the PK, PD, efficacy, safety, or tolerability of the 
different treatment groups, and for the identification of genetic factors associated with TRD or 
MDD. Specifically, genetic and epigenetic changes in genes known to be in pathways relevant to 
depression (eg, hypothalamic-pituitary-adrenal [HPA] axis, inflammation, growth factors, 
monoamine transporters, ion channels, and circadian rhythm, etc.) will be evaluated.
Protein, metabolite, and ribonucleic acid (RNA) biomarkers may aid in the elucidation of the 
mechanism of action of the different treatment groups or help to explain inter-individual 
variability in clinical outcomes or may help to identify population subgroups that respond 
differently to a drug or may help to identify subgroups that are more susceptible to relapse. The 
goal of the biomarker analyses is to evaluate the PD of the different treatment groups, and aid in 
evaluating the drug-clinical response relationship.
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On the day of biomarker sample collection, it is recommended that subjects adhere to a 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.
STUDY 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.
4.1.
Inclusion Criteria
1. Each potential subject must satisfy all of the following criteria to be enrolled in the study. 

At the time of signing the informed consent form (ICF), subject must be a man or 
woman 65 years of age or older.
2. At the start of the screening/prospective observational phase, subject must meet the DSM-5
diagnostic criteria for single-episode MDD (if single episode MDD, the duration of episode 
must be 2 years) or recurrent MDD, without psychotic features, based upon clinical 
assessment and confirmed by the Mini International Neuropsychiatric Interview (MINI).
3. Criterion modified per Amendment 1
3.1 Criterion modified per Amendment 2
3.2 Criterion modified per Amendment 3
3.3 At the start of the screening/prospective observational phase, subject must have had 
nonresponse (≤25% improvement) to 1 but 8 (if current episode is >2 years, upper limit 
applicable to only the last 2 years) oral antidepressant treatments in the current episode of 
depression, assessed using the MGH-ATRQ and confirmed by documented records (eg, 
medical/pharmacy/prescription records, or a letter from the treating physician, etc,). In 
addition, subject is taking a different oral antidepressant treatment (on the MGH-ATRQ) for 
at least the previous 2 weeks at or above the minimum therapeutic dose.

For specific tricyclic antidepressants which are ongoing and being taken at a dose 
below the MGH-ATRQ minimum therapeutic dose, a blood level that is within the
therapeutic (antidepressant) range, is acceptable to establish the adequacy of the 
antidepressant treatment.

Subjects must be adherent to the continued oral antidepressant medication(s) (without 
adjustment in dosage) through the screening/prospective observational phase, as 
documented on the PAQ. Missing 4 days of antidepressant medication in the prior 
2-week period will be considered as inadequate adherence.

Subjects who are nonresponders to the antidepressant medication(s) from the 
screening/prospective observational phase (as assessed by independent, remote raters) 
may be eligible for randomization if all other entry criteria are met. Non-response at 
the end of the screening/prospective observational phase is defined as ≤25% 
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improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total 
score of ≥24 on Week 2 and Week 4.
4. Criterion modified per Amendment 3
4.1. 
At the start of the screening/prospective observational phase, subject must have an 
IDS-C30 total score of 31.
5. Criterion modified per Amendment 2
5.1. Criterion modified per Amendment 3
5.2 
The subject’s current major depressive episode, depression symptom severity 
(Week 1 MADRS total score ≥24 required), and antidepressant treatment response in the
current depressive episode, must be confirmed using the Site Independent Qualification 
Assessment.
6. Subject must be medically stable on the basis of physical examination, medical history, vital 
signs (including blood pressure), pulse oximetry, and 12-lead ECG performed in the
screening/prospective observational phase. If there are any abnormalities that are not 
specified in the inclusion and exclusion criteria, 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.
7. Criterion modified per Amendment 1
7.1 Criterion modified per Amendment 2
7.2 Criterion modified per Amendment 3
7.3 
Subject must be medically stable on the basis of clinical laboratory tests 
performed in the screening/prospective observational phase. If the results of the serum 
chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the 
subject may be included only if the investigator judges the abnormalities or deviations from 
normal to be not clinically significant or to be appropriate and reasonable for the population 
under study. This determination must be recorded in the subject's source documents and 
initialed by the investigator.

Subjects with a pre-existing history of thyroid disease/disorder who are treated with 
thyroid hormones must be on a stable dosage for 3 months prior to the start of the 
screening/prospective observational phase.

For any subject (regardless of thyroid history), if the thyroid stimulating hormone 
(TSH) value is out of range, a free thyroxine (fT4) will be conducted. If the fT4 value 
is abnormal and considered to be clinically significant (after discussion with the 
medical monitor), the subject is not eligible.
8. Subject must be comfortable with self-administration of intranasal medication and be able to 
follow the intranasal administration instructions provided.
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9. Criterion modified per Amendment 2
9.1. Criterion modified per Amendment 3
9.2 During the study (ie, from Day 1 of the double-blind induction phase, prior to 
randomization) and for a minimum of 1 spermatogenesis cycle (defined as approximately 
90 days) after receiving the last dose of intranasal study medication, a man who is sexually 
active with a woman of childbearing potential

must be practicing a highly effective method of contraception with his female partner 
from those listed above (see examples of highly effective methods of contraception 
provided for female subjects). 

must use a condom if his partner is pregnant.

must agree not to donate sperm.
Note: If the female partner’s childbearing potential changes after start of the study, the female 
partner of a male study subject must begin a highly effective method of birth control, as
described above.
10. Subject must be willing and able to adhere to the prohibitions and restrictions specified in 
this protocol.
11. 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.
4.2.
Exclusion Criteria
1. Criterion modified per Amendment 1
1.1. Criterion modified per Amendment 2
1.2. Any potential subject who meets any of the following criteria will be excluded from 
participating in the study.
The subject’s depressive symptoms have previously demonstrated nonresponse to:

Esketamine or ketamine in the current major depressive episode per clinical judgment, 
or

All of the oral antidepressant treatment options available in the respective country for 
the double-blind induction phase (ie, duloxetine, escitalopram, sertraline, and 
venlafaxine XR) in the current major depressive episode (based on MGH-ATRQ), or

An adequate course of treatment with electroconvulsive therapy (ECT) in the current 
major depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT. 
2. Criterion modified per Amendment 2
2.1. Subject who has received vagal nerve stimulation (VNS) or who has received deep brain 
stimulation (DBS) in the current episode of depression will be excluded.
3. Criterion modified per Amendment 1
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3.1. Criterion modified per Amendment 2
3.2. 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 episode only), intellectual disability (DSM-5 diagnostic codes 
317, 318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, borderline personality 
disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic 
personality disorder.
4. Subject has homicidal ideation/intent, per the investigator’s clinical judgment, or has suicidal 
ideation with some intent to act within 6 months prior to the start of the 
screening/prospective observational phase, per the investigator’s clinical judgment or based 
on the Columbia Suicide Severity Rating Scale (C-SSRS), corresponding to a response of 
“Yes” on Item 4 (active suicidal ideation with some intent to act, without specific plan) or 
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 start of the 
screening/prospective observational phase. Subjects reporting suicidal ideation with intent to 
act or suicidal behavior prior to the start of the double-blind induction phase should be 
excluded.
5. Subject has a history of moderate or severe substance or alcohol use disorder according to 
DSM-5 criteria, except nicotine or caffeine, within 6 months before the start of the 
screening/prospective observational phase. 

A history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide 
(LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use 
disorder
6. Subjects with a current or past history of seizures (uncomplicated childhood febrile seizures 
with no sequelae are not exclusionary)
7. Criterion deleted per Amendment 3
8. Criterion modified per Amendment 2
8.1. Subject has one of the following cardiovascular-related conditions:

Cerebrovascular disease with a history of stroke or transient ischemic attack.

Aneurysmal vascular disease (including intracranial, thoracic, or abdominal aorta, or 
peripheral arterial vessels).

Coronary 
artery 
disease 
with 
myocardial
infarction, 
unstable 
angina,
or
revascularization procedure (eg, coronary angioplasty or bypass graft surgery) within 
12 months before the start of the screening/prospective observational phase. Subjects 
who have had a revascularization performed >12 months prior to screening and are 
clinically stable and symptom-free, per investigator’s clinical judgment, can be 
included.

Hemodynamically significant valvular heart disease such as mitral regurgitation, aortic 
stenosis, or aortic regurgitation. 
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
New York Heart Association (NYHA) Class III-IV heart failure of any etiology (refer 
to Attachment 2).
9. Criterion modified per Amendment 2
9.1. Subject has a history of uncontrolled hypertension despite diet, exercise, or 
antihypertensive therapy at the start of the screening/prospective observational phase or any 
past history of hypertensive crisis or ongoing evidence of uncontrolled hypertension defined 
as a supine systolic blood pressure (SBP) >150 mm Hg or diastolic blood pressure (DBP) 
>90 mm Hg during screening/prospective observational phase which continues to be above 
this range with repeated testing during this phase. Note: On Day 1 of the double-blind 
induction phase prior to randomization a supine SBP >150 mm Hg or DBP >90 mm Hg is 
exclusionary.

A potential subject may have his/her current antihypertensive medication(s) adjusted 
during the screening/prospective observational phase and be re-evaluated to assess their 
blood pressure control. The subject must be on a stable regimen for at least 2 weeks 
before Day 1 of the double-blind induction phase.
10. Subject has a current or past history of significant pulmonary insufficiency/condition or with 
an arterial blood oxygen saturation of <93% at the start of the screening/prospective 
observational phase or Day 1 prior to randomization will be excluded. 
11. Criterion modified per Amendment 3.
11.1.
Subject has a Mini Mental State Examination (MMSE) <25 or <22 for those 
subjects with less than an equivalent of high school education.
12. Criterion modified per Amendment 3. 
12.1.
Subject has neurodegenerative disorder (eg, Alzheimer’s Disease, Vascular 
dementia, Parkinson’s disease with clinical evidence of cognitive impairment) or evidence of
mild cognitive impairment (MCI).
13. Criterion modified per Amendment 2
13.1. Criterion modified per Amendment 3
13.2.
Subject has clinically significant ECG abnormalities at the start of the 
screening/prospective observational phase or on Day 1 of the double-blind induction phase
prior to randomization, defined as:

During screening a QT interval corrected according to Fridericia's formula (QTcF): 
450 msec; if the QTcF is prolonged on the initial ECG, the average QTcF of 
three ECGs, recorded at least 4 minutes apart must not be 450 msec.
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
On Day 1 (predose), a QT interval corrected according to Fridericia's formula (QTcF): 
450 msec based on the site-evaluated ECG; if the QTcF is prolonged on the initial 
ECG, the average QTcF of three ECGs, recorded at least 4 minutes apart, must not be 
450 msec.

Evidence of 2nd and 3rd degree AV block, or, 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]).
14. Criterion modified per Amendment 2
14.1 Subject has a history of additional risk factors for Torsades des Pointes (eg, heart 
failure, hypokalemia, family history of Long QT Syndrome).
15. Criterion modified per Amendment 2
15.1 Subject has history of, or symptoms and signs suggestive of, liver cirrhosis (eg, 
esophageal varices, ascites, and increased prothrombin time) OR alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) values 2 times the upper limit of normal or total 
bilirubin >1.5 times the ULN in the screening/prospective observational phase.

Repeat of the screening test for abnormal ALT and AST is permitted once during the 
screening period, per investigator discretion, provided there is an explanation for a 
transient out of range value.

For elevations in bilirubin if, in the opinion of the investigator and agreed upon by the 
sponsor’s medical officer, the elevation in bilirubin is consistent with Gilbert’s disease, 
the subject may participate in the study.
16. Criterion modified per Amendment 2
16.1. Criterion modified per Amendment 3
16.2
Subject has positive test result(s) for drugs of abuse (including barbiturates, 
methadone, opiates, cocaine, phencyclidine, and amphetamine/methamphetamine) at the 
start of the screening/prospective observational phase or Day 1 of the double-blind induction 
phase prior to randomization.

Subjects who have a positive test result at screening due to prescribed psychostimulants 
(eg, amphetamine, methylphenidate, etc,) taken for an indication other than MDD are 
permitted to continue to take this medication during the study in accordance with 
Attachment 1.
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
Otherwise, subjects who have a positive test result at screening due to prescribed/over-
the-counter opiates, or barbiturates
may be permitted to continue in the 
screening/prospective observational phase if the medication is discontinued at least 
1 week or 5 half-lives, whichever is longer, before Day 1 of the double-blind induction 
phase (prior to randomization) (for barbiturates or amphetamines/methamphetamine) or
used in accordance with Attachment 1 restrictions (for opiates). 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.

Prior intermittent use of cannabinoids prior to the start of the screening/prospective 
observational phase is not exclusionary as long as the subject does not meet the criteria 
for substance use disorder. Although tested at screening, a positive test for cannabinoids 
at the start of the screening/prospective phase is not exclusionary; however, a positive 
test result for cannabinoids predose on Day 1 of the double-blind induction phase is 
exclusionary.
17. Subjects who are taking a total daily dose of benzodiazepines greater than the equivalent of 
6 mg/day of lorazepam at the start of the screening/prospective observational phase.
18. Criterion modified per Amendment 2
18.1. Subject has uncontrolled diabetes mellitus, as evidenced by HbA1c >9% in the 
screening/prospective observational phase or history in the prior 3 months prior to the start of 
the screening/prospective observational phase of diabetic ketoacidosis, hyperglycemic coma, 
or severe hypoglycemia with loss of consciousness.
19. 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.
20. Criterion modified per Amendment 2
20.1. Subject has any anatomical or medical condition that, per the investigator’s clinical 
judgment based on assessment, may impede delivery or absorption of the intranasal study 
drug.
21. Criterion deleted per Amendment 2 
22. Subject has a history of malignancy within 5 years before the start of the 
screening/prospective observational phase (exceptions are squamous and basal cell 
carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that, in the opinion 
of the investigator, with concurrence with the sponsor's medical monitor, is considered cured 
with minimal risk of recurrence).
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23. Subject has known allergies, hypersensitivity, intolerance, or contraindications to 
esketamine/ketamine and/or its excipients or all of the available oral antidepressant treatment 
options for the double-blind induction phase.
24. Subject has taken any prohibited therapies that would not permit dosing on Day 1, as noted in 
Section 8 (Prestudy and Concomitant Therapy) and Attachment 1.
25. Criterion modified per Amendment 2
25.1 Subject has a score of 5 on the STOP-Bang questionnaire, in which case obstructive 
sleep apnea must be ruled out (eg, apnea-hypopnea index [AHI] <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.
26. Criterion modified per Amendment 2
26.1 Subject has received an investigational drug (including investigational vaccines) or used 
an invasive investigational medical device within 60 days before the start of the 
screening/prospective observational phase, or has participated in 2 or more MDD or other 
psychiatric condition clinical interventional studies (with different investigational drugs 
including investigational vaccines or investigational medical devices for each study) in the 
previous 1 year before the start of the screening/prospective observational phase, or is 
currently enrolled in an investigational interventional study.
27. Subject has a diagnosis of acquired immunodeficiency syndrome (AIDS). Human 
immunodeficiency virus (HIV) testing is not required for this study.
28. 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.
29. Subject has had major surgery, (eg, requiring general anesthesia) within 12 weeks before the 
start of the screening/prospective observational phase, or will not have fully recovered from 
surgery, or has surgery planned during the time the subject is expected to participate in the 
study. 

Note: subjects with planned surgical procedures to be conducted under local anesthesia 
may participate.
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.
31. Subject has severe renal impairment (creatinine clearance <30 ml/min).
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) 
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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.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:

Refer to Section 4.1, Inclusion Criteria for information regarding contraception requirements
for males who are sexually active with a woman of childbearing potential.

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.

Subjects taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day 
of lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, 
zaleplon) during the screening/prospective observational phase can continue these 
medications during the induction phase. No dose increases beyond the equivalent of 6 
mg/day of lorazepam or new benzodiazepine medications are permitted during the induction 
phase, with the exception of the use of permitted benzodiazepine rescue medication. 
Benzodiazepines and non-benzodiazepine sleeping medication (eg, zolpidem, zaleplon, 
eszopiclone, and ramelteon) are prohibited within 12 hours prior to the start of each 
intranasal treatment session or cognition testing.

A positive urine drug screen after Day 1 for use of PCP or cocaine from Day 1 of the 
induction phase through the final visit in the double-blind induction phase will lead to 
discontinuation.

Subjects must abstain from using alcohol within 24 hours before and after each intranasal 
treatment session. If a subject appears intoxicated, dosing should not occur (delayed per the 
permitted visit window; see the Time and Events Schedule).

On all intranasal study drug dosing days, all subjects must remain at the clinical study site 
until study procedures have been completed and the subject is ready for discharge. Subjects 
should be accompanied by a responsible adult when released from the clinical study site. 
Subjects must not drive a car or work with machines for 24 hours after study drug dosing.

ECT, DBS, transcranial magnetic stimulation (TMS), and VNS are prohibited from study 
entry through the end of the double-blind induction phase.

Subjects receiving psychotherapy (including cognitive behavioral therapy; CBT) can 
continue receiving psychotherapy; however, CBT must have been ongoing for the last 
3 months prior to the screening/prospective observational phase. With the exception of new 
CBT, which is prohibited, new psychotherapy is allowed during this study. Any change in 
existing therapy or new therapy must be documented on the concomitant therapies form.
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5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation and Randomization
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups in a 1:1 ratio based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor. The randomization will be 
balanced by using randomly permuted blocks and will be stratified by country and class of oral 
antidepressant (SNRI or SSRI) to be initiated in the double-blind induction phase The interactive 
web response system (IWRS) will assign a unique treatment code, which will dictate the 
treatment assignment and matching study drug kits for the subject. After the investigator selects 
the oral antidepressant treatment for the double-blind induction phase, the site will enter this 
information into IWRS. The requestor must use his or her own user identification and personal 
identification number when contacting the IWRS, and will then give the relevant subject details 
to uniquely identify the subject.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (eg, intranasal study drug plasma 
concentrations, treatment allocation) will be handled with special care to ensure that the integrity 
of the blind is maintained and the potential for bias is minimized. This can include making 
special provisions, such as segregating the data in question from view by the investigators, 
clinical team, or others as appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment/course of action would be dictated by knowing the treatment status of the 
subject. In such cases, the investigator may in an emergency determine the identity of the 
treatment by contacting the IWRS. It is recommended that the investigator contact the sponsor or 
its designee, if possible, to discuss the particular situation, before breaking the blind. Telephone 
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In 
the event the blind is broken, the sponsor must be informed as soon as possible. The date and
time of the unblinding will be documented by the IWRS, and reason for the unblinding must be 
documented in the electronic CRF (eCRF) and in the source document. The documentation 
received from the IWRS indicating the code break must be retained with the subject’s source 
documents in a secure manner.
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled early withdrawal and follow-up visits.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. For interim analysis, the randomization codes and, if required, the 
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translation of randomization codes into treatment and control groups will be disclosed to those 
authorized and only for those subjects included in the interim analysis.
To maintain the blinding of intranasal study medication, the esketamine and placebo intranasal 
devices will be indistinguishable. Please refer to Section 14 (Study Drug Information) for 
information on the physical characteristics of the study drugs and devices. In order to manage 
clinical supplies, the clinical supplies group will be informed of the decision made at interim 
analysis so that only the required amount of study medication will be packaged.
6.
DOSAGE AND ADMINISTRATION
6.1.
Screening/Prospective Observational Phase
As described in Section 9.1.2, at the start of screening/prospective observational phase, the 
subject must have had documented nonresponse to at least one antidepressant treatment (based 
on MGH-ATRQ criteria) in the current episode of depression, and the subject is taking a 
different oral antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at 
or above the minimum therapeutic dose. This antidepressant treatment, as well as any other 
ongoing medications being taken for depression at screening (including adjunctive/augmentation 
therapies), will continue from the start of Week 1 through the end of Week 4 of the 
screening/prospective observational phase. Dose adjustment is permitted per clinical judgment, 
but the oral antidepressant treatment is to remain at or above the minimum therapeutic dose (per 
the MGH-ATRQ) through the end of Week 4. 
Non-response at the end of the screening/prospective observational phase is defined as ≤25% 
improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total score of 
≥24 on Week 2 and Week 4.
The sponsor will not supply these antidepressant medication(s).
During this phase, antidepressant treatment adherence will be assessed using the PAQ.
After the completion of 4 weeks of prospective antidepressant treatment and assessment of the 
antidepressant treatment response, eligible subjects will have all antidepressant medication(s), 
including 
adjunctive/augmentation 
therapies 
discontinued. 
Of 
note, 
subjects 
taking 
benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of lorazepam) 
and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, zaleplon) during the 
screening/prospective observational phase can continue these medications. No dose increases 
beyond the equivalent of 6 mg/day of lorazepam or new benzodiazepine medications are 
permitted during the screening/prospective observational phase. If clinically indicated, the 
antidepressant treatment(s) may be tapered and discontinued over a period of up to 3 weeks per 
the local prescribing information or clinical judgment (eg, antidepressants with short half-lives, 
such as venlafaxine XR). Eligible subjects who do not require a tapered discontinuation of their 
antidepressant treatment(s) can immediately proceed into the double-blind induction phase.
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6.2.
Double-Blind Induction Phase
During this phase subjects will self-administer double-blind intranasal treatment with flexibly 
dosed intranasal esketamine (28 mg, 56 mg or 84 mg) or placebo twice per week for 4 weeks as a 
flexible dose regimen at the study site. In addition, subjects will simultaneously initiate a new, 
open-label oral antidepressant (ie, duloxetine, escitalopram, sertraline, or venlafaxine XR) on 
Day 1 that will be continued for the duration of this phase.
Intranasal Study Drug
On all intranasal treatment session days, a site staff member with training in cardiopulmonary 
resuscitation (eg, Basic Life Support course or equivalent courses) that is up to date per local 
regulations must be present with the subject during the intranasal treatment sessions and the 
postdose observation period. In addition, equipment for supportive ventilation and resuscitation 
needs to be present.
Table 3 describes how each intranasal treatment session will be administered in the double-blind 
induction phase. Please refer to Section 6.2.1 for guidance on blood pressure monitoring on 
intranasal dosing days.
Table 3:
Intranasal Treatment Sessions Administration During the Double-blind Induction Phase
Time of Intranasal Device Administration
Intranasal Treatment
0a
5 minutes
10 minutes
Intranasal Deviceb
1st
2nd
3rd
Placebo for 28 mg
1 spray of placebo to each 
nostril
Not applicable
Not applicable
Esketamine 28 mg
1 spray of esketamine to 
each nostril
Not applicable
Not applicable
Placebo for 56 mg
1 spray of placebo to each 
nostril
1 spray of placebo to each 
nostril
Not applicable
Esketamine 56 mg
1 spray of esketamine to 
each nostril
1 spray of esketamine to 
each nostril
Not applicable
Placebo for 84 mg
1 spray of placebo to each 
nostril
1 spray of placebo to each 
nostril
1 spray of placebo to each 
nostril
Esketamine 84 mg
1 spray of esketamine to 
each nostril
1 spray of esketamine to 
each nostril
1 spray of esketamine to 
each nostril
a
Time 0 is defined as the time of administration of the first intranasal spray to one nostril from the first intranasal 
device. 
b
One device will be used at each time point. Each individual intranasal device contains 2 sprays. The intranasal 
devices containing esketamine deliver 14 mg per spray, for a total of 28 mg per individual device (ie, 2 sprays).
Instructions for use documents (subject and healthcare provider versions) for intranasal study 
drug administration will be provided as separate documents. Details regarding study drug 
administration will be recorded in the source documents and the eCRF.
All subjects will self-administer the intranasal study drug (esketamine or placebo) at treatment 
sessions twice a week for 4 weeks at the study site. The first treatment session will be on Day 1. 
Intranasal treatment sessions should not take place on consecutive days.

Prior to the first intranasal dose on Day 1, subjects will practice spraying (into the air, not 
intranasally) a demonstration intranasal device that is filled with a placebo solution.
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
Instructions for intranasal dosing:

After Day 1 (28 mg), all dosing decisions are to be determined by the investigator based 
on efficacy and tolerability.

Prior to intranasal dosing, subjects must not have a blood pressure >150 mm Hg systolic 
and/or >90 mm Hg diastolic.

Prior to any dose escalation, subjects must have had a postdose blood pressure, on the 
prior intranasal dosing day, of <180 mm Hg for systolic and <100 mm Hg for diastolic 
blood pressure.

Dose titration of intranasal esketamine will be performed as outlined in Table 4:
Table 4
Dose Titration of Intranasal Esketamine*
Day 
Dose
Dose Titration Guidance
Day 1
28 mg
Day 4
28 or 56 mg
The dose may remain at 28mg  or be increased to 56mg , as 
determined by the investigator based on efficacy and tolerability
Days 8, 11, 15
28, 56 or 84 mg
The dose may be maintained, or increased or reduced by 28mg 
from the previous dosing session, as determined by the 
investigator based on efficacy and tolerability. No dose increase 
is permitted beyond Day 15.
Days 18, 22 and 25
28, 56 or 84 mg
No dose increase is permitted beyond Day 15. If needed for 
tolerability, dose reduction by 28mg from the previous dose is 
permitted on Days 18, 22 and 25.
* Dose changes are determined by the investigator based on efficacy and tolerability and in accordance with blood 
pressure guidelines.
From Day 8 to Day 15, inclusive, for those who have had a prior down titration from a higher 
dose, a dose increase by 28 mg is allowed based on clinical judgment. 
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 may be used to 
reduce congestion. Subjects should wait for at least 1 hour after using an intranasal decongestant 
before administering intranasal study drug.
For all intranasal treatment sessions, subjects must remain at the clinical site until study 
procedures have been completed and the subject is ready for discharge, and should be 
accompanied by a responsible adult when released from the clinical study site. Subjects must not 
drive a car or work with machines for 24 hours after intranasal treatment sessions.
Oral Antidepressant Medication
Starting on Day 1, a new, open-label oral antidepressant treatment will be initiated in all subjects, 
and continued for the duration of this phase. The oral antidepressant will be 1 of 4 oral 
antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine XR). The 
antidepressant medication will be assigned by the investigator based on review of the 
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MGH-ATRQ and relevant information regarding prior antidepressant treatments, and will be one
that the subject has not previously had a nonresponse to in the current depressive episode, has 
not been previously intolerant to (lifetime), and is available in the participating country. 
Dosing of the oral antidepressant will begin on Day 1. A mandatory titration schedule is 
provided in Attachment 3. Doses are not to exceed the maximum dose defined in the titration 
schedule. As patients may not be able to tolerate the higher doses of the oral antidepressant 
during the induction phase, a down titration of the dose is permitted based on clinician’s 
judgment.
All subjects entering the follow-up phase will be provided with an additional 2-week supply of 
the oral antidepressant medication following the double-blind induction phase, to ensure there is 
no interruption of antidepressant therapy during the transition to further clinical/standard of care 
in the follow-up phase.
Study-site personnel will instruct subjects on how to take/use and store the oral antidepressants 
supplied during this study for at-home use as indicated in this protocol. A subject diary to 
capture oral antidepressant study medication use will be provided.
On intranasal dosing days, it is recommended that the oral antidepressant medication not be 
taken until at least 3 hours after an intranasal treatment session. 
6.2.1.
Guidance for Blood Pressure Monitoring on Intranasal Treatment 
Session Days
Given the potential for treatment emergent transient elevation in systolic and diastolic blood 
pressure, the following guidance should be followed on intranasal dosing days:

If subsequent to fulfilling the inclusion and exclusion criteria on Day 1 (ie, applicable for all 
other intranasal treatment session days after Day 1), a subject’s predose SBP is >150 mmHg 
and/or DBP is >90 mmHg, it is recommended that the blood pressure measurement is 
repeated after the subject rests in sitting or recumbent position. If after rest and repeated 
measurements, the predose SBP is >150 mmHg and/or the DBP is >90 mmHg, then dosing 
should be postponed and the subject scheduled to return on the following day or within the 
given visit window. If the blood pressure elevation still persists on the next visit, the subject 
will be scheduled for a consultation by cardiologist, other specialist, or a primary care 
physician prior to further dosing.

If at any postdose time point on the dosing day the SBP is 180 mm Hg but <190 mm Hg 
and/or the DBP is 100 mm Hg but <110 mm Hg, 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 of the investigator for the subject to continue in the study, the subject 
may continue with intranasal dosing if the pre-dose blood pressure at the next scheduled 
visit is within the acceptable range (see bullet above).
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
If at any postdose time point on a dosing day the SBP is 190 mm Hg and/or the DBP is 
110 mm Hg, the subject must discontinue from further dosing and 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 
and/or the DBP 100 mm Hg, assessments should continue every 30 minutes until:

the 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 

the subject is referred for appropriate medical care if clinically indicated.
If the blood pressure remains ≥ 180 SBP and/or  ≥110 mmHg DBP 2 hours after dosing, the 
subject should be referred for immediate medical treatment.
6.3.
Follow-up Phase
Subjects who receive at least 1 dose of intranasal study medication in the double-blind induction 
phase, but do not enter the subsequent ESKETINTRD3004 safety study, will proceed into the 
2-week follow-up phase. A 2-week supply of oral antidepressant will be provided for subjects 
entering the follow-up phase.
No intranasal study medication will be administered during this phase.
At the start of the follow-up phase, further clinical/standard of care for the treatment of 
depression will be arranged by the study investigator and/or the subject’s treating physician. All 
subjects will be provided with an additional 2-week supply of the oral antidepressant medication 
to ensure there is no interruption of antidepressant therapy during the transition to further 
clinical/standard of care. 
The decision to continue the oral antidepressant medication in this phase will be at the discretion 
of the investigator; however, in order to better assess potential withdrawal symptoms from the 
intranasal study medication and facilitate maintenance of clinical benefit following the 4-week 
double blind treatment phase, the oral antidepressant medication should be continued for the 
2 weeks of 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 and oral antidepressant medication dispensed and returned. Drug supplies for each subject 
will be inventoried and accounted for throughout the study.
Subjects will receive instructions on compliance with the oral antidepressant treatment. During 
the course of the study, the investigator or designated study-site personnel will be responsible for 
providing additional instruction to re-educate any subject to ensure compliance with taking the 
oral antidepressant. A subject diary will be provided to capture oral antidepressant study 
medication use.
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Antidepressant treatment adherence during the screening/prospective observational phase will be 
assessed using the PAQ. Missing 4 days of antidepressant medication in the prior 2-week 
period will be considered inadequate compliance.
Antidepressant treatment adherence during the double-blind induction and follow-up phases will 
be assessed by performing pill counts (ie, compliance check) and drug accountability.
All doses of intranasal study drug will be self-administered by the subjects at the investigative 
site under the direct supervision of the investigator or designee, and will be recorded.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy non-antidepressant therapies administered up to 30 days before the start of the 
screening/prospective observational phase must be recorded at the start of this phase.
All antidepressant treatment(s), including adjunctive treatment for MDD, taken during the 
current depressive episode (ie, including those taken more than 30 days prior to the start of the 
screening/prospective 
observational 
phase) 
will 
be 
recorded 
at 
the 
start 
of 
the 
screening/prospective observational phase. In addition, information will also be obtained 
regarding any history of intolerance to any of the 4 antidepressant choices (ie, duloxetine, 
escitalopram, sertraline, and venlafaxine XR). Antidepressant treatments which are not listed on 
the MGH-ATRQ but were used or are currently being used as antidepressant treatment in the 
current depressive episode must be recorded on the ‘Concomitant Therapy’ eCRF.
Any medication that is listed on the MGH-ATRQ and is being taken at the start of the 
screening/prospective observational phase for an indication other than depression (eg, insomnia) 
should be continued during the screening/prospective observational phase but must be 
discontinued before the start of the double-blind phase.
Concomitant therapies must be recorded throughout the study, beginning with signing of the 
informed consent and continuing up to the last visit. Information on concomitant therapies 
should also be obtained beyond this time only in conjunction with new or worsening adverse 
events until resolution of the event.
Subjects should continue to take their permitted concomitant medications (eg, antihypertensive 
medications) at their regular schedule, taking into account any restrictions as outlined in 
Section 4.3 and Attachment 1. Of note, if a subject has routinely taken his/her oral 
antihypertensive medications in the morning, the morning dose should be taken prior to 
intranasal dosing.
Subjects receiving psychotherapy (including cognitive behavioral therapy; CBT) can continue 
receiving psychotherapy; however, CBT must have been ongoing for the last 3 months prior to 
the start of the screening/prospective observational phase. With the exception of new CBT, 
which is prohibited, new psychotherapy is allowed during the study. Any change in existing 
therapy or new therapy must be documented on the concomitant therapies form.
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All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; nonpharmacologic therapies such as psychotherapy, electrical stimulation [eg, VNS 
or DBS], acupuncture, special diets, and exercise regimens, cognitive behavioral therapy) 
different from the study drug must be recorded in the eCRF. Modification of an effective 
preexisting therapy should not be made for the explicit purpose of entering a subject into the 
study, unless permitted by protocol (eg, adjustment of blood pressure medications).
Rescue Medications
Rescue medications will not be supplied by the sponsor. In case of treatment-emergent adverse 
events that cannot be resolved by stopping further administration of intranasal 
esketamine/placebo, the following rescue medications may be considered:

For agitation or anxiety: As required, midazolam (maximum dose 2.5 mg orally or IM) or 
short acting benzodiazepine

For nausea: As required, ondansetron 8 mg sublingually, metoclopramide (10 mg orally or 
IV or IM) or dimenhydrinate (25 to 50 mg, IV or IM)

Unless clinically indicated, it is recommended that transient increases in blood pressure not 
be treated, as the blood pressure typically returns to predose values in 2 hours. The effect of 
any treatment may result in hypotension. 
Prohibited Medications
A list of prohibited medications is provided in Attachment 1 as general guidance for the 
investigator (but is not all inclusive).
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, PK, biomarker, 
pharmacogenomic, health economic, and safety measurements applicable to this study.
With the exception of postdose assessments, visit-specific patient-reported outcomes (PRO)
assessments should be conducted or completed before any tests, procedures, or other 
consultations for that visit to prevent influencing subject perceptions. A recommended order of 
study procedures will be provided to the sites as a separate document.
Actual dates and times of assessments will be recorded in the source documentation and eCRF.
The approximate total blood volume to be collected from each subject will be approximately
112.0 mL (Table 5). Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples. 
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Table 5:
Volume of Blood to Be Collected From Each Subject
Type of Sample
Volume per 
Sample (mL)
No. of Samples 
per Subject
Total Volume of 
Blood (mL)a
Screening/Prospective Observational Phase
Serum chemistryb
5
1
5
TSH
3.5
1
3.5
Hematologyc
2
1
2
Biomarker: protein
10
1
10
Biomarker: DNA
      Biomarker: RNA
      Tricyclic Antidepressant Blood leveld
6
2.5
6
1
1
1
6
2.5
6
fT4e
3.5
1
3.5
Double-blind Induction Phase
Serum chemistry
2.5
2
5
Hematology
2
2
4
Pharmacokinetic
2
2
4
Biomarker: protein (at Visits 2.1, 2.3, and 2.8)
10
3
30
Biomarker: DNA
6
1
6
Biomarker: RNA
2.5
3
7.5
Follow-up Phase
Serum chemistry
2.5
1
2.5
Hematology
2
1
2
Biomarker: protein
10
1
10
Biomarker: RNA
2.5
1
2.5
Approximate volume of blood collected during the study
112.0 mL
Abbreviations: DNA, deoxyribonucleic acid; fT4, free thyroxine; RNA, ribonucleic acid; TSH, thyroid-stimulating hormone.
a
Calculated as number of samples multiplied by amount of blood per sample.
b
Serum chemistry includes lipid panel.
c
As needed, HbA1c will be measured from the sample collected for hematology.
d
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.
e
For any subject (regardless of thyroid history), if the TSH value is out of range, a free thyroxine (FT4) will be conducted.
Note: An indwelling IV cannula may be used for blood sample collection.
Note: Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
9.1.2.
Screening/Prospective Observational Phase
Prior to conducting any study procedure, the investigator (or designated study personnel) will 
review and explain the written ICF to each subject. After signing the ICF, subjects who are 
65 years of age and older, will be screened to determine eligibility for study participation (please 
refer to the study entry criteria listed in Section 4).
Subjects must meet DSM-5 diagnostic criteria for single episode MDD (if single episode MDD, 
duration of episode must be 2 years) or recurrent MDD, without psychotic features, based upon 
clinical assessment and confirmed by the MINI. Subjects must also have a mini mental state 
examination (MMSE) total score of <25. In addition, at the start of the screening/prospective 
observational phase, the subject must have an IDS-C30 total score 31.
At the start of this phase, subjects must have had nonresponse (≤25% improvement) to 1 but 8
(if current episode is >2 years, upper limit applicable to only the last 2 years) different oral 
antidepressant treatments taken at adequate dosage and for adequate duration, as assessed using
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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. 
At the start of the screening/prospective observational phase, the subject must have had 
documented nonresponse to at least one antidepressant treatment (based on the MGH-ATRQ
criteria) in the current episode of depression, and the subject is taking a different oral 
antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or above the 
minimum therapeutic dose. This antidepressant treatment, as well as any other ongoing 
medications being taken for depression at screening (including adjunctive/augmentation 
therapies), will continue from the start of Week 1 through the end of Week 4 of the 
screening/prospective observational phase. Dose adjustment is permitted per clinical judgment, 
but the oral antidepressant treatment is to remain at or above the minimum therapeutic dose (per 
the MGH-ATRQ) through the end of Week 4.
Antidepressant treatment adherence will be assessed using the PAQ. Missing 4 days of 
antidepressant medication in the prior 2-week period will be considered as inadequate adherence.
The subject’s current major depressive episode, depression symptom severity (Week 1 MADRS 
total score ≥24 required) and antidepressant treatment response to antidepressant therapies used 
during the current depressive episode will be confirmed using the Site Independent Qualification 
Assessment.
An independent, blinded rater will perform remote MADRS assessments to assess depressive 
symptoms during this phase. 
After 4 weeks, subjects who are nonresponders to the current oral antidepressant treatment may 
be eligible to proceed to the double-blind induction phase. Non-response at the end of the 
screening/prospective observational phase is defined as ≤25% improvement in the MADRS total 
score from Week 1 to Week 4 and a MADRS total score of ≥24 on Week 2 and Week 4. Eligible 
subjects who are entering the double-blind induction phase will discontinue all of their current 
medication(s) being used for depression treatment, including adjunctive/augmentation therapies 
and any other prohibited psychotropic medications, including adjunctive atypical antipsychotics. 
Subjects who are taking benzodiazepines (at dosages equal to or less than the equivalent of 
6 mg/day of lorazepam) and/or permitted nonbenzodiazepine sleep medications (eg, zolpidem, 
zaleplon) during the screening/prospective observational phase can continue these medications 
during the induction phase. No dose increases beyond the equivalent of 6 mg/day of lorazepam 
or new benzodiazepine medications are permitted during the induction phase, with the exception 
of the use of permitted benzodiazepine rescue medication. Benzodiazepines and non-
benzodiazepine sleeping medications (eg, zolpidem, zaleplon, eszopiclone, and ramelteon) are 
prohibited within 12 hours prior to the start of each intranasal treatment session or cognition 
testing.
All other subjects who do not proceed to the double-blind induction phase will end study 
participation at this time. No further study visits or follow-up is required.
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Optional Antidepressant Taper Period
Since all nonresponder subjects will be starting a new oral antidepressant during the double-blind 
induction phase, no washout or drug-free period is required after discontinuing the current 
antidepressant treatment. However, an additional, optional period of up to 3 weeks is permitted 
to taper and discontinue the current oral antidepressant medication per the local prescribing 
information or clinical judgment.
If clinically indicated, a subject’s current antidepressant treatment(s) may be tapered and 
discontinued over an additional optional period of up to 3 weeks, per the local prescribing
information or per clinical judgment. This 3 week period may also be used to optimize medical 
management if needed to facilitate subject participation (eg, treatment of blood pressure or 
diabetes, wean from other medications, etc,). In such cases, if there is no planned taper, the oral 
regimen should be continued in the interim and then discontinued by Day 1 of the double-blind 
induction phase.  
The taper period should not begin until after the completion of 4 weeks of prospective 
antidepressant treatment and assessment of the antidepressant treatment response.
9.1.3.
Double-Blind Induction Phase
During this phase, subjects will self-administer double-blind intranasal treatment with 
flexibly-dosed intranasal esketamine (28 mg, 56 mg or 84 mg) or placebo twice per week for 
4 weeks as a flexible dose regimen. In addition, subjects will simultaneously initiate a new, 
open-label oral antidepressant (please refer to Section 6, Dosage and Administration).
On Day 1, approximately 148 eligible subjects with TRD will be randomly assigned to 1 of the 
following 2 double-blind treatment groups, in a 1:1 ratio (approximately 74 subjects per group):

Intranasal placebo

Intranasal esketamine
On the same day (ie, Day 1), subjects will be switched to a new, open-label oral antidepressant 
treatment. The oral antidepressant will be 1 of 4 oral antidepressant medications (duloxetine, 
escitalopram, sertraline, or venlafaxine XR). The selection of the antidepressant medication 
assigned by the investigator (based on review of the MGH-ATRQ and relevant prior 
antidepressant treatment information) and will be one that the subject has not previously had a 
nonresponse to in the current depressive episode, has not been previously intolerant to (lifetime), 
and is available in the participating country. Dosing of the oral antidepressant will begin on 
Day 1. A mandatory titration schedule is provided in Attachment 3. Doses are not to exceed the 
maximum dose defined in the titration schedule. A dose reduction for tolerability is permitted.
For information obtained via telephone contact, written documentation of the communication 
must be available for review in the source documents. During telephone contact visits with the 
subject by site personnel, adverse event and concomitant therapy information will be obtained. In 
addition, specified clinician-administered assessments (eg, PWC-20) will be performed by 
appropriately qualified staff.
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At the end of the double-blind induction phase, subjects may be eligible to enter the subsequent 
long term safety study (Study ESKETINTRD3004). Subjects who do not complete the induction 
phase of this study will not be eligible to participate in the ESKETINTRD3004 study. To 
maintain 
study 
blinding, 
the 
blind 
will 
not 
be 
broken 
for 
subjects 
entering
Study ESKETINTRD3004. Participation in ESKETINTRD3004 will begin immediately after the 
completion of the double-blind induction phase. These subjects will be instructed to continue 
taking their oral antidepressant medication through their next study visit (ie, first study visit 
Study ESKETINTRD3004).
Those subjects who do not enter Study ESKETINTRD3004 will proceed into a 2-week 
follow-up phase. 
Early Withdrawal
If a subject withdraws before the end of the double-blind induction phase for reasons other than 
withdrawal of consent, the Early Withdrawal visit should be conducted within 1 week of the date 
of discontinuation, followed by the follow-up phase. If the Early Withdrawal visit occurs on the 
same day as a scheduled visit, the early withdrawal visit can be performed on the same day and 
duplicate assessments are not required.
Further clinical/standard of care for the treatment of depression will be arranged by the study 
investigator and/or the subject’s treating physician. The study investigator and/or treating 
physician will determine whether or not the current oral antidepressant medication will continue.
Subjects who withdraw early will receive additional oral antidepressant medication, if 
applicable, and they should continue taking the oral antidepressant medication for the 2 weeks of 
the follow-up phase, unless determined as not clinically appropriate.
9.1.4.
Follow-up Phase
All subjects who receive at least 1 dose of intranasal study medication in the double-blind 
induction phase and are not participating in the subsequent ESKETINTRD3004 study will 
proceed into the 2-week follow-up phase. Clinic visits and remote assessment visits will be 
performed as specified in the Time and Events Schedule. During this phase, safety and 
tolerability, including potential withdrawal symptoms, following discontinuation of intranasal 
esketamine will be assessed. In order to better assess potential withdrawal symptoms from the 
intranasal medication it is recommended that the oral antidepressant medication be continued in 
the follow-up phase unless determined as not clinically appropriate.
Further clinical/standard of care for the treatment of depression will be arranged by the study 
investigator and/or the subject’s treating physician. No intranasal study medication will be
administered during this phase. All subjects will be provided with an additional 2-week supply of 
their oral antidepressant medication, to ensure there is no interruption of antidepressant therapy 
during the transition to further clinical/standard of care. In order to better assess potential 
withdrawal symptoms from the intranasal medication and facilitate maintenance of clinical 
benefit following the 4-week double blind treatment phase, the oral antidepressant medication 
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should be continued for the 2 weeks of the follow-up phase unless determined as not clinically 
appropriate. The decision to continue the antidepressant will be at the discretion of the 
investigator.
If information is obtained via telephone contact, written documentation of the communication 
must be available for review in the source documents. 
Any clinically significant abnormalities persisting at the end of the study will be followed by the 
investigator until resolution or until a clinically stable endpoint is reached. All adverse events 
and special reporting situations, whether serious or non-serious, will be reported until completion 
of the subject's last study-related procedure.
9.2.
Efficacy
9.2.1.
Evaluations
It is recommended that the patient-reported outcome assessments be completed prior to other 
procedures. 
9.2.1.1.
Primary Efficacy Evaluation
The primary efficacy evaluation will be the change from baseline in the MADRS total score 
from Day 1 pre-randomization to the end of the 4-week double-blind induction phase. The 
structured interview guide for the MADRS (SIGMA) will be used for each administration. The 
MADRS will be performed by independent remote raters during the study.
The MADRS is a clinician-rated scale designed to measure depression severity and detects 
changes due to antidepressant treatment.49 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.
9.2.1.2.
Secondary Efficacy Evaluations (Clinician-completed)
9.2.1.2.1.
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.35 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; 
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7=among the most extremely ill patients. The CGI-S permits a global evaluation of the subject’s 
condition at a given time.
9.2.1.3.
Other Secondary Efficacy Evaluations (Patient-reported Outcomes)
9.2.1.3.1.
EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily 
designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and 
the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L descriptive system comprises the 
following 
5 
dimensions: 
mobility, 
self-care, 
usual 
activities, 
pain/discomfort 
and 
anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems 
(Level 1 indicating no problem, Level 2 indicating slight problems, Level 3 indicating moderate 
problems, Level 4 indicating severe problems, and Level 5 indicating extreme problems).27,31
The subject selects an answer for each of the 5 dimensions considering the response that best 
matches his or her health “today.” The descriptive system can be represented as a health state. 
The EQ-VAS self-rating records the respondent’s own assessment of his or her overall health 
status at the time of completion, on a scale of 0 to 100. 
The time taken to complete the questionnaire varies with age, health status, and setting but is 
likely to be around 1 minute. 
9.2.2.
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 (Day 1 prior to randomization) to the end of the 4-week double-blind 
induction phase.
9.2.2.2.
Secondary Endpoints

Proportion of responders (50% reduction from baseline in MADRS total score) at the end of 
the 4-week double-blind induction phase

Proportion of subjects in remission (MADRS 12) at the end of the 4-week double-blind 
induction phase

Change from baseline (Day 1 prior to randomization) to the end of the 4 week double-blind 
induction phase in: 
o
Severity of depressive illness, using the CGI-S
o
Health-related quality of life and health status, as assessed by the EQ-5D-5L
9.3.
Pharmacokinetics
Whole blood samples will be used to evaluate the PK of esketamine. 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 serum samples. 
Subject confidentiality will be maintained.
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9.3.1.
Evaluations
Venous blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of esketamine, noresketamine, and other metabolites (if warranted) at the time 
points specified in the Time and Events Schedule. The exact dates and times of PK blood 
sampling must be recorded.
9.3.2.
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of esketamine (and noresketamine, 
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, 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 relationship between MADRS total score (and possibly selected AEs as additional 
PD parameters) and PK metrics of esketamine may be evaluated. If there is any visual trend in 
graphical analysis, suitable models will be applied to describe the exposure-effect relationships. 
The results of the exposure-response evaluations will be presented in a separate report.
9.5.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations
During the study, blood will be collected for the assessment of biomarkers at the time points 
indicated in the Time and Events schedule. The biomarker blood samples should be collected 
prior to dosing. It is preferred that subjects adhere to a low fat diet on the day of sample 
collection.
In blood, biomarkers (protein, metabolite, and ribonucleic acid [RNA]) related to (but not limited 
to) the immune system activity, 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.
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The biomarker data obtained from this study may also be included in an ongoing cross-study 
analysis to investigate the relationship between depression severity and phenotypes and 
biomarkers.
Blood samples for DNA analyses will be collected at the time points indicated in the Time and 
Events Schedule for the assessment of genetic and epigenetic variation in genes in pathways 
relevant to depression (eg, HPA axis, inflammation, growth factors, monoamine transporters, ion 
channels, and circadian rhythm).
Genotyping will be conducted only on the screening sample; pharmacogenomic and epigenetic 
evaluations may be performed on any/all collected samples.
DNA samples will be used for research related to esketamine, oral antidepressants, TRD, or 
MDD. They may also be used to develop tests/assays related to esketamine, oral antidepressants, 
TRD, or MDD. Pharmacogenomic research may consist of the analysis of 1 or more candidate 
genes or of the analysis of genetic markers throughout the genome (as appropriate) in relation to 
esketamine, oral antidepressants, TRD, or MDD clinical endpoints.
Further information regarding handling, shipment, and labeling of biological samples will be 
provided in a separate laboratory manual.
9.6.
Safety Evaluations
Details regarding the Independent Data Monitoring Committee are provided in Section 11.9.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule.
There may be instances when a subject has started a scheduled clinic visit which includes a 
planned intranasal treatment session, but due to predose vital sign measurements (eg, blood 
pressure value), a decision is made to postpone/delay the intranasal treatment session within the 
visit window permitted per protocol. In such cases, all time points (including predose, if 
applicable) of the following assessments must be repeated on the actual intranasal treatment 
session day: vital signs (ie, blood pressure, pulse, respiratory rate, and temperature), 12-lead 
ECG, C-SSRS (since last visit), MOAA/S, pulse oximetry, BPRS+, and CADSS.
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.
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TEAEs of special interest will be examined separately (please refer to Sections 3.2.6 and 11.8).
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and a urine sample for urinalysis will be 
collected. The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the adverse event section of the 
eCRF. The laboratory reports must be filed with the source documents.
The use of local laboratories is allowed in cases where initiation of treatment or safety follow-up 
is time-critical and the central laboratory results are not expected to be available before the need 
to begin dosing or if actions need to be taken for safety reasons.
The following tests will be performed by the central laboratory, unless noted otherwise:

Hematology Panel
-hemoglobin
-platelet count
-hematocrit
-red blood cell (RBC) count
-white blood cell (WBC) count with differential

Serum Chemistry Panel
-sodium
-alkaline phosphatase
-potassium
-creatine phosphokinase (CPK)
-chloride
-calcium
-bicarbonate
-phosphate
-blood urea nitrogen (BUN)
-albumin
-creatinine
-total protein
-glucose
-total bilirubin
-aspartate aminotransferase (AST)
-alanine aminotransferase (ALT)
-gamma-glutamyltransferase (GGT)
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
Urinalysis
Dipstick
Sediment (if dipstick result is
abnormal)
-specific gravity
-red blood cells
-pH
-white blood cells
-glucose
-epithelial cells
-protein
-crystals
-blood
-casts
-ketones
-bacteria
-bilirubin
-urobilinogen
-nitrite
-leukocyte esterase
If dipstick result is abnormal, flow cytometry or microscopy will be used to measure 
sediment. In case of discordance between the dipstick results and the flow cytometric 
results, the sediment will be examined microscopically.
The following tests will be done at time points specified in the Time and Events Schedule or as 
required based on subject status (noted below):

Lipid panel: total cholesterol, low density lipoprotein (LDL)-cholesterol, high density 
lipoprotein (HDL)-cholesterol, and triglycerides

Urine Drug Screen: barbiturates, methadone, opiates, cocaine, cannabinoids (cannabinoids 
are only exclusionary at Day 1 predose), PCP, and amphetamine/methamphetamine

Alcohol breath test 

Thyroid-stimulating hormone (TSH) 

Free thyroxine, only if required for abnormal TSH (see inclusion criterion 7.2 in Section 4.1)

Calculation of creatinine clearance

Glycated hemoglobin (HbA1c) test (Screening only)
Single, 12-Lead ECG
During the collection of ECGs, subjects should be in a quiet setting without distractions (eg, 
television, cell phones). Subjects should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs.
All ECG tracings will be sent to a central ECG laboratory. The ECGs will be read at the 
scheduled time points and summarized by a central ECG laboratory. The central ECG laboratory 
will send the sponsor an electronic copy of the data for inclusion in the clinical database. In 
addition, the investigator or sub-investigator is required to review all ECGs at the study visit to 
assess for any potential safety concerns or evidence of exclusionary conditions.
The subject must be discontinued at any time point after baseline (Day 1, predose) if:
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
QTcF change from baseline is ≥60 msec AND QTcF >480 msec, or

QTcF >500 msec.
Vital Signs (temperature, pulse/heart rate, respiratory rate, blood pressure)
Blood pressure and pulse/heart rate measurements will be assessed in a supine position with a 
completely automated device or using manual techniques.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of 
rest in a quiet setting without distractions (eg, television, cell phones).
For further details regarding blood pressure, please see Guidance for Blood Pressure Monitoring 
on Intranasal Dosing Days (Section 6.2.1).
Tympanic temperature is recommended.
An automated device will be used for measurement of respiratory rate.
Pulse Oximetry
Pulse oximetry will be used to measure arterial oxygen saturation. 
On each dosing day, the device will be attached to the finger, toe, or ear before the first nasal 
spray and then, after the first spray it will be monitored and documented. Any arterial oxygen 
saturation <93% should be confirmed by an additional measurement on another part of the body.
On intranasal treatment session days, pulse oximetry will be performed every 15 minutes from 
predose to t=1.5 hours postdose. If oxygen saturation levels are <93% at any time during the 1.5 
hour postdose interval, pulse oximetry will be performed every 5 minutes until the level returns 
to 93% or until the subject is referred for appropriate medical care, if clinically indicated.
Physical Examination, Height, Body Weight and Neck Circumference
Physical examinations, body weight, and height will be performed or measured per the Time and 
Events Schedule.
In addition, body mass index (BMI) will be calculated and neck circumference measured as part 
of the information required for the STOP-Bang questionnaire.
Nasal Examinations 
Nasal examinations (including the upper respiratory tract/throat) will be conducted by a qualified 
healthcare practitioner. The objective of the examination at screening is to rule out any subjects 
with anatomical or medical conditions that may impede drug delivery or absorption. 
Subsequent examinations will consist of a visual inspection of the nostrils, nasal mucosa, and 
throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption, and epistaxis,
and will be graded as follows: absent, mild, moderate, or severe.
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Nasal Symptom Questionnaire
Subjects will complete a nasal symptom questionnaire. The nasal symptom questionnaire was 
developed by the sponsor to assess nasal symptoms following intranasal administration of study 
drug. The questionnaire asks about nasal symptoms, which are rated by the subject as none, mild, 
moderate, or severe, based on how he or she feels at the time of the assessment.
C-SSRS
The C-SSRS will be performed to assess potential suicidal ideation and behavior. 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed in the National Institute of Mental Health Treatment of Adolescent Suicide 
Attempters Study to assess severity and track suicidal events through any treatment.69 It is a 
clinical interview providing a summary of both suicidal ideation and behavior that can be 
administered during any evaluation or risk assessment to identify the level and type of suicidality 
present. The C-SSRS can also be used during treatment to monitor for clinical worsening.
Two versions of the C-SSRS will be used in this study, the Baseline/Screening version, and the 
Since Last Visit version. The Baseline/Screening version of the C-SSRS will be used in the 
screening/prospective observational phase. In this version, suicidal ideation will be assessed at 
2 time points (“lifetime” and “in the past 6 months”) and suicidal behavior will be assessed at 
2 time points (“lifetime” and “in the past year”). All subsequent C-SSRS assessments in this 
study will use the Since Last Visit version, which will assess suicidal ideation and behavior since 
the subject’s last visit.
CADSS
The CADSS is an instrument for the measurement of present-state dissociative symptoms,5 and 
will be administered to assess treatment-emergent dissociative symptoms.
The CADSS consists of 23 subjective items, divided into 3 components: Depersonalization 
(Items 3 to 7, 20, and 23), derealization (Items 1, 2, 8 to 13, 16 to 19, and 21) and amnesia 
(Items 14, 15, and 22). Participant’s responses are coded on a 5-point scale (0=not at all to 
4=extremely). CADSS has excellent inter-rater reliability and internal consistency. 
BPRS+
Four items of the BPRS will be administered to assess potential treatment-emergent psychotic 
symptoms. 
The BPRS is an 18-item rating scale that is used to assess a range of psychotic and affective 
symptoms, rated from both observation of the subject and the subject's own report.61 It reportedly 
provides a rapid and efficient evaluation of treatment response in clinic drug studies and in 
clinical settings.75
Only the 4-item positive symptom subscale BPRS+ (ie, suspiciousness, hallucinations, unusual 
thought content, and conceptual disorganization) will be used in this study. It is highly sensitive 
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to change, and excellent inter-rater reliability can be achieved with training and a standard 
interview procedure. 
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) continuum.64
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 t=+1.5 hours postdose. 

If the score is 3 at any time during the 1.5 hour postdose interval, the MOAA/S will be 
performed every 5 minutes until a score of 4 is reached (at which point a frequency of every 
15 minutes can be resumed until t=+1.5 hours post dose). 

If a subject does not have a score of at least 5 at t=+1.5 hours postdose, they should continue 
to be monitored. For subjects with a score of 4, the assessment should be repeated every 15 
minutes. And for subjects with a score of 3, the assessment should be repeated every 5 
minutes until the score returns to 5 or the subject is referred for appropriate medical care, if 
clinically indicated.
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 adverse 
events)?”
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.
PWC-20
The PWC-20 will be administered to assess potential withdrawal symptoms following cessation 
of intranasal esketamine treatment. An assessment will be performed for all subjects on Day 25 
to establish a baseline prior to discontinuation of intranasal esketamine treatment (if applicable). 
In order to better assess potential withdrawal symptoms from the intranasal medication it is 
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recommended that the oral antidepressant medication be continued for the 2 weeks of the follow-
up phase unless determined as not clinically appropriate.
The PWC-20 is a 20-item simple and accurate method to assess potential development of 
discontinuation symptoms after stopping of study drug. The PWC-20 is a reliable and sensitive 
instrument for the assessment of discontinuation symptoms.72 Discontinuation symptoms occur 
early and disappear rather swiftly, depending upon speed of taper, daily medication dose, and 
drug elimination half-life. 
BPIC-SS
The BPIC-SS is a patient-reported outcome measure that was developed to identify an 
appropriate bladder pain syndrome/interstitial cystitis population for clinical studies evaluating
new treatments for bladder pain syndrome.40
The BPIC-SS will be used to monitor subjects for potential symptoms of cystitis, bladder pain, 
and interstitial cystitis. 
The BPIC-SS includes 8 questions with a recall period of the past 7 days, and addresses key 
symptoms identified by subjects with BPS including symptom concepts of pain and/or pressure
of the bladder, and urinary frequency. Subjects respond to items using a 5-point scale (0=never, 
1=rarely, 2=sometimes, 3=most of the time, 4=always for frequency-based questions, and 0=not 
at all, 1=a little, 2=somewhat, 3=moderately, and 4=a great deal for items related to bother 
associated with symptoms). Question 8 records the worst bladder pain in the last 7 days using a 
0-10 numerical rating scale. A total score is calculated by adding up the numbers beside the 
response options chosen by the subject. The range of scores for the scale is 0 to 38.
A total score of 19 or more has demonstrated good sensitivity/specificity and is considered a 
relevant cut-off to distinguish those with significant bladder symptoms and/or cytitis.40
If any items are missing, a total score cannot be calculated.
In the current study, if a subject has a score >18 on the BPIC-SS scale and there is no evidence 
of urinary tract infection based on urinalysis and microscopy, he or she will be referred to a 
specialist for further evaluation. If a subject is determined to have a diagnosis of ulcerative 
cystitis, the subject must be discontinued from the study and followed up with appropriate 
medical care. As such, in addition to urinalysis, a urine culture should also be obtain if BPIC-SS 
score is >18 on applicable study day.
Cognition Testing: Computerized Cognitive Battery and HVLT-R
The computerized cognitive battery provides assessment of multiple cognitive domains,
including attention, visual learning and memory, and executive function. The tests use culture-
neutral stimuli, enabling use in multilingual/multicultural settings. The computerized battery 
includes:
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
Simple and choice reaction time tests; scored for speed of response (mean of the 
log 10-transformed reaction times for correct responses)

Visual episodic memory; visual recall test scored using arcsine transformation of the 
proportion of correct responses

Working memory (n-back); scored for speed of correct response (mean of the 
log 10-transformed reaction times for correct responses)

Executive function; maze/sequencing test, scored for total number of errors
All measures have been validated against traditional neuropsychological tests and are sensitive to 
the effects of various drugs on cognitive performance, including alcohol and benzodiazepines.
Completing the cognitive battery requires approximately 25 minutes.
The HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test.
Administration includes 3 learning trials, a delayed recall (20-minute) trial, and a 24-word 
recognition list (including 12 target and 12 foil words).4 The test administrator reads instructions 
and word lists aloud, and records words recalled/recognized by the subject.Scores include 
learning, delayed recall, and recognition. The HVLT-R is a well-validated and widely used 
measure of verbal episodic memory.49
The tests will be administered in the following order: HVLT-R, computerized cognitive test 
battery, and HVLT-R Delayed.
All subjects will complete a practice session for the computerized cognitive battery during the 
screening/prospective observational phase. There is no practice session for the HVLT-R.
UPSIT
To assess any potential treatment-emergent effects on the sense of smell, olfactory function will 
be qualitatively and quantitatively assessed using a validated standardized olfactory test prior to
and at specified time points during the study. 
The UPSITassesses a subject’s ability to identify odors. This standardized test, the most widely 
used olfactory test in the world, is derived from basic psychological test measurement theory and 
focuses on the comparative ability of subjects to identify odorants at the suprathreshold level. 
The UPSIT consists of 3 envelope-sized booklets, each containing 10 “scratch and sniff” 
odorants embedded in 10- to 50-µm polymer microcapsules positioned on brown strips at the 
bottom of the pages of the booklets. The internal consistency and test-retest reliability 
coefficients of this instrument are >0.90.22,21 Numerous studies have shown this and related tests 
to be sensitive to subtle changes in smell function associated with multiple etiologies, including 
those due to viruses, head trauma, and a number of neurodegenerative diseases.
The UPSIT test will be administered bilaterally (ie, both nostrils at the same time). Testing will 
occur during the screening/prospective observational phase to establish a subject’s baseline 
sensitivity. The degree of change from this baseline will be determined subsequently over time. 
The percent change from baseline will serve as the dependent measure for each subject for each 
test. 
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9.7.
Other Evaluations
MINI
Subjects will undergo MINI (a brief, structured diagnostic interview) to confirm the diagnosis of 
MDD and to determine if there are other psychiatric conditions present. It has an administration 
time of approximately 15 minutes.
MGH-ATRQ
The MGH-ATRQ is used to determine treatment resistance in MDD.18
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.
MMSE
The MMSE is a validated, brief examination that rates subjects on orientation (total score, 10), 
registration (total score, 3), attention and calculation (total score, 5), recall (total score, 3), and 
language (total score, 9).32 The MMSE is effective as a screening tool for cognitive impairment 
with older community dwelling, hospitalized and institutionalized adults. The maximum score is 
30. The MMSE will be completed at screening only. A total score <25 or <22 for those subjects 
with less than an equivalent of a high school education, will be used in the current study in order 
to exclude subjects with potential neurodegenerative disorder.
STOP-Bang Questionnaire 
Snoring, Tiredness, Observed Apnea, High Blood Pressure, Body Mass Index, Age, Neck 
Size, Gender (STOP-Bang) Questionnaire 
The STOP-Bang questionnaire is a concise, easy-to-use, validated, and sensitive screening tool 
for obstructive sleep apnea (OSA). This questionnaire has 8 items which address key risk factors 
for obstructive sleep apnea: snoring, tiredness, observed breathing interruption during sleep, high 
blood pressure, body mass index, age, neck size, and gender. The STOP-Bang questions do not 
specify a recall period. Subjects will answer yes or no to questions about snoring, tiredness, 
observed breathing interruption, and high blood pressure (these are the STOP items in the 
STOP-Bang acronym); this takes approximately 1 minute.6
Study site staff will answer yes or no to questions about body mass index (more than 35 kg/m²?), 
age (older than 50 years?), neck circumference (larger than 17 inches [43 cm] in men, or larger 
than 16 inches [41 cm] in women?), and gender (male?).
The total STOP-Bang score is calculated by summing the number of positive responses, yielding 
a score range of 0 to 8. A score of 5 on the STOP-Bang indicates a moderate to severe risk for 
OSA (AHI of >30).6
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Site Independent Qualification Assessment
Independent psychiatrists/psychologists will perform the Site Independent Qualification 
Assessment in the screening/prospective observational phase for all subjects to confirm diagnosis 
of depression and eligibility for the study.86
Further information regarding this assessment will be provided to sites in a separate document.
IDS-C30
The 30-item IDS-C30 is designed to assess the severity of depressive symptoms.76 The IDS 
assesses all the criterion symptom domains designated by the DSM-5 to diagnose a major 
depressive episode. These assessments can be used to screen for depression, although they have 
been used predominantly as measures of symptom severity. The 7-day period prior to assessment 
is the usual time frame for assessing symptom severity. The psychometric properties of the 
IDS-C30 have been established in various study samples.86
PAQ
Subjects’ 
adherence 
to 
their 
oral 
antidepressant 
treatment 
regimen 
during 
the 
screening/prospective observational phase will be assessed using the PAQ. It is a brief, 2-item 
self-report scale, developed at the University of Texas Southwestern Medical Center to assess 
how often the subject has taken, and whether he or she has made any changes to, his/her 
antidepressant treatment regimen in the last 2 weeks. The total score is based on the response 
selected to Question 1, and is interpreted as 0-1=adherent and 2 or more=nonadherent.58
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 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.
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10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the double-blind induction phase of the study if 
he or she has completed the MADRS assessments at the end of the 4-week double-blind 
induction phase (ie, Day 28 MADRS).
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.
10.2.
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 “Withdrawal of Consent” section below; this should only 
be selected as a reason for withdrawal if the subject does not agree to any further study 
assessments or procedures. If the subject is agreeable to participating in the Early Withdrawal 
visit and the follow-up phase, another reason for withdrawal should be selected.)

Violation of protocol procedures (determined on a case-by-case basis)

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 
adverse event) it is in the best interest of the subject to discontinue the study. See also 
guidance on blood pressure monitoring on intranasal dosing days (Section 6.2.1).

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

Death

Study is terminated by Sponsor for futility
If the subject withdraws from the study before the end of the double-blind induction phase, an 
Early Withdrawal 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 including phone numbers of 
relatives), as well as other contact information (eg, e-mail addresses) from subjects before 
randomization. In addition, the study site should emphasize the importance of follow-up 
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information to the subject before randomization. The measures taken to follow up must be 
documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Subjects who withdraw will not be 
replaced. 
Withdrawal of Consent
Every effort will be made in the study to ensure withdrawal of consent is not selected as a reason 
for discontinuation when in fact the subject withdrew for an identifiable reason (eg, due to an 
adverse event or lack of efficacy). 
Subjects who wish to withdraw from the study should be asked if they are agreeable to continue 
to an early withdrawal visit (if withdrawing from the double-blind induction phase) and the 
follow-up phase, or to be contacted to collect follow-up information. Subjects who are not 
agreeable to follow-up contact will be withdrawn from the study as “withdrawal of consent.”
Subjects who no longer wish to take study drug but agree to provide follow-up information will 
be withdrawn from the double-blind 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 
subject’s source records.
The investigator will be responsible for making all required notifications to the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC).
10.3.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, Long-
Term Retention of Samples for Additional Future Research). In such a case, samples will be 
destroyed after they are no longer needed for the clinical study. Details of the sample retention
for research are presented in the main ICF.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
11.1.
Subject Information
The primary efficacy and safety analysis sets are defined below.

Full Analysis Set: All randomized subjects who receive at least 1 dose of intranasal study 
medication and 1 dose of oral antidepressant medication in the double-blind induction phase. 
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
Safety Analysis Set: All randomized subjects who receive at least 1 dose of intranasal study 
medication or 1 dose of oral antidepressant medication in the double-blind induction phase.
11.2.
Sample Size Determination
The maximum sample size planned for this study was calculated assuming a treatment difference 
after 4 weeks of treatment in the double-blind induction phase of 6.5 points in MADRS total 
score between esketamine and the active comparator, a standard deviation of 12, a 1-sided 
significance level of 0.025, and a drop-out rate of 25%. A maximum of about 74 subjects will 
need to be randomized to each treatment group to achieve 80% power using a fixed design with 
no interim analysis. The treatment difference and standard deviation used in this calculation were 
based on results of Panel A of the ESKETINTRD2003 study and clinical judgment.
As detailed below, an interim analysis is planned to re-estimate sample size or to stop the study 
due to futility.
11.3.
Interim Analysis for Sample Size Re-estimation or Stopping for Futility
One unblinded interim analysis will be performed 4 weeks after randomizing 50 subjects in the 
study (approximately 25 per treatment group). It is projected that at that time approximately 
36 subjects in the full analysis set would have completed the double-blind induction phase of the 
study (approximately 18 subjects per treatment group). The dropout rate will be monitored to 
ensure that a sufficient number of subjects are included in the interim analysis. As the 
assumptions of the expected treatment difference and variability may or may not be upheld, the 
purpose of the interim analysis is to either re-estimate sample size or to stop the study due to 
futility. The sample size may be adjusted to achieve the desired power while maintaining control 
of the overall Type I error. The maximum sample size planned for this study is 74 per treatment 
group.
A rigorous interim statistical analysis plan (SAP) and charter will be developed detailing the 
algorithm for a sample size re-estimation based on the interim data and how the analysis will be 
executed. An IDMC will perform the interim analysis and will make recommendations for any 
sample size adjustment based on the rules defined in the interim SAP. Any changes to sample 
size will be communicated by the IDMC (or the statistician from the Statistical Support Group) 
to the IWRS vendor to ensure that the appropriate number of subjects is enrolled in the study. 
None of the esketamine team members or staff members at the investigational sites conducting 
the clinical study will be informed of the results of the interim analysis or of any specific sample 
size adjustment resulting from this interim analysis. However, the Clinical Supplies group will 
be informed of the decision made at the interim analysis so that only the required amount of 
study medication will be packaged.
Procedures will be in place to ensure that the results of the interim analysis do not influence the 
conduct of the study, investigators, or subjects.
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11.4.
Efficacy Analyses
Efficacy analyses will be performed on the FAS, which will include all randomized subjects who 
receive at least 1 dose of intranasal study medication and 1 dose of oral antidepressant 
medication during the double-blind induction phase.
With the exception of the European Union (EU) dossier, the primary efficacy variable, change 
from baseline in MADRS total score at Week 4 in the double-blind induction phase, will be 
analyzed using MMRM. The model will include baseline MADRS total score as a covariate, and 
treatment, country, class of antidepressant (SNRI or SSRI), day, and day-by-treatment 
interaction as fixed effects, and a random subject effect. Comparison of the intranasal esketamine 
plus oral antidepressant arm versus oral antidepressant plus intranasal placebo will be performed 
using the appropriate contrast.
For the EU dossier, the primary efficacy analysis will be based on an analysis of covariance 
(ANCOVA) model using last observation carried forward (LOCF) data. The model will include 
factors for treatment, country, and class of oral antidepressant (SNRI or SSRI) and baseline 
MADRS total score as a covariate. Comparison of the intranasal esketamine plus oral 
antidepressant arm versus intranasal placebo plus oral antidepressant will be performed using the 
appropriate contrast.
Response and remission rates will be summarized at each visit.
The ranks of change from baseline in CGI-S scores at the end of the double-blind induction 
phase will be analyzed based on LOCF data using an ANCOVA model, with country and class 
of antidepressant (SNRI or SSRI) as factors, and the baseline score (unranked score) as the 
covariate. 
Dimension scores of EQ-5D-5L, health status index, and the overall health status score will be 
summarized over time.
Additionally, scores of all efficacy endpoints will be summarized for all visits in the double-
blind induction phase. Summaries will be provided to show consistency of effect among relevant 
subgroups (eg, antidepressant class SNRI and SSRI).
11.5.
Pharmacokinetic Analyses
Plasma esketamine (and noresketamine, if warranted) concentrations will be listed for all 
subjects. The plasma concentration-time data of esketamine (and noresketamine, if warranted) 
will be analyzed using population PK modeling. Data may be combined with those of other 
selected studies to support a relevant structural model. Typical population values of basic PK
parameters will be estimated together with the inter-individual variability. 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.
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11.6.
Pharmacokinetic/Pharmacodynamic Analyses
The relationship between MADRS total score (and possibly selected adverse events as additional 
PD parameters), and PK metrics of esketamine may be evaluated. If there is any visual trend in 
graphical analysis, suitable models will be applied to describe the exposure-effect relationships. 
The results of the PK/PD analyses may be reported separately.
11.7.
Biomarker and Pharmacogenomic Analyses
Baseline biomarker values and changes from baseline biomarker values to the time points 
specified in the Time and Events Schedule will be summarized. Exploratory analyses may 
include comparison of biomarker measures between the treatment groups and correlation with 
baseline and change from baseline biomarker values in the efficacy and other measures. 
Additional exploratory analyses may also include relationship of baseline and change from 
baseline in biomarker measures to clinical response, maintenance/stabilization of response, 
relapse, and 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, and MDD/TRD. Expression analyses may include testing of known messenger 
RNA/microRNA (mRNA/miRNA) transcripts or transcriptome-wide analysis in relationship to 
antidepressant treatment response and MDD/TRD.
Details of the analysis plan and summary of results from both biomarker and pharmacogenomics 
analyses will be reported separately.
11.8.
Safety Analyses
Safety data will be analyzed for the double-blind induction phase using the safety analysis set.
The safety data from the follow-up phase will be summarized separately.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the MedDRA. All reported adverse events with onset during the double-blind induction 
phase (ie, TEAEs, and adverse events that have worsened since baseline) will be included in the 
analysis. For each adverse event, the percentage of subjects who experience at least 1 occurrence 
of the given event will be summarized by treatment group. Adverse events occurring during the 
follow-up phase will be summarized separately.
TEAEs of special interest will be examined separately (please refer to Section 3.2.6). Adverse 
events of special interest will be further listed in the SAP.
Subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event will be summarized separately.
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Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline 
and at each scheduled time point in each phase of the study. Changes from baseline results will 
be presented. Frequency tabulations of the abnormalities will be provided. Listings of subjects 
with laboratory results outside the reference ranges and markedly abnormal results will also be 
provided.
ECG
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. These tables will include observed values and change from baseline 
values.
Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will be 
calculated at baseline, and for observed values and changes from baseline at each scheduled time 
point. Frequency tabulations of the abnormalities will be made.
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, 
and corrected QT (QTc) interval using the following correction methods QT corrected according 
to Fridericia's formula (QTcF), which will be the primary correction factor, and QT corrected 
according to Bazett's formula (QTcB).39,76
Descriptive statistics of QTc intervals and changes from double-blind baseline will be 
summarized at each scheduled time point. The percentage of subjects with QTc interval 
>450 msec, >480 msec, or >500 msec will be summarized, as will the percentage of subjects 
with QTc interval increases from baseline <30 msec, 30-60 msec, or >60 msec.
All important abnormalities in ECG waveform that are changes from the baseline readings will 
be reported (eg, changes in T-wave morphology or the occurrence of U-waves).
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, pulse oximetry, and blood 
pressure (systolic and diastolic) (supine) values and changes from baseline will be summarized at 
each scheduled time point. The percentage of subjects with values beyond clinically important 
limits will be summarized.
Nasal Examination
Changes in findings from the baseline nasal examination (including the upper respiratory 
tract/throat) will be listed by treatment group. Examinations will provide ratings (absent, mild, 
moderate, or severe) that are based on a visual inspection of the nostrils, nasal mucosa, and 
throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption and epistaxis. A 
shift table for changes from double-blind baseline in ratings for each examination will be 
presented by treatment group.
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Nasal Symptom Questionnaire
Scoring from the nasal symptom questionnaire will be summarized descriptively for each 
scheduled time point by treatment group.
C-SSRS 
Suicide-related thoughts and behaviors based on the C-SSRS will be summarized by treatment 
group in incidence and shift tables. Separate endpoints for suicidal ideation and suicidal behavior 
will be defined and summarized descriptively by treatment group. Missing scores will not be 
imputed.
CADSS, BPRS+, and MOAA/S
Descriptive statistics of each of the scores and changes from predose will be summarized at each 
scheduled time point.
CGADR, PWC-20, UPSIT, BPIC-SS
Descriptive statistics of each of the scores and changes and/or percent changes from baseline will 
be summarized at each scheduled time point.
Cognition Testing
Descriptive statistics of each of the cognitive domain scores and changes from baseline will be 
summarized at each scheduled time point.
11.9.
Independent Data Monitoring Committee
An IDMC will be established to monitor data on an ongoing basis to ensure the continuing safety 
of the subjects enrolled in this study. In addition, the committee will review 1 interim analysis 
for a sample size re-estimation. The committee will meet every 6 months to review safety data 
and will meet once to review efficacy data after the interim analysis has been completed. After 
the reviews, the IDMC will make recommendations regarding the continuation of the study or, in 
the case of the interim analysis for efficacy, to either stop the study due to futility or to adjust the 
sample size to achieve the desired power while maintaining control of the overall Type I error. 
The details will be provided in a separate IDMC charter.
The IDMC will consist of at least one medical expert in the relevant therapeutic area and at least 
one statistician. The IDMC responsibilities, authorities, and procedures will be documented in its 
charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
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12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (for example, the subject was at risk of death at the time of the event. “Life 
threatening” does not refer to an event that hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is medically important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality).
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Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For esketamine, the expectedness of an adverse 
event will be determined by whether or not it is listed in the Reference Safety Information 
Section of the Investigator's Brochure. 
For duloxetine, escitalopram, sertraline, and venlafaxine XR, the expectedness of an adverse 
event will be determined by whether or not it is listed in the SmPC or US prescribing 
information.24,23,28,29,81,82,87,88
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, eg,
concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
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Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure (which may include contact for follow-up of safety), with the exception 
of pregnancy which will be reported up to 6 weeks after the last dose of study medication 
(females) or 90 days after the last dose of study medication (partners of male participants).
Serious adverse events, including those spontaneously reported to the investigator, must be 
reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. Anticipated events will be 
recorded and reported as described in Attachment 4.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the eCRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
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management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. A SUSAR will be reported to regulatory 
authorities unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR 
summary, unless otherwise specified.
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the 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
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
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)

Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of 
hospitalization) that occurs during the course of a subject's participation in a study must be 
reported as a serious adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility).

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.

For convenience the investigator may choose to hospitalize the subject during a treatment 
period.
The cause of death of a subject in a study, whether or not the event is expected or associated with 
the study drug, is considered a serious adverse event.
12.3.3.
Pregnancy
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel 
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered serious adverse events and must be reported using 
the Serious Adverse Event Form. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported by the study-site personnel within 24 hours of their 
knowledge of the event using the appropriate pregnancy notification form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
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and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 1 business 
day after being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
Intranasal Study Drug
Esketamine will be supplied as a clear, colorless intranasal solution of esketamine HCl
(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 HCl (equivalent to 140 mg of 
esketamine base) formulated in 0.12 mg/mL ethylenediaminetetraacetic acid (EDTA) and 
1.5 mg/mL citric acid at a pH of 4.5 in water for injection. It is provided in a nasal spray pump, 
which delivers 16.14 mg esketamine HCl (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.42
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Oral Antidepressant Medications
Duloxetine
Duloxetine 30 mg will be obtained from commercial stock and provided under the responsibility 
of the sponsor. Refer to the SmPC/USPI for the physical description and a list of excipients.24,23
Escitalopram
Escitalopram 10mg will be obtained from commercial stock and provided under the 
responsibility of the sponsor. Refer to the SmPC/USPI for the physical description and a list of 
excipients.28,29
Sertraline
Sertraline 25 mg and 50 mg (as applicable) will be obtained from commercial stock and provided 
under the responsibility of the sponsor. Refer to the SmPC/USPI for the physical description and 
a list of excipients.81,82
Venlafaxine XR
Venlafaxine 37.5mg and 75 mg (as applicable) will be obtained from commercial stock and 
provided under the responsibility of the sponsor. Refer to the SmPC/USPI for the physical 
description and a list of excipients.87,88
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 230 µL (of which ~30µL is the residual 
volume). Each device delivers 16.14 mg esketamine HCl (14 mg esketamine base) or 0.1 µg of 
denatonium benzoate per 100 µL spray. 
Each nasal spray device will be individually packaged in a blister tray and subsequently put into a 
carton box. Each carton box constitutes a non-child-resistant subject kit, labeled with a unique 
medication kit number.
Device for Practicing Intranasal Study Drug Administration
The demonstration intranasal device will also be supplied by the sponsor and will contain placebo 
solution. Subjects will practice spraying (into the air, not intranasally).
Oral Antidepressant Medication
Oral antidepressant tablets or capsules will remain in their commercial packaging. 
If blisters are supplied; each blister will be packaged into a child-resistant dose pack to constitute a 
subject kit. All kits will be labeled with a unique medication kit number, and labeled according to 
applicable regulatory requirements.
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14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
Study drug will be stored at the study site in a secure area with restricted access until dispensed to 
the subjects. 
All study drug must be stored at controlled temperatures as indicated on the product-specific 
labeling.
Refer to the pharmacy manual/study site investigational product manual for additional guidance on 
study drug preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study.
The dispensing of study drug to the subject, and the return of study drug from the subject (if 
applicable), must be documented on the drug accountability form. Subjects must be instructed to 
return all original containers, whether empty or containing study drug.
The study drug administered to the subject must be documented on the drug accountability form. 
All study drug will be stored and disposed of according to the sponsor's instructions. Study-site 
personnel must not combine contents of the study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the investigational product destruction form. When the study site is an authorized 
destruction unit and study drug supplies are destroyed on-site, this must also be documented on 
the investigational product destruction form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject.
Whenever a subject brings his or her study drug to the study site for pill count (ie, compliance 
check), this is not seen as a return of supplies.
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Study drug may not be relabeled or reassigned for use by other subjects. The investigator agrees 
neither to dispense the study drug from, nor store it at, any site other than the study sites agreed 
upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Practice intranasal devices

Investigator’s Brochure for esketamine

Local prescribing information for oral antidepressant options in double-blind induction phase

Investigational Product (IP) Binder, including the IP Procedures Manual

Laboratory manual and materials

Clinician-administered and patient-reported outcome assessments
o
Paper versions, as applicable
o
Electronic devices and associated materials

IWRS Manual

ECG equipment and associated materials (eg, manual)

Instructions for Use documents (subject and healthcare provider versions) for intranasal 
study medication

Rater qualifications/requirements for select clinician-administered assessments

Computerized cognitive battery and HVLT-R, and all associated equipment and materials

Device to measure respiratory rate

Procedural documents for Site Independent Qualification Assessment

Procedural documents for independent, remote rater interviews

Guidance on recommended order of study procedures

MGH-ATRQ guidance document

SmPCs of the active comparators: Duloxetine, escitalopram, sertraline, and venlafaxine XR

Subject diary
16.
ETHICAL ASPECTS
16.1.
Study-specific Design Considerations
Clinical Study in Treatment-resistant Major Depression
Major depressive disorder is a common, severe, chronic, and often life-threatening illness. It is 
now the leading cause of disability worldwide. There is a clear need to develop novel and 
improved therapeutics for treatment-resistant depression in the elderly population.
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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 intranasal esketamine plus an oral 
antidepressant for the treatment of TRD in the elderly population. Thus, the study cannot be 
completed in healthy subjects. 
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation.
For eligibility, subjects must have had nonresponse to at least one prior antidepressant treatment 
and be currently taking an antidepressant treatment at the start of the screening/prospective 
observational
phase 
that 
will 
be 
continued 
as 
prospective 
treatment 
in 
the 
screening/prospective/observational phase. Only subjects with nonresponse to their current 
antidepressant treatment after 4 weeks of prospectively observed treatment (for a total duration 
of antidepressant treatment of at least 6 weeks by the end of the screening/prospective 
observational phase), will be eligible to proceed to the double-blind induction phase, when all 
subjects will receive a new oral antidepressant in addition to intranasal esketamine or placebo. 
Subjects will receive 4 weeks of treatment in the double-blind induction phase and at the end of 
this phase, may participate in the open-label safety study (ESKETINTRD3004). Subjects who do 
not complete the double-blind induction phase of this study will not be eligible to participate in the 
ESKETINTRD3004 study. Subjects who choose not to enter the ESKETINTRD3004 study will 
proceed to the 2-week follow-up phase, during which all subjects will be provided with an 
additional 2-week supply of oral antidepressant and appropriate follow-up care will be arranged.
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 adverse events of the study, and provide their consent voluntarily will be enrolled.
Justification for Using Placebo
Intranasal placebo is being used as a double-blind for intranasal esketamine to maintain study 
blinding. All subjects will also receive a newly initiated oral antidepressant during the induction 
phase. Subjects will not be on placebo alone. Assessment of the potential efficacy of a new 
compound for the treatment of treatment-resistant major depression requires adequate and 
well-controlled clinical studies. This superiority study will compare intranasal esketamine plus a 
newly-initiated oral antidepressant to switching to an oral antidepressant as an active comparator. 
Recent analyses have shown response to placebo varies considerably, from 10% to 55%. 
Therefore, there is a concern that randomized, controlled studies that rely on comparison with 
standard antidepressant treatments alone will generate unreliable results with limited assay 
sensitivity. However, some have considered it unethical to do placebo-controlled studies in major 
depression due to the potential risk of irreversible harm.74 In a meta-analysis of drug studies 
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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.47 These studies showed annual suicide rates of 0.8% on the investigational drug, 
0.7% on the active comparator, and 0.4% on placebo. Thus, the risk of irreversible harm was not 
higher in the placebo arm compared with the active control arms.
Some subjects may decide not to participate in a placebo-controlled study due to the potential for 
increased distress and dysfunction from prolonged depression. 
Therefore, the use of an active-controlled study allows for assessment of efficacy of a new 
compound to allow for scientifically meaningful results. 
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 
include evaluation of suicidal ideation/behavior at each clinic visit. At any point in the study, the 
subject may withdraw consent or be removed from the study by the investigator if there are any 
clinical concerns.
Intranasal esketamine may not be available for subjects after the study. However, following 
completion of the double-blind induction phase, those subjects not continuing into the 
ESKETINTRD3004 study can be treated according to standard of care. 
Precautions to Ensure Subject Safety in the Study 
Subjects may participate in the study only if they have adequate capacity to give consent and 
after fully understanding the potential risks and giving an informed consent. Determination of 
capacity will be made by the study investigator. Subjects may discontinue the study at any time. 
The probability of receiving placebo and the concept of random assignment will be explained to 
the subject. The duration of the study is short, minimizing the time on intranasal placebo (which 
is being administered with a newly-initiated oral antidepressant). Potential disadvantages and 
adverse events of participating in the study and alternative treatment options will be discussed. 
For subjects who do not meet predefined response criteria during the study, clinical care will be 
arranged between the study investigator and their physician.
Compensation for any procedure will be fair per local standards and approved by the 
participating sites IRB in order to not offer any undue incentive to participate in the study.
Subjects will be carefully monitored during the study and subjects who are unable to tolerate 
study drug during the double-blind 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 6.2.1). In addition to a 12 lead ECG performed at Screening and pre-dose and post-
dose on Day 1 (baseline), on subsequent dosing days all subjects will have an ECG at 1 hour 
post-dose.
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Only subjects who had nonresponse to their current oral antidepressant treatment, where a 
clinician would consider changing it in the future due to lack of response, will be enrolled.
Only qualified and trained investigators will participate in the study.
The total blood volume to be collected is considered to be within the normal range allowed for this 
subject population over this time frame. The approximate total blood volume to be collected is 
approximately 117 mL, which will be less than a Red Cross blood donation.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
(IEC/IRB)
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Sponsor-approved training and informational materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
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consequences for subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the study 
drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required. The reapproval should be documented in writing (excluding the ones that are purely 
administrative, with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-
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related activity. The ICF(s) that is/are used must be approved by both the sponsor and by the 
reviewing IEC/IRB and be in a language that the subject can read and understand. The informed 
consent should be in accordance with principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his or her disease. Subjects will be told 
that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow-up if needed and that their records 
may be accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject is authorizing such access, and agrees to allow his or her study 
physician to re-contact the subject for the purpose of obtaining consent for additional safety 
evaluations, if needed.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject.
Where local regulations require, a separate ICF may be used for the required DNA component of 
the study.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.
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The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory PK, PD, biomarker, DNA, and RNA research is not conducted under standards 
appropriate for the return of data to subjects. In addition, the sponsor cannot make decisions as to 
the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to subjects or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand esketamine, oral 
antidepressants, to understand depression, to understand differential drug responders, and to 
develop tests/assays related to esketamine, oral antidepressants, and depression. The research 
may begin at any time during the study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal From the Use of Samples in Future 
Research]).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
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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 adverse events and follow-up of adverse events; concomitant medication; 
drug receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
Some subject- and clinician-completed scales and assessments designated by the sponsor will be 
recorded directly into an electronic device and will be considered source data.
The minimum source documentation requirements for Section 4.1, Inclusion Criteria, and 
Section 4.2 (Exclusion Criteria) that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
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
Antidepressant treatment in the current episode of depression
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. All CRF entries, corrections, 
and alterations must be made by the investigator or authorized study-site personnel. The 
investigator must verify that all data entries in the CRF are accurate and correct.
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an eCRF, and transmitted in a secure 
manner to the sponsor within the timeframe agreed upon between the sponsor and the study site. 
The electronic file will be considered to be the eCRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject’s source documents. Data must be entered into 
eCRFs in English. Study site personnel must complete the eCRF as soon as possible after a 
subject visit, and the forms should be available for review at the next scheduled monitoring visit.
The investigator must verify that all data entries in the eCRFs are accurate and correct. All eCRF
entries, corrections, and alterations must be made by the investigator or other authorized study-
site personnel. If necessary, queries will be generated in the eDC tool. The investigator or study-
site personnel must adjust the eCRF (if applicable) and complete the query.
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 
either of the following ways:

Investigator and study site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, and uploading 
data transfers from external service providers into the sponsor's data base. Written instructions 
will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review eCRFs for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
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designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the eCRF
with source documents (eg, 
hospital/clinic/physician’s office medical records); a sample will be reviewed. The nature and 
location of all source documents will be identified to ensure that all sources of original data 
required to complete the eCRF are known to the sponsor and study-site personnel and are 
accessible for verification by the sponsor study-site contact. If electronic records are maintained 
at the study site, the method of verification must be discussed with the study-site personnel. 
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review will be discussed with the study-site personnel. The sponsor expects that, during 
monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
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documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
In addition to on-site monitoring visits, the monitor may contact the site by telephone for an 
update on study progress. It is expected that study-site personnel will be available to provide an 
update on the progress of the study at the site.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last study assessment for the last subject 
participating in the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject assessment at that study site, in the time frame 
specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development

Study is terminated by the sponsor due to futility.
17.10. On-site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the eCRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
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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 eCRF data from all study sites that participated in the study and will represent 
uploaded data transferred from external service providers into the sponsor's database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomic or 
exploratory biomarker analyses performed after the Clinical Study Report has been issued will 
be reported in a separate report and will not require a revision of the Clinical Study Report. 
Study subject identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and sub-study approaches, secondary results 
generally should not be published before the primary endpoints of a study have been published. 
Similarly, investigators will recognize the integrity of a multicenter study by not submitting for 
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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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148
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Attachment 1: Prohibited Concomitant Medications with Intranasal Study Medication
(Esketamine or Placebo)
This list of medications is not all-inclusive; if necessary, please contact the medical monitor for any 
questions regarding a medication(s).
Please refer to the local prescribing information of the subject’s oral antidepressant treatment for 
information regarding prohibited concomitant medications. 
Except where specifically noted, the prohibited medications listed in the following table are prohibited 
from 1 week (or 5 half-lives, whichever is longer) prior to the first dose of intranasal study medication 
until after the last dose of intranasal study medication. Note: If a medication is part of the antidepressant 
treatment regimen being taken at the time of signing the ICF (ie, start of screening/prospective 
observational phase), dose adjustment is permitted per clinical judgment, but the oral antidepressant 
treatment is to remain at or above the minimum therapeutic dose (per the MGH-ATRQ) through the end 
of Week 4. . If the investigator determines it is clinically appropriate, the antidepressant medication may 
be tapered during the optional, up to 3-week, taper period.
Note in the following table: N, Prohibited; Y, Permitted, with restrictions (please refer to the column labeled 
“Comments” for additional guidance)
Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for 
Prohibition
ADHD medications (eg, 
atomoxetine, guanfacine)
N
Y
Can be continued but must not be taken 
within 12 hours prior to the intranasal 
treatment session or for 2 hours after the 
intranasal treatment session.
Safety
Amantadine
N
N
PD interaction
Anorexiants 
(eg, phentermine, 
phendimetrazine)
N
N
Safety
Anticholinesterase 
inhibitors
N
N
Subject 
population is 
excluded
Anticonvulsants
N
N
Subjects with seizures are excluded. 
Use as adjunctive treatment for major 
depressive disorder (MDD) is 
prohibited. 
-
Note: Anticonvulsants used for 
indications other than seizures may be 
allowed (eg, valproate for migraine, 
pregabalin)
Safety and PD 
interaction
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Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for 
Prohibition
Antidepressants 
(other than the specific 
antidepressant started in 
the induction phase of the 
study)
N
N
-
Only 1 of the 4 predefined oral 
antidepressant treatment options are 
permitted
-
If a subject is taking a monoamine 
oxidase inhibitor (MAOI) during the 
screening/prospective observational 
phase, there must be a minimum 
washout interval of 2 weeks prior to 
the first dose of intranasal study 
medication.
-
Even if used for indications other 
than MDD (eg, trazodone 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
N
N
PD interaction
Benzodiazepines (at 
dosages less than or equal 
to the equivalent of 6 
mg/day of lorazepam) and 
non-benzodiazepine 
sleeping medication 
(including: zolpidem, 
zaleplon, eszopiclone, and 
ramelteon)
Y
Y
Prohibited within 12 hours prior to the 
start of each intranasal treatment session 
or cognition testing
Safety and PD 
interaction
Benztropine
Y
N
Prohibited if use is continuous and 
prohibited within 12 hours prior to the 
start of cognition testing
Safety and PD 
interaction. 
Chloral hydrate, 
melatonin, valerian
N
N
Safety and PD 
interaction
Clonidine
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 medication administration.
Pseudoephedrine-containing oral
products should not be used within 12 
hours prior to an intranasal treatment 
session
Safety and PD 
interaction
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Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for 
Prohibition
CYP3A4 inducers - Potent
N
N
Subjects may not take a known potent 
inducer of hepatic CYP3A activity 
within 2 weeks of the first 
administration of intranasal study 
medication until at least 24 hours after 
the last intranasal dose of study 
medication.
Examples (not all-inclusive): Efavirenz, 
nevirapine, barbiturates, carbamazepine, 
glucocorticoids, modafinil, 
oxcarbazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, and St. 
John's wort
PK
Dextromethorphan
N
N
PD interaction
Diphenhydramine
Y
N
Prohibited within 12 hours prior to the 
start of each intranasal treatment session
Safety
Ketanserin
N
N
Safety
Lithium
N
N
PD interaction
Memantine
N
N
PD interaction
Methyldopa
N
N
Safety and PD 
Interaction
Metyrosine
N
N
Safety and PD 
interaction
Non-vitamin K antagonist 
oral anticoagulation agents 
(eg, dabigatran, 
rivaroxaban, apixaban)
N
N
Safety
Opioids
N
N
PD interaction
Psychostimulants 
(eg, amphetamines, 
methylphenidate 
modafinil, armodafinil)
N
Y
Prescribed psychostimulants taken for 
indications other than MDD can be 
continued but must not be taken within 
12 hours prior to the intranasal 
treatment session or for 2 hours after the 
intranasal treatment session.
Cardiovascular 
safety
Reserpine
N
N
PD interaction
Scopolamine
N
N
PD interaction
St. John’s Wort
N
N
PD interaction 
and PK
Thyroid hormone 
supplement for treatment 
of thyroid condition only 
(not for depression)
N
Y
Safety
Thyroxine/ 
triiodothyronine (T3), 
thyroid hormone 
prescribed for depression
N
N
PD interaction
Warfarin
N
N
Primary 
condition 
where used is 
excluded
Abbreviations: ADHD, attention deficit hyperactivity disorder; N, Prohibited; PD, pharmacodynamics; PK, 
pharmacokinetics; QTc, QT corrected; Y, Permitted, with restrictions (please refer to the column labeled 
“Comments” for additional guidance).
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Attachment 2: New York Heart Association Classification of Cardiac Disease
New York Heart Association Classification of Cardiac Disease
Category
Description
Functional Capacity
Class I
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
Class II
Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
Class III
Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable 
at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any 
physical activity is undertaken, discomfort is increased.
Objective Assessment
A
No objective evidence of cardiovascular disease.
B
Objective evidence of minimal cardiovascular disease.
C
Objective evidence of moderately severe cardiovascular disease.
D
Objective evidence of severe cardiovascular disease.
Source: Criteria Committee of the New York Heart Association. Functional capacity and objective assessment. In: 
Dolgin M, ed. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels, 9th ed. Boston, 
MA: Little, Brown & Co; 1994, 253-255.
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Attachment 3: Oral Antidepressant Titration Schedule for Double-Blind Induction Phase
The titration schedule for the 4 oral antidepressants to be used in the current study is provided below. 
Prescribing Information: 
Oral Antidepressant
(Active Comparator)
Titration Schedule
Week 1
(Starting Day 1)
Week 2
(Starting Day 8)
Week 3
(Starting Day 15)
Week 4
(Starting Day 22)
Duloxetine
30 mg
60 mg
60 mg
60 mg
Escitalopram
10 mg
10 mg
10 mg
10 mg
Sertraline
25 mg
50 mg
100 mg
150 mg
Venlafaxine XR
37.5 mg
75 mg
150 mg
150 mg
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Attachment 4: Anticipated Events
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease related) or background regimen. For 
the purposes of this study the following events will be considered anticipated events.24,23,28,29,42,81,82,87,88
For esketamine and major depressive disorder (MDD) (including treatment-resistant depression [TRD]; 
based on DSM-5):

Suicidal thinking, ideation, and behavior

Sleep changes, difficulty sleeping, reduced sleep, abnormal sleep, abnormal sleep, tiredness, fatigue, 
and reduced energy

Difficulty in sexual desire, performance or satisfaction

Reduced appetite and weight changes (loss or increase)

Activation or hypomania/ mania

Excessive happiness

Irritability, anger, and impulsive behavior

Agitation, feeling anxious/anxiety, tension, panic attacks, and phobia
For esketamine, regarding events related to concomitant therapy with oral antidepressants (from the 
product’s reference safety information/US prescribing information):

Duloxetine

Most commonly observed adverse reactions from pooled studies of all indications (incidence of 
at least 5% and at least twice the incidence in placebo subjects) were nausea, dry mouth, 
somnolence, fatigue, constipation, decreased appetite, and hyperhidrosis (sweating). Duloxetine 
treatment worsens glycemic control in some subjects with diabetes.

Increased the risk compared to placebo of suicidal thinking and behavior; serotonin syndrome; 
hepatotoxicity; hepatic failure; orthostatic hypotension, syncope; abnormal bleeding; severe 
skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS); activation 
of mania or hypomania; hyponatremia.

Venlafaxine XR

According to the US prescribing information, adverse events in short-term studies occurring in 
at least 5% of subjects receiving venlafaxine XR and at a rate twice the incidence in placebo 
subjects: abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), 
central nervous system complaints (dizziness, somnolence, and abnormal dreams), and 
sweating. Sustained hypertension is noted within Warnings and Precautions section.

Increased the risk compared to placebo of suicidal thinking and behavior, treatment-emergent 
insomnia and nervousness, activation of mania/hypomania, hyponatremia, mydriasis, abnormal 
bleeding, sustained hypertension, and serotonin syndrome.

Escitalopram

Most commonly observed adverse reactions (incidence of approximately 5% or greater and 
approximately twice the incidence in placebo subjects) were insomnia, ejaculation disorder 
(primarily ejaculatory delay), nausea, sweating increased, fatigue, and somnolence.

Increased the risk compared to placebo of suicidal thinking and behavior, serotonin syndrome, 
activation of mania/hypomania, hyponatremia and abnormal bleeding

Sertraline
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
Most common treatment-emergent AEs associated with sertraline (incidence of at least 5% for 
sertraline or at least twice the incidence in placebo subjects) were ejaculation failure, dry mouth, 
increased sweating, somnolence, tremor, dizziness, fatigue, pain, malaise, abdominal pain, 
anorexia, constipation, diarrhea/loose stools, dyspepsia, nausea, agitation, insomnia, and 
decreased libido, and serotonin syndrome. 

Increased the risk compared to placebo of suicidal thinking and behavior, activation/mania; 
bleeding events related to SSRI use (have ranged from ecchymosis, hematomas, epistaxis, and 
petechiae to life-threatening hemorrhages), hyponatremia (appears to be the result of the 
syndrome of inappropriate antidiuretic hormone secretion [SIADH]); serotonin syndrome
Reporting of Anticipated Events
These events will be captured on the CRF and in the database, and will be reported to the sponsor as 
described in Section 12.3.1, All Adverse Events. Any event that meets serious adverse event criteria will 
be reported to the sponsor within the appropriate timeline as described in Section 12.3.2, Serious Adverse 
Events. These anticipated events are exempt from expedited reporting as individual single cases to Health 
Authorities. However, if based on an aggregate review, it is determined that an anticipated event is 
possibly related to study drug, the sponsor will report these events in an expedited manner.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of pre-specified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug. 
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).
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INVESTIGATOR AGREEMENT
NCT02422186

SAP_001.pdf: 
1
Approved, Date: 10 January 2017
Janssen Research & Development *
Statistical Analysis Plan
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 Treatment-resistant Depression
Trial of Rapid-acting Intranasal Esketamine for Treatment-resistant Major Depressive Disorder 
(TRANSFORM-3)
Protocol ESKETINTRD3005; Phase 3
JNJ-54135419 (esketamine)
Status:
Approved
Date:
10 January 2017
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-122279246, 2.0
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.
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JNJ-54135419 (esketamine)
Statistical Analysis Plan ESKETINTRD3005
2
Approved, Date: 10 January 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 4
LIST OF IN-TEXT FIGURES ........................................................................................................................ 4
ABBREVIATIONS ........................................................................................................................................ 5
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Trial Objectives ................................................................................................................................ 7
1.2.
Trial Design ...................................................................................................................................... 8
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 11
1.4.
Sample Size Justification ............................................................................................................... 11
1.5.
Interim Analysis for Sample Size Re-Estimation or Stopping for Futility ....................................... 12
1.6.
Randomization and Blinding .......................................................................................................... 12
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 13
2.1.
Pooling Algorithm........................................................................................................................... 13
2.2.
Analysis Phases............................................................................................................................. 13
2.2.1.
Study Reference Start and End Dates ....................................................................................... 13
2.2.2.
Analysis Phase Start and End Dates.......................................................................................... 13
2.2.3.
Study Day and Relative Day....................................................................................................... 14
2.3.
Baseline and End Point.................................................................................................................. 14
2.4.
Visit Windows................................................................................................................................. 14
2.5.
Analysis Sets.................................................................................................................................. 19
2.5.1.
All Randomized Analysis Set...................................................................................................... 19
2.5.2.
Full Analysis Set ......................................................................................................................... 19
2.5.3.
Safety Analysis Set..................................................................................................................... 19
2.5.4.
Follow-up Analysis Set ............................................................................................................... 19
2.6.
Definition of Subgroups.................................................................................................................. 19
2.7.
Imputation Rules for Missing AE Dates ......................................................................................... 20
2.8.
Imputation Rules for Missing AE time of Onset/Resolution ........................................................... 21
2.9.
Imputation Rules for Missing Concomitant Medication Dates ....................................................... 21
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 21
4.
SUBJECT INFORMATION................................................................................................................ 22
4.1.
Demographics and Baseline Characteristics ................................................................................. 22
4.2.
Disposition Information................................................................................................................... 23
4.3.
Extent of Exposure......................................................................................................................... 23
4.4.
Protocol Deviations ........................................................................................................................ 24
4.5.
Prior and Concomitant Medications ............................................................................................... 24
5.
EFFICACY ......................................................................................................................................... 24
5.1.
Analysis Specifications................................................................................................................... 25
5.1.1.
Level of Significance................................................................................................................... 25
5.1.2.
Data Handling Rules................................................................................................................... 25
5.1.3.
Imputation Methods for Missing Items........................................................................................ 25
5.2.
Primary Efficacy Endpoint.............................................................................................................. 25
5.2.1.
Definition..................................................................................................................................... 25
5.2.2.
Primary Estimand ....................................................................................................................... 26
5.2.3.
Analysis Methods........................................................................................................................ 26
5.3.
Other Efficacy Variables................................................................................................................. 31
5.3.1.
Responders ................................................................................................................................ 31
5.3.1.1.
Definition.................................................................................................................................. 31
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Approved, Date: 10 January 2017
5.3.1.2.
Analysis Methods .................................................................................................................... 31
5.3.2.
Remitters .................................................................................................................................... 32
5.3.2.1.
Definition.................................................................................................................................. 32
5.3.2.2.
Analysis Methods .................................................................................................................... 32
5.3.3.
CGI-S.......................................................................................................................................... 32
5.3.3.1.
Definition.................................................................................................................................. 32
5.3.3.2.
Analysis Methods .................................................................................................................... 32
5.3.4.
EuroQol Group; 5 Dimension; 5 Level (EQ-5D-5L) .................................................................... 33
5.3.4.1.
Definition.................................................................................................................................. 33
5.3.4.2.
Analysis Methods .................................................................................................................... 33
5.3.5.
Sheehan Disability Scale (SDS) ................................................................................................. 34
5.3.5.1.
Definition.................................................................................................................................. 34
5.3.5.2.
Analysis Methods .................................................................................................................... 34
5.3.6.
PHQ-9......................................................................................................................................... 34
5.3.6.1.
Definition.................................................................................................................................. 34
5.3.6.2.
Analysis Methods .................................................................................................................... 34
6.
SAFETY............................................................................................................................................. 35
6.1.
Adverse Events .............................................................................................................................. 35
6.2.
Clinical Laboratory Tests................................................................................................................ 36
6.3.
Vital Signs, Weight, and BMI ......................................................................................................... 37
6.4.
Electrocardiogram.......................................................................................................................... 38
6.5.
Nasal Examination ......................................................................................................................... 39
6.5.1.
Nasal Symptom Questionnaire................................................................................................... 39
6.6.
Other Safety Parameters ............................................................................................................... 40
6.6.1.
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................... 40
6.6.2.
Clinician Administered Dissociative States Scale (CADSS)....................................................... 41
6.6.3.
Brief Psychiatric Rating Scale (BPRS) ....................................................................................... 41
6.6.4.
Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) .......................................... 42
6.6.5.
Clinical Global Assessment of Discharge Readiness (CGADR) ................................................ 42
6.6.6.
Physician Withdrawal Checklist (PWC-20)................................................................................. 43
6.6.7.
Computerized Cognitive Battery and Hopkins Verbal Learning Test-Revised (HVLT-R) .......... 43
6.6.8.
University of Pennsylvania Smell Inventory Test (UPSIT) ......................................................... 43
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 44
REFERENCES............................................................................................................................................ 45
ATTACHMENTS......................................................................................................................................... 46
Attachment 1:
Criteria of Markedly Abnormal Laboratory Values ..................................................... 46
Attachment 2:
Statistical Analysis Plan for Cogstate......................................................................... 47
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LIST OF IN-TEXT TABLES
Table 1:
Analysis Visits ........................................................................................................................... 16
Table 2:
Demographic Variables and Baseline Characteristics.............................................................. 22
Table 3:
Psychiatric History at Baseline Variables ................................................................................. 23
Table 4:
Efficacy Variables ..................................................................................................................... 25
Table 5:
Analysis Types and Assumptions ............................................................................................. 28
Table 6:
Treatment-Emergent Abnormality Categories for Vital Signs................................................... 37
Table 7:
Limits for HR, PR, QRS and QT Interval Abnormality .............................................................. 38
Table 8:
Criteria for Abnormal QTc Values and Changes From Baseline.............................................. 39
LIST OF IN-TEXT FIGURES
Figure 1:
Study Design for ESKETINTRD3005 ....................................................................................... 11
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ABBREVIATIONS
AD
antidepressant
AE
adverse event
ANCOVA
analysis of covariance
ASA
American Society of Anesthesiologists
BMI
body mass index
BP
Blood Pressure
BPIC-SS
Bladder Pain / Interstitial Cystitis Symptom Score
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
CMH
Cochran-Mantel-Haenszel
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
DB
Double-blind
D/C
discontinued
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders (4th edition)
ECG
Electrocardiogram
eCRF
electronic case report form
EQ-5D-5L
EuroQol Group; 5 dimension; 5 level
EQ-VAS
EuroQol Group: visual analogue scale
EU
European Union
FDA
Food and Drug Administration
FU
Follow-Up
HVLT-R
Hopkins Verbal Learning Test-Revised
IDMC
Independent Data Monitoring Committee
ICH
International Conference on Harmonization
IDS-C30
Inventory of Depressive Symptoms-Clinician rated, 30 item
IWRS
Interactive web response system
LOCF
last observation carried forward
MADRS
Montgomery-Asberg Depression Rating Scale
MCMC
Markov Chain Monte Carlo
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MGH-ATRQ
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire
MI
multiple imputation
MINI
Mini International Neuropsychiatric Interview
MMRM
Mixed-effects model using repeated measures
MOAA/S
Modified Observer’s Assessment of Alertness/Sedation
OL
open-label 
PBO
placebo
PD
Pharmacodynamics
PHQ-9
Patient Health Questionnaire – 9 item
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
TEAEs
Treatment-emergent adverse events
TEMA
treatment-emergent markedly abnormal
TRD
Treatment Resistant Depression
ULN
upper limit of normal
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Statistical Analysis Plan ESKETINTRD3005
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UPSIT
University of Pennsylvania Smell Identification Test
XR
extended release
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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and
statistical methods for all planned analyses for study JNJ54135419-ESKETINTRD3005.
1.1.
Trial Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of switching elderly subjects with 
treatment-resistant depression (TRD) from a prior antidepressant treatment (to which they have 
not responded) to flexibly dosed intranasal esketamine (28 mg, 56 mg or 84 mg) plus a newly 
initiated oral antidepressant compared with switching to a newly initiated oral antidepressant 
(active comparator) plus intranasal placebo, in improving depressive symptoms, as assessed by 
the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total 
score from Day 1 (pre-randomization) to the end of the 4-week double-blind induction phase.
Secondary Objectives

To assess the effect of intranasal esketamine plus a newly initiated oral antidepressant 
compared with a newly initiated oral antidepressant (active comparator) plus intranasal 
placebo on the following parameters in elderly subjects with TRD:

Depression response rates

Depression remission rates

Overall severity of depressive illness

Health-related quality of life and health status

To investigate the safety and tolerability of intranasal esketamine plus a newly initiated oral 
antidepressant compared with a newly initiated oral antidepressant (active comparator) plus 
intranasal placebo in elderly subjects with TRD, including the following:

Treatment-emergent adverse events (TEAEs), including AEs of special interest

Local nasal tolerability

Effects on heart rate, blood pressure, respiratory rate, and blood oxygen saturation

Effects on alertness and sedation

Potential psychosis-like effects

Dissociative symptoms 

Potential effects on cognitive function

Potential effects on suicidal ideation/behavior

Potential treatment-emergent symptoms of cystitis and/or lower urinary tract symptoms

Potential withdrawal and/or rebound symptoms following cessation of intranasal 
esketamine treatment

Potential effects on sense of smell
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
To assess the pharmacokinetics (PK) of intranasal esketamine in elderly subjects with TRD 
receiving intranasal esketamine plus a newly-initiated oral antidepressant
Exploratory Objectives

To assess the PK/pharmacodynamic (PK/PD) relationship of intranasal esketamine and 
MADRS total score in elderly subjects with TRD

To assess the potential relationship of biomarkers with response/non-response to intranasal 
esketamine or oral antidepressants in elderly subjects with TRD
1.2.
Trial Design
This is a randomized, double-blind, active-controlled, multicenter study in male and female 
elderly subjects with TRD to assess the efficacy, safety, and tolerability of flexibly dosed 
intranasal esketamine (28 mg, 56 mg or 84 mg) plus a newly initiated oral antidepressant 
compared with a newly initiated oral antidepressant (active comparator) plus intranasal placebo. 
The study has 3 phases:
Screening/prospective observational phase (4-week duration + optional 3-week taper 
period)
This phase will prospectively assess treatment response to the subject’s current oral 
antidepressant treatment regimen.
At the start of the screening/prospective observational phase, the subject must have had 
documented nonresponse to at least one antidepressant treatment (based on MGH-ATRQ 
criteria) in the current episode of depression, and the subject is taking a different oral 
antidepressant treatment(s) (on the MGH-ATRQ) for at least the previous 2 weeks at or above 
the minimum therapeutic dose. This antidepressant treatment, as well as any other ongoing 
medications being taken for depression at screening (including adjunctive and augmentation 
therapies), will continue from the start of Week 1 through the end of Week 4 of the 
screening/prospective observational phase. Dose adjustment is permitted per clinical judgment, 
but the oral antidepressant treatment is to remain at or above the minimum therapeutic dose (per 
the MGH-ATRQ) through the end of Week 4.
After 4 weeks, subjects who are non-responders to their current oral antidepressant treatment 
may be eligible to proceed to the double-blind induction phase. Non-response at the end of the 
screening/prospective observational phase is defined as ≤25% improvement in the MADRS total 
score from Week 1 to Week 4 and a MADRS total score of ≥24 on Week 2 and Week 4.
Eligible subjects who are entering the double-blind induction phase will discontinue all of their 
current medication(s) being used for depression treatment, including adjunctive/augmentation 
therapies. Of note, subjects taking benzodiazepines (at dosages equal to or less than the 
equivalent of 6 mg/day of lorazepam) and/or permitted non-benzodiazepine sleep medications 
(eg, zolpidem, zaleplon) during the screening/prospective observational phase, can continue 
these medications, but no dose increases beyond the equivalent of 6 mg/day of lorazepam or new 
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benzodiazepine medications are permitted during the screening/prospective observational phase. 
If clinically indicated, a subject’s current antidepressant treatment(s) may be tapered and 
discontinued over an additional, optional period of up to 3 weeks per the local prescribing 
information or clinical judgment. This 3 week period may also be used to optimize medical 
management if needed to facilitate subject participation (e.g., treatment of blood pressure or 
diabetes, wean from other medications, etc.). In such cases, if there is no planned taper, the oral 
regimen should be continued in the interim and then discontinued by Day 1 of the double-blind 
induction phase.
As a new oral antidepressant will be initiated on Day 1 of the double-blind induction phase, 
eligible subjects who do not require a tapered discontinuation of their antidepressant treatment(s) 
can proceed immediately into the double-blind induction phase.
Double-blind induction phase (4-week duration)
Approximately 148 subjects will be randomly assigned at a 1:1 ratio (n=74 subjects per treatment 
arm) to receive double-blind treatment with either intranasal esketamine or intranasal placebo. 
The intranasal treatment sessions (esketamine or placebo) will occur twice weekly. In addition, 
all subjects will initiate a new open-label oral antidepressant on Day 1 that will be taken daily for 
the duration of this phase. The assigned oral antidepressant will be 1 of 4 oral antidepressant 
medications (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]), that the 
subject has not previously had a nonresponse to in the current depressive episode, has not been 
previously intolerant to (lifetime), and is available in the participating country.
Subjects who were taking benzodiazepines (at dosages equal to or less than the equivalent of 
6 mg/day of lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem, 
zaleplon) during the screening/prospective observational phase can continue these medications 
during the induction phase. No dose increases beyond the equivalent of 6 mg/day of lorazepam 
or new benzodiazepine medications are permitted during the induction phase, with the exception 
of the use of permitted benzodiazepine rescue medication.
At the end of the induction phase, regardless of response status, subjects may be eligible to 
participate in the subsequent study ESKETINTRD3004 if they meet all other study entry criteria 
(ESKETINTRD3004 is a longer-term open-label safety study involving repeated treatment 
sessions of intranasal esketamine). 
If a subject withdraws from the study before the end of the double-blind induction phase for 
reasons other than withdrawal of consent, an Early Withdrawal visit should be conducted within 
1 week of the date of discontinuation, followed by the follow-up phase.
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Follow-up phase (2-week duration)
This phase will include all subjects who are not eligible or who choose to not participate in the 
subsequent ESKETINTRD3004 safety study, and have received at least 1 dose of intranasal 
study medication in the double-blind induction phase. There will be no intranasal treatment 
administered during this phase.
At the start of the follow-up phase, further clinical/standard of care for the treatment of 
depression will be arranged by the study investigator and/or the subject’s treating physician. All 
subjects will be provided with an additional 2-week supply of the oral antidepressant medication 
to ensure that there is no interruption of oral antidepressant therapy during the transition to 
further clinical/standard of care. The decision to continue the oral antidepressant in this phase 
will be at the discretion of the investigator, however, in order to better assess potential 
withdrawal symptoms from intranasal study medication, the oral antidepressant medication 
should be continued for the 2 weeks of the follow-up phase unless determined as not clinically 
appropriate.
Taking into consideration the up to 3-week optional taper period, the duration of a subject’s 
study participation will be 8 to 11 weeks (for subjects continuing into ESKETINTRD3004) or 
13 weeks (for subjects completing the follow-up phase).
A diagram of the study design is provided in Figure 1. 
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Figure 1:
Study Design for ESKETINTRD3005
* followed by optional, up to 3 week Taper if clinically indicated. 
AD=antidepressant. DB=double-blind. D/C=discontinued. Esk=Esketamine. MDD=major depressive disorder. 
OL=open-label. PBO=placebo. 
Note: Subjects who withdraw early from the double-blind induction phase and receive at least 1 dose of intranasal 
study medication in the double-blind induction phase will have an Early Withdrawal visit performed and then 
proceed into the follow-up phase. 
1.3.
Statistical Hypotheses for Trial Objectives
The hypothesis for this study is that, in elderly subjects with TRD, switching from a failed 
antidepressant treatment to intranasal esketamine plus a newly initiated oral antidepressant is 
superior to switching to a newly initiated oral antidepressant treatment (active comparator) plus 
intranasal placebo in improving depressive symptoms.
1.4.
Sample Size Justification
The maximum sample size planned for this study was calculated assuming a treatment difference 
for the double-blind induction phase of 6.5 points in MADRS total score between esketamine 
and the active comparator, a standard deviation of 12, a 1-sided significance level of 0.025, and a 
drop-out rate of 25%. A maximum of about 74 subjects will need to be randomized to each 
treatment group to achieve 80% power using a fixed design with no interim analysis. The 
treatment difference and standard deviation used in this calculation were based on results of 
Panel A of the ESKETINTRD2003 study and on clinical judgment.
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As detailed below, an interim analysis is planned to re-estimate sample size or to stop the study 
due to futility.
1.5.
Interim Analysis for Sample Size Re-Estimation or Stopping for Futility
One unblinded interim analysis will be performed 4 weeks after randomizing 50 subjects in the 
study (approximately 25 per treatment group). It is projected that at that time approximately 
36 subjects in the full analysis set would have completed the double-blind induction phase of the 
study (approximately 18 subjects per treatment group). The dropout rate will be monitored to 
ensure a sufficient number of subjects are included in the interim analysis. As the assumptions of 
the expected treatment difference and variability may or may not be upheld, the purpose of the 
interim analysis is to either re-estimate sample size or to stop the study due to futility. The 
sample size may be adjusted to achieve the desired power while maintaining control of the 
overall Type I error. The maximum sample size planned for this study is 74 subjects per 
treatment group.
A separate rigorous interim analysis statistical analysis plan (SAP) and charter will be developed 
detailing the algorithm for a sample size re-estimation based on the interim data and how the 
analysis will be executed. An Independent Data Monitoring Committee (IDMC) will perform the 
interim analysis and will make recommendations for any sample size adjustment based on the 
rules defined in the interim SAP. Any changes to sample size will be communicated by the 
IDMC (or the statistician from the Statistical Support Group) to the IWRS vendor to ensure that 
the appropriate number of subjects is enrolled in the study. None of the esketamine team 
members or staff members at the investigational sites conducting the clinical study will be 
informed of the results of the interim analysis and any adjustments that will be made to the 
sample size; however, the clinical supplies group will be informed of the decision made at the 
interim analysis so that only the required amount of study medication will be packaged.
Procedures will be in place to ensure that the results of the interim analysis do not influence the 
conduct of the study, investigators, or subjects.
1.6.
Randomization and Blinding
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups. 
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups (placebo or flexible dose esketamine) in a 1:1 ratio based on a computer-
generated randomization schedule prepared before the study under the supervision of the 
sponsor. The randomization will be balanced by using randomly permuted blocks and will be 
stratified by country and class of oral antidepressant (SNRI or SSRI) to be initiated in the 
double-blind induction phase. The interactive web response system (IWRS) will assign a unique 
treatment code, which will dictate the treatment assignment and matching study drug kits for the 
subject. 
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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 (e.g., study drug plasma 
concentrations, study drug accountability data) will be handled with special care to ensure that 
the integrity of the blind is maintained and the potential for bias is minimized. 
An intranasal placebo control will be used in the double-blind induction phase to establish the 
frequency and magnitude of changes in clinical endpoints that may occur in the absence of 
intranasal active treatment. Blinded intranasal treatment will be used to reduce potential bias 
during data collection and evaluation of clinical endpoints.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Pooling Algorithm
A total of 15 countries (Brazil, Belgium, France, Poland, Spain, US, Italy, South Africa, United 
Kingdom, Sweden, Australia, Bulgaria, Finland, Lithuania, Republic of Korea) are to enroll 
subjects.  Due to low enrollment in some countries, countries would be pooled by region: North 
America, Europe and Other. Region will be used as a factor in the statistical models to analyze 
efficacy to account for region variability.
2.2.
Analysis Phases
There are 2 analysis phases defined in this study: Double-Blind Induction and Follow-up (post 
treatment). Each analysis phase has its own analysis phase start and end dates.
2.2.1.
Study Reference Start and End Dates
The reference start date for the study is defined as the earlier date of the first dose of intranasal 
study drug, or the oral antidepressant study drug (the date is missing for screened subjects who 
did not take any intranasal study drug or oral antidepressant study drug). The reference end date 
for the study is the end of trial date including the last follow-up visit.
2.2.2.
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 earlier of 
date of the first dose of intranasal study medication, or the oral antidepressant 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. If no intranasal 
study medication is administered or it is administered after the start of oral antidepressant, then 
the time will be left blank.
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Follow-up Phase
The start date of the follow-up phase (referred to as ‘F/U start date’) is the day after the DB end 
date. The follow-up phase end date (referred to as ‘F/U end date’) is the maximum of the last 
follow-up visit date or end of trial date.
2.2.3.
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 double-blind 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.
2.3.
Baseline and End Point
Baseline is defined as the last observation before receiving the first dose of any study medication 
in the double-blind induction phase. Baseline is defined for each parameter/assessment.
The double-blind end point value will be the final post baseline value assessed during the 
double-blind induction phase. 
2.4.
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 any 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.
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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).
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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)
MADRS
Screening
Week 1 (SC)
Week 2 (SC)
Week 4 (SC)
DB
1
Baseline
≤1
1
8
Day 8
2-11
8
15
Day 15
12-18
15
22
Day 22
19-24
22
28
Day 28
25 to end of DB
28
DB final visit
End Point (DB)
2 to end of DB
Follow-up
7
Week 1(F/U)
1 to 10
7
14
Week 2(F/U)
11 to end of F/U
14
F/U final visit
End Point (F/U)
1 to end of F/U
PHQ-9
Screening
Week 1 (SC)
DB 
1
Baseline
≤1
1
15
Day 15
2-21
15
28
Day 28
22 to end of DB
28
DB final visit
End Point (DB)
2 to end of DB
Follow-up
14
Week 2 (F/U) 
1 to end of F/U 
14
SDS
Screening
Week 1 (SC)
DB
1
Baseline
≤1
1
15
Day 15
2-21
15
28
Day 28
22 to end of DB
28
DB final visit
End Point (DB)
2 to end of DB
Follow-up
14
Week 2 (F/U) 
1 to end of F/U 
14
CGI-S
Screening
Week 1 (SC)
DB
1
Baseline
≤1
1
4
Day 4
2-6
4
8
Day 8
7-9
8
11
Day 11
10-13
11
15
Day 15
14-16
15
18
Day 18
17-20
18
22
Day 22
21-23
22
25
Day 25
24-26
25
28
Day 28
27 to end of DB
28
DB final visit
End Point (DB)
2 to end of DB
Follow-up
14
Week 2 (F/U) 
1 to end of F/U 
14
EQ-5D-5L, 
EQ-VAS and 
Health Status 
Index
Screening
Week 1 (SC)
DB
1
Baseline
≤1
1
15
Day 15
2-21
15
28
Day 28
22 to end of DB
28
DB final visit
End Point (DB)
2 to end of DB
Follow-up
14
Week 2 (F/U) 
1 to end of F/U 
14
Vital Signs 
(TEMP 
[predose at 
each visit], 
BPb, HR, 
RESP [at each 
visit, predose, 
40M, 1H, 
1.5H])
DB
1
Day 1:
Predose
Day 1: 40M
Day 1: 1H
Day 1: 1H30M
≤ 1 / predose 
1
4
Day 4: Predose
Day 4: 40M
Day 4: 1H
Day 4: 1H30M
2-6
4
8
Day 8: Predose
Day 8: 40M
Day 8: 1H
7-9
8
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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)
Day 8: 1H30M
11
Day 11: Predose
Day 11: 40M
Day 11: 1H
Day 11: 1H30M
10-13
11
15
Day 15: Predose
Day 15: 40M
Day 15: 1H
Day 15: 1H30M
14-16
15
18
Day 18: Predose
Day 18: 40M
Day 18: 1H
Day 18: 1H30M
17-20
18
22
Day 22: Predose
Day 22: 40M
Day 22: 1H
Day 22: 1H30M
21-23
22
25
Day 25: Predose
Day 25: 40M
Day 25: 1H
Day 25: 1H30M
24 to end of DB
25
DB final visit
End Point (DB)
Day 1: 40M to end 
of DB
Follow-up
14
Week 2 (F/U)
1 to end of F/U
14
Weight and 
BMI
DB
Screening, 1
Baseline
≤ 1 / predose
1
28
Day 28
2 to end of DB
28
DB final visit
End Point (DB)
2 to end of DB
ECG
DB
Screening, 1
Average Predose
≤ 1 / predose
1
1
Day 1: 1H
1
1
4
Day 4: 1H
2-6
4
8
Day 8: 1H
7-9
8
11
Day 11: 1H
10-13
11
15
Day 15: 1H
14-16
15
18
Day 18: 1H
17-20
18
22
Day 22: 1H
21-23
22
25
Day 25: 1H
24 to end of DB
25
DB final visit
End Point (DB)
1 to end of DB
Follow-up
14
Week 2 (F/U)
1 to end of F/U
14
Lab
DB
Screening, 1
Baseline
≤ 1 / predose
1
28
Day 28
1 to end of DB
28
DB final visit
End Point (DB)
1 to end of DB
Follow-up
14
Week 2 (F/U)
1 to end of F/U
14
C-SSRS
Screening
Week 1 (SC)
Week 2 (SC)
Week 4 (SC)
DB
1
Baseline
≤1
1
4
Day 4
2-6
4
8
Day 8
7-9
8
11
Day 11
10-13
11
15
Day 15
14-16
15
18
Day 18
17-20
18
22
Day 22
21-23
22
25
Day 25
24-26
25
28
Day 28
27 to end of DB
28
DB final visit
End Point (DB)
2 to end of DB
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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)
Follow-up
14
Week 2 (F/U)
1 to end of F/U
14
MOAA/Sc
Oxygen 
Saturationd
(predose and 
every 
15 minutes to 
1.5H)
BPRS+ and 
CADSS 
(predose, 40M, 
1.5H)
CGADRe (1H, 
1.5H)
DB
1
Day 1
1
1
4
Day 4
2-6
4
8
Day 8
7-9
8
11
Day 11
10-13
11
15
Day 15
14-16
15
18
Day 18
17-20
18
22
Day 22
21-23
22
25
Day 25
24 to end of DB
25
PWC-20
DB
25
Day 25
2 to end of DB
25
Follow-up
7
Week 1 (F/U)
1 to 10
7
14
Week 2 (F/U)
11 to end of F/U
14
Nasal exam
DB
1
Baseline
1
1
28
Day 28
2 to end of DB
28
DB final visit
End Point (DB)
2 to end of DB
Follow-up
14
Week 2 (F/U)
1 to end of F/U
14
Nasal 
questionnaire
DB
1
Baseline
1
1
4
Day 4
2-7
4
11
Day 11
8-14
11
18
Day 18
15-21
18
25
Day 25
22 to end of DB
25
DB final visit
End Point (DB)
2 to end of DB
BPIC-SS
DB
1
Baseline
1
1
15
Day 15
2-21
15
28
Day 28
22 to end of DB
28
DB final visit
End Point (DB)
2 to end of DB
Follow-up
14
Week 2 (F/U)
1 to end of F/U
14
UPSIT
Screening
Week 2 (SC)
DB
28
Day 28
2 to end of DB
28
DB final visit
End Point (DB)
2 to end of DB
Cogstate / 
HVLT-R
DB
1
Baseline
1
1
28
Day 28
2 to end of DB
28
Follow-up
14
Week 2 (F/U)
1 to end of F/U
14
a
For DB phase, time interval is relative to the first day of the double-blind induction phase.
For follow-up phase, time interval is relative to the first day of the follow-up 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 <100 or investigator’s clinical judgment the subject it is clinical stable and 
can be discharged from the clinical site.
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.
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2.5.
Analysis Sets
Subjects will be classified into the following analysis sets: all randomized, full, safety and 
follow-up. Due to Good Clinical Practice (GCP) issues, 
 will not be included 
in any of the analysis sets.  However, data for this site will be presented in listings.
2.5.1.
All Randomized Analysis Set
This analysis set will include all subjects who were randomized (i.e., subjects who reported a 
randomization date, or were assigned a randomization number) regardless of whether or not 
treatment was received. This analysis set will be used for summarizing the overall study 
completion/withdrawal information.
2.5.2.
Full Analysis Set
The efficacy analyses of data in the double-blind induction phase will be based on the full 
analysis set. The full analysis set is defined as all randomized subjects who received at least 
1 dose of intranasal study medication and 1 dose of oral antidepressant medication during the 
double-blind induction phase.
2.5.3.
Safety Analysis Set
The safety analysis set is defined for the double-blind induction phase. The safety analysis set
includes all randomized subjects who received at least 1 dose of intranasal study medication or
1 dose of oral antidepressant medication during the double-blind induction phase. Analyses of 
change from baseline will include only subjects who have both baseline and at least 1 post-
baseline observation during that phase. Screen failures and randomized subjects who received no 
double-blind study medication will be excluded from the safety analysis set. Subjects who 
received an incorrect treatment will be analyzed under the planned treatment.
2.5.4.
Follow-up Analysis Set
The Follow-up analysis set is defined as all subjects who enter the follow-up phase. This analysis 
set will be used for both efficacy and safety analyses.
2.6.
Definition of Subgroups
Analyses will be provided for the primary endpoint, change from baseline in MADRS total 
score, using the following subgroups.

Sex

Race (White, Black, Other)

Age Group (65-74 years, ≥75 years)

Region (North America, Europe, Other)

Country (Brazil, Belgium, France, Poland, Spain, US, Italy, South Africa, United Kingdom, 
Sweden, Australia, Bulgaria, Finland, Lithuania, Republic of Korea)

Number of Previous Treatment Failures in Current Episode (based on ATRQ)
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
Baseline MADRS total score (</> median)

Class of antidepressant study medication (SNRI or SSRI)
2.7.
Imputation Rules for Missing AE Dates
Treatment-emergent adverse events (TEAEs) for the double-blind induction phase are those 
events with an onset date/time on or after the start of study medication, and occurred on or before 
the end of the double-blind phase. Adverse events (AEs) for the follow-up phase are those events 
with an onset date on or after the start of the follow-up phase, and occurred on or before the end 
of the follow-up phase. A conservative approach will be used to handle the missing dates for 
adverse events.
Onset Date
If the onset date of an adverse event is missing day only, it will be set to:
i)
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
ii)
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
iii) 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 adverse event is missing both day and month, it will be set to the earliest 
of:
i)
January 1 of the year of onset, as long as this date is after the DB start date. 
ii)
One day after the DB start 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 DB start date.
Resolution Date
The missing day of resolution of an adverse event will be set to the last day of the month of 
resolution.
If the resolution date of an adverse event is missing both day and month, it will be set to earlier 
of the date of withdrawal, study completion, or December 31 of the year.
A completely missing resolution date of an adverse event that is not recorded as ongoing will be 
set to the date of withdrawal or study completion.
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2.8.
Imputation Rules for Missing AE time of Onset/Resolution
If the time of onset is missing, it will be imputed as follows:
(i)
00:00 if the date of onset is after DB start date
(ii) 00:00 if the date is the same as DB start date, but the intranasal study medication in 
the double-blind induction phase was started after the oral antidepressant medication 
in this phase
(iii) The time of intranasal medication start in the double-blind induction phase if the 
intranasal medication was started on or before the oral antidepressant medication in 
this 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.
2.9.
Imputation Rules for Missing Concomitant Medication Dates 
If a partial date is reported, it is assumed the medication (or therapy) was taken in all phases that 
overlap with the partial date. If both start and end dates are missing but this concomitant 
medication was taken both prior to the study entry and still ongoing at study end, it is assumed 
medication was taken in all phases.
The rules for estimating an incomplete concomitant medication start date are as follows:
If the month of the concomitant medication start date is equal to the month of the start of the 
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.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
An IDMC will be established to monitor data on an ongoing basis to ensure the continuing safety 
of the subjects enrolled in this study. In addition, the committee will review 1 interim analysis 
for sample size re-estimation. The committee will meet every 6 months to review safety data and 
will meet once to review efficacy data after the interim analysis has been completed. After the 
reviews, the IDMC will make recommendations to the team regarding the continuation of the 
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study, or, in the case of the interim analysis for efficacy, to either stop the study due to futility or 
to adjust the sample size to achieve the desired power while maintaining control of the overall 
Type I error. Recommendation of adjustment to sample size will be relayed only to the IWRS 
vendor and to clinical supplies.
To protect the integrity of the clinical study, the IDMC members (medical and statistical experts) 
are not study team personnel or otherwise directly involved in the study conduct, data 
management, or statistical analysis for the study. Details about the review to be performed and 
the roles and responsibilities of the IDMC are presented in a separate IDMC charter.
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Demographic and baseline characteristics (Table 2) and psychiatric history at baseline (Table 3) 
will be summarized by treatment group for the Safety and Full analysis sets. 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.
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 (65-74, 75)

Sex (male, female)

Racea (White, Black or African American, Asian, American Indian or Alaskan 
native, Native Hawaiian or other Pacific islander, other)

Ethnicity (Hispanic or Latino, not Hispanic or Latino)

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)

Hypertension Status

Class of antidepressant (SSRI/SNRI)

Oral antidepressant

Country

Region
a If multiple race categories are indicated, then Race is recorded as “Multiple”.
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Table 3:
Psychiatric History at Baseline Variables
Continuous Variables:

Baseline MADRS total score

Screening IDS-C30 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)

Antidepressant treatment history (number of medications taken for at least 2 weeks 
during the current episode as obtained in the MGH-ATRQ) 

Family history of
-
Depression
-
Anxiety Disorder
-
Bipolar Disorder
-
Schizophrenia
-
Alcohol Abuse
-
Substance Abuse
4.2.
Disposition Information
The distribution of the number of subjects who are randomized, receive double-blind treatment, 
and complete the double-blind induction phase will be presented by treatment group. In addition, 
the distribution of reasons for discontinuation will be presented. These summaries will be 
provided for the All Randomized and Safety analysis sets. 
A subject will be considered to have completed the double-blind induction phase if he or she has 
completed the MADRS assessment at the end of the 4-week double-blind induction phase (ie 
Day 28 MADRS). 
The distribution of the number of subjects who enter the follow-up phase and complete all 
follow-up visits will be presented by treatment group and overall. The reasons for 
discontinuation will be presented. In addition, the number of subjects who enroll in study 
ESKETINTRD3004 will be provided. 
A subject will be considered to have completed the follow-up phase if he or she has completed 
the MADRS assessment at Week 2 of the follow-up phase.
4.3.
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 for the Full analysis set and the Safety analysis 
set.
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The total duration of exposure for the intranasal study drug and for each type of oral 
antidepressant (AD) during the double-blind induction phase is defined as the time between the 
first and the last dose of each type of study medication. 
Descriptive statistics (N, mean, SD, median, minimum and maximum) of total duration of 
exposure of intranasal study drug will be presented. The total duration of intranasal study drug 
exposure in the double-blind 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 during the double-blind induction 
phase will be presented. A frequency distribution of dose level will be presented for each dosing 
session. The total duration of exposure of oral AD will be summarized similarly to the intranasal 
study drug, however the following categories will be used for the double-blind induction phase: 
7 days, 8-14 days, 15-21 days, 22-28 days, >28 days, and the following categories will be used 
for the follow-up phase: 7 days, >7 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. Mean dose of 
a subject is calculated as the sum of doses during the double-blind phase divided by the total 
number of days exposed. The final dose is the last non-zero dose received during the double-
blind 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. Doses of oral AD will be summarized using 
descriptive statistics of the mean dose (days on drug), mode dose (days on drug) and the final 
dose, by each type of oral AD for both the double-blind induction and follow-up phases. In 
addition, percent compliance of the oral AD calculated as days actually dosed/days expected to 
be dosed*100, will be summarized.
4.4.
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, non-compliance, regulatory requirement. 
More categories may be included depending on the nature of the protocol deviation.
4.5.
Prior and Concomitant Medications
Antidepressant medications taken prior to the baseline visit will be summarized by treatment 
group for the Safety analysis set.
The number and percent of subjects who receive concomitant therapies will be summarized by 
treatment group and phase using the generic term of the medication for the Safety analysis set 
and for the Follow-Up analysis set. 
5.
EFFICACY
The efficacy variables for this study are listed in Table 4.
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Table 4:
Efficacy Variables
Endpoint
MADRS
Change in MADRS from Baseline to Day 28 or End Point (DB)
Primary
Response rates over time (at least 50% improvement from baseline)
Secondary
Remission rates over time (MADRS≤12)
Secondary
CGI-S
Change in CGI-S from Baseline to End Point (DB)
Secondary
EQ-5D-5L, EQ-VAS
and health status
index
Change from Baseline to End Point (DB)
Secondary
SDS†
N/A
PHQ-9†
N/A
†:  SDS and PHQ-9 were efficacy variables collected prior to Protocol Amendment 3 but are no longer in the current 
protocol (Protocol Amendment 3).
5.1.
Analysis Specifications
5.1.1.
Level of Significance
Statistical analysis tests will be conducted at a 1-sided 0.025 level of significance unless 
specified otherwise. One unblinded interim analysis will be performed with the purpose of either 
re-estimating the sample size or stopping the study for futility.
To adjust for the interim analysis, the primary endpoint will be analyzed using a weighted 
combination test as described in Section 5.2.3. 
5.1.2.
Data Handling Rules
For endpoints using analysis of covariance (ANCOVA), the last observation carried forward 
(LOCF) method will be applied to the MADRS total score and CGI-S for the double-blind 
induction phase. 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 post-baseline time points as 
well. These imputed time points will be labeled ‘DAY X LOCF’.
5.1.3.
Imputation Methods for Missing Items
Imputation of the MADRS total score is described in Section 5.2.1. For all other scales where 
multiple items are summed to create a total, if any item of the scale is missing at a visit, the total 
score for that scale at that visit will be left blank.
5.2.
Primary Efficacy Endpoint
5.2.1.
Definition
The primary efficacy endpoint is the change in MADRS total score from Day 1 to Day 28. The 
MADRS is a clinician-rated scale designed to measure depression severity and to detect changes 
due to antidepressant treatment9. 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 
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evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, 
lassitude, interest level, pessimistic thoughts, and suicidal thoughts. The test exhibits high 
inter-rater reliability.
If 2 or more items are missing, no imputation will be performed and the total score will be left 
missing. Otherwise, the total score will be calculated as sum of the non-missing items multiplied 
by the ratio of the maximum number of items (i.e., 10) to the number of non-missing items.
5.2.2.
Primary Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is 
defined by the following 3 components:
Population: elderly subjects with treatment-resistant depression
Endpoint: change from baseline to Day 28 in the MADRS total score (see previous section)
Measure of Intervention: the effect of the initially randomized treatment together with the oral 
AD that would have been observed had all subjects remained on their treatment throughout the 
DB induction phase. 
The primary analysis will be based on the full analysis set, as described in Section 2.4.2, and the 
MADRS total scores collected during the DB induction phase.
5.2.3.
Analysis Methods
MMRM
With the exception of the European Union (EU) dossier, 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 Measures (MMRM) based on observed case 
data. The MMRM analysis will be performed for each stage (Stage 1-all data collected on 
subjects used for sample size re-estimation at the interim analysis and Stage 2-all data collected
on the remaining subjects). The models will include baseline MADRS total score as a covariate, 
and treatment, region, class of antidepressant (SNRI or SSRI), day (see Table 1), and day-by-
treatment interaction as fixed effects. The within-subject covariance between visits will be 
estimated via an unstructured variance-covariance matrix. In case of convergence problems,
alternative variance-covariance structures will be tried in the following order, with the first 
structure that converges being used in the analysis: heterogeneous Toeplitz; standard Toeplitz; 
and AR(1) with separate subject random effect. Comparison of the esketamine plus oral 
antidepressant arm versus oral antidepressant plus intranasal placebo will be performed using the 
appropriate contrast.
ANCOVA
For the EU dossier, the primary efficacy analysis will be based on an analysis of covariance 
(ANCOVA) model using change from baseline to Day 28 based on LOCF data. The ANCOVA 
analysis will be performed for each stage separately (Stage 1- all data collected on subjects used 
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for sample size re-estimation at the interim analysis and Stage 2-all data collected on the 
remaining subjects). The models will include factors for treatment, region, and class of oral 
antidepressant (SNRI or SSRI) and baseline MADRS total score as a covariate. 
Weighted Combination Test
To account for sample size reassessment, the weighted combination test will be used for the
comparison of interest. The combination test will be defined by an approach described in 
Lehmacher et al8(also Cui et al3.) which defines the test statistics as a weighted sum of the 
Stage 1 (before the interim analysis) and Stage 2 (after the interim analysis) test statistics. The 
two stages will be weighted equally in the combination test. 
 = √0.5 ×  + √0.5 × 
where Z1 =Φ-1(1-p1) and Z2 = Φ-1(1-p2) denote the z-values corresponding to the one-sided 
stage-wise p-values p1 and p2, respectively, for the hypothesis of interest based on the MMRM or 
ANCOVA analysis of Stage 1 and Stage 2 data separately. The null hypothesis will be rejected 
for the large positive values of ZC.
The weighted combination test will be provided for both the MMRM comparisons for all 
dossiers with the exception of the EU and for the ANCOVA comparisons for the EU dossier.
The median-unbiased estimate will be used for point estimation for the treatment difference from 
placebo, refer to Brannath et al1. For example, let  and  denote the estimated treatment 
effects (difference from placebo) at Stage 1 and Stage 2, and SE() and SE() are the standard 
errors of the estimates obtained from Stage 1 and Stage 2, respectively. Using the pre-specified 
combination test weights w1 =√0.5 and w2= √0.5 the median-unbiased estimate of the treatment 
effect  is given by
 =

SE()  + 
 
SE() 

SE() + 
 
SE()
The two-sided flexible confidence interval at level (1-2α) will be symmetric about the median-
unbiased point estimator. In order to have a proper coverage probability in the design with SSR, 
the flexible confidence interval will be based on the duality of confidence intervals and 
hypothesis tests1. That is, for the parameter  of interest, the one-sided flexible interval with a 
coverage probability 1- α is defined by the set { : ZC<zα }. For analysis of the primary endpoint, 
the two-sided confidence interval for the treatment effect at level (1-2α) will be defined by
 −


SE +
 
SE()
,    +


SE() + 
 
SE()

where zα denotes the 100(1-α)-th percentile of the standard normal distribution.
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The median-unbiased estimate of the treatment effect and the corresponding confidence interval 
will be provided for both the MMRM comparisons for all dossiers with the exception of the EU 
and for the ANCOVA comparisons for the EU dossier.
For the MADRS total score, descriptive statistics of actual values and changes from baseline will 
be provided for observed case and LOCF data during the double-blind phase and for observed 
case data during the follow-up phase.
In addition, to explore the course of treatment effect over time, a standard ANCOVA (i.e. no 
adjustments for the sample size re-estimation) on both LOCF and observed case data will be 
performed for each scheduled assessment time point with factors for treatment, region, class of 
oral antidepressant (SNRI or SSRI) and baseline MADRS total score as a covariate. In addition, 
contrasts at each scheduled assessment time point based on the MMRM analysis will be 
provided.
Means (standard error [SE]), mean changes (SE) from baseline, and least square mean 
changes (SE) from baseline will be presented graphically for the double-blind induction phase
for the observed cases and separately for the LOCF evaluations.
Model Diagnostics
The normality and equal variance assumptions underlying both the primary MMRM and 
ANCOVA 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. 
Missing Data Sensitivity Analysis
The following table (Table 5) shows the assumptions of each considered analysis for the primary 
efficacy endpoint, all applied to the same full analysis set defined in Section 2.5.2:
Table 5:
Analysis Types and Assumptions
Analysis Type
Analysis Method
Assumption
Primary Analysis 
(non-EU)
MMRM 
Missing at Random – MAR
Primary Analysis 
(EU)
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 
Delta worsening adjustments applied to 
standard multiple imputation regression 
Efficacy scores worsen after study discontinuation 
To evaluate the robustness of the MMRM analysis to increasing deviations from the MAR 
assumption, a delta adjustment multiple imputation method will be used for sensitivity analysis. 
This type of method is regarded to be an informative sensitivity analysis in clinical trials
(2010 National Research Council report on missing data10 and T Permutt11).
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This method will employ the following 3 steps:
Step 1 – Multiple Imputation (MI)
Note: Most missing data will be a result of subjects dropping out of the study and having 
observations at every scheduled visit up to the point they dropped but no observations thereafter. 
This is a monotone missing data pattern. Some subjects may have ‘’intermediate missing’ data 
between non-missing observations. This is a non-monotone missing data pattern.
If there are subjects with a non-monotone missing data pattern, datasets with only monotone 
missing data patterns will be created first by imputing the intermediate missing values using the 
MCMC (Markov Chain Monte Carlo) method. This will be done using SAS PROC MI and the 
MCMC statement with the following specifications:
PROC MI DATA=INPUT NIMPUTE=500 SEED=234 OUT=IN_MCMC;
VAR …; (treatment group, region, class of antidepressant (SNRI or SSRI), and the 
preceding non-missing values in the order of clinical visits: baseline, Day 2, Day 8, Day 15, 
Day 22 and Day 28)
MCMC CHAIN=SINGLE NBITER=200 NITER=100 IMPUTE=MONOTONE;
RUN;
Note: Graphical diagnostic tools available in the MCMC statement (TIMEPLOT(WLF) and 
ACFPLOT(WLF)) will be used to assess if convergence has not been achieved.
If all subjects have a monotone missing data pattern (either directly from the study or created by 
the previous step), the MAR-based multiple imputation with the regression option will be used to 
impute missing values. This analysis will be performed using SAS PROC MI with the 
MONOTONE statement and the REGRESSION option with the following specifications:
PROC MI DATA=IN_MCMC NIMPUTE=1 (see note) SEED=234 OUT=OUTPUT;
VAR …; (treatment group, region, class of antidepressant (SNRI or SSRI), and the 
preceding non-missing values in the order of clinical visits: baseline, Day 2, Day 8, Day 15, 
Day 22 and Day 28)
CLASS…; (treatment group, region, class of antidepressant (SNRI or SSRI))
MONOTONE REGRESSION;
RUN;
Note: NIMPUTE=500 if MCMC was NOT applied at the previous step.
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Step 2 – Delta Adjustments
The imputed values for subjects who discontinued will be adjusted by adding  to the imputed 
values for subjects randomized to placebo and adding  to the imputed values for subjects 
randomized to an active esketamine arm. Delta-adjusted fully imputed datasets will be generated 
for different combinations of  and  values as defined below:

 = 0 and  = 0  ! Δ
∗ in increments of 1 (active-only adjustment analysis)

 = /2 and  = 0  ! Δ
∗ in increments of 1 (analysis with a control adjustment that is 
half of the active adjustment)

 =  = 0  ! Δ&
∗in increments of 1 (all arms adjustment analysis).
Adding positive values results in higher (worse) scores. Δ
∗, Δ
∗ and Δ&
∗represent the adjustments 
leading to the ‘tipping point’, so the smallest delta adjustments values at which conclusions 
change from favorable to drug (i.e. statistically significant: one-sided p-value ≥0.025, with the p-
value associated to the weighted combination test described above; see note below on delta 
adjustment and combination test) to unfavorable (acceptance of the null hypothesis of no 
treatment difference).
Step 3 – Analysis and Pooling
For each (, ) combination:

Same MMRM as described for the primary efficacy analysis will be performed for each set 
of the adjusted fully imputed datasets;

Multiple imputation combining rules in PROC MIANALYZE will be applied to the MMRM 
results from the imputed datasets to produce final inferences. 
Between-group comparisons to placebo at Day 28 (e.g. p-values, point estimates for treatment 
difference) will be displayed graphically for each considered (, ) combination, up to the 
‘tipping point’ adjustment. 
Note - Delta Adjustment and the Combination Test: Due to the interim analysis, a weighted 
combination test will be used for each comparison of interest as presented in the previous 
section. Each (, ) delta adjustment as described above in Steps 1-3 will be applied first to 
each of the 2 stages and then the combination test will be applied to produce the p-value 
corresponding to this delta adjustment.
The delta adjustment MI method as described above will be applied to all subjects who 
discontinued from the DB induction phase and have missing efficacy scores in this phase. In 
addition, another version of this method will be applied. In this version, the delta adjustments 
from Step 2 will be applied to all subjects who discontinued, except those with a discontinuation 
reason that was not considered related to the study drug, including Lost to Follow-Up, 
Withdrawal by Subject or Other. A process is in place to obtain clarification on reasons of 
Withdrawal by Subject and Other to confirm they are not related to the study drug.
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Subgroup Analysis
Forest plots will be provided displaying analysis results for each subgroup listed in Section 2.6. 
The point estimate of the treatment difference and its 95% confidence interval for each subgroup 
will be based on an MMRM analysis for the primary endpoint using the appropriate contrast. The 
model will include baseline MADRS total score as a covariate, and treatment, region, class of 
antidepressant (SNRI or SSRI), day, subgroup, day-by-treatment interaction, treatment-by-
subgroup and day-by-treatment-by-subgroup interaction as fixed effects. A similar forest plot 
will be provided using an ANCOVA analysis. The model will include factors for treatment, 
region, class of oral antidepressant (SNRI or SSRI), subgroup, treatment-by-subgroup and 
baseline MADRS total score as a covariate. The terms in the models (both ANCOVA and 
MMRM) will be adjusted for the subgroup of country and baseline MADRS total score 
(≤/>median). Region will not be included as a term when country is included in the model and 
baseline MADRS total score (as a continuous covariate) will not be included in the model when 
the dichotomized baseline MADRS total score is included in the model.
5.3.
Other Efficacy Variables
5.3.1.
Responders
5.3.1.1.
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 (e.g., percent change ≤-50% indicates 
improvement ≥50%).
A subject is defined a responder (yes=1 and no=0) at a given time point if the percent 
improvement in MADRS total score is ≥50%. 
5.3.1.2.
Analysis Methods
The proportion of subjects who achieve a response will be summarized at each time point during 
the double-blind induction phase for both observed case and LOCF data. The proportion of 
subjects who achieve a response will be also be summarized by class of antidepressant study 
medication (SNRI or SSRI) at each time point.
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.
Response rates at Week 2 of the follow-up phase will also be summarized.
The cumulative distribution function of the time to sustained response will be estimated by the 
Kaplan-Meier method. Time to sustained response will be summarized (number of sustained 
responders, number of censored subjects, median, 25th and 75th percentile, if estimable) by 
treatment group. Sustained response is defined as the first occurrence of response that is 
maintained through the Day 28 assessment. Subjects who discontinue early are not considered to 
have sustained response.
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5.3.2.
Remitters
5.3.2.1.
Definition
Subjects who have a MADRS total score of ≤ 12 will be considered remitters.
5.3.2.2.
Analysis Methods
The proportion of subjects who achieve remission will be summarized at each time point during 
the double-blind induction phase for both observed case and LOCF data. The proportion of 
subjects who achieve remission will be also be summarized by class of antidepressant study 
medication (SNRI or SSRI) at each time point.
The number and percentage of subjects meeting criteria for remission will also be provided at 
Week 2 of the follow-up phase.
The cumulative distribution function of the time to sustained remission will be estimated by the 
Kaplan-Meier method. Time to sustained remission will be summarized (number of sustained 
responders, number of censored subjects, median, 25th and 75th percentile, if estimable) by 
treatment group. Sustained remission is defined as the first occurrence of remission that is 
maintained through the Day 28 assessment. Subjects who discontinue early are not considered to 
have sustained remission.
5.3.3.
CGI-S
5.3.3.1.
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 function6. The 
CGI-S evaluates the severity of psychopathology on a scale of 0 to 7. Considering total clinical 
experience, a subject is assessed on severity of mental illness at the time of rating according to: 
0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately 
ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. The CGI-S permits a 
global evaluation of the subject’s condition at a given time.
5.3.3.2.
Analysis Methods
Descriptive statistics of actual values and changes from baseline by treatment group will be 
provided for observed case and LOCF data. Frequency distributions will be provided at each 
assessment time point during the double-blind and follow-up phases.
The ranks of the change from baseline for the CGI-S score in the double-blind induction phase 
will be analyzed at each time point based on observed case and LOCF data using an ANCOVA 
model, with treatment, region and class of antidepressant (SNRI or SSRI) as factors, and 
unranked baseline score as the covariate.
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5.3.4.
EuroQol Group; 5 Dimension; 5 Level (EQ-5D-5L)
5.3.4.1.
Definition
The EQ-5D-5L (EuroQol Group - 5 Dimension - 5 Level4,5) is a standardized 2-part instrument 
for use as a measure of health outcome, primarily designed for self-completion by respondents. It 
essentially consists of the EQ-5D-5L descriptive system and the EQ visual analogue scale 
(EQ VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is 
divided into 5 levels of perceived problems (Level 1 indicating no problem, Level 2 indicating 
slight problems, Level 3 indicating moderate problems, Level 4 indicating severe problems, and 
Level 5 indicating extreme problems).
The subject selects an answer for each of the 5 dimensions considering the response that best 
matches his or her health “today.” The descriptive system can be represented as a health state. 
The EQ VAS self-rating records the respondent’s own assessment of his or her overall health 
status at the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the 
best health you can imagine). 
The time taken to complete the questionnaire varies with age, health status, and setting but is 
likely to be around 1 minute.
Individual scores from the 5 dimensions will be used to obtain a weighted health status index as 
shown below: 
(i)
Scores from each dimension will be combined to obtain a 5L profile score or health 
state: eg, a score of 1 for each dimension will give a 5L profile score of 11111. 
Dimension scores will be combined in the following order: Mobility, Self-Care, 
Usual Activities, Pain/Discomfort, Anxiety/Depression
(ii)
The value set of the Health Status Index for various values of 5L profile scores is 
published for Canada in the following website: 
https://www.ncbi.nlm.nih.gov/pubmed/26492214
(iii)
The Canadian value set will be used to get the HSI values for all the countries 
participating in the study
In addition, a sum score will be derived as follows: The scores of the five dimensions (values 1-5) 
will be added (sums between 5 and 25). From this score, subtract 5 (range 0-20) and multiply by 
5 (range 0-100).
5.3.4.2.
Analysis Methods
Descriptive statistics of actual values and changes from baseline by treatment group will be 
provided for the weighted EQ-5D health status index, the EQ-VAS, and the sum score at each 
time point for the double-blind and follow-up phases.
Individual dimension responses will also be summarized at each visit using a frequency 
distribution by treatment group for the double-blind and follow-up phases.
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5.3.5.
Sheehan Disability Scale (SDS)
5.3.5.1.
Definition
The SDS is a subject-reported oustcome 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 
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. SDS was only collected for subjects enrolled prior to implementation of Amendment 3 of 
the protocol.
5.3.5.2.
Analysis Methods
Descriptive statistics of actual values and changes from baseline by treatment group will be 
provided at each time point for the double-blind and follow-up phases. The total score as well as 
the individual item scores will be summarized separately. In addition, the proportion of subjects 
who achieve response and remission will be summarized at each time point during the double-
blind induction phase.
5.3.6.
PHQ-9
5.3.6.1.
Definition
The PHQ-9 is a 9-item, self-report scale assessing depressive symptoms13. Each item is rated on 
a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly 
every day), with a total score range of 0-27. A higher score indicates greater severity of 
depression. The recall period is 2 weeks. The scale scores each of the nine symptom domains of 
the Diagnostic and Statistical Manual of Mental Disorders (DSM) Major Depressive Disorder
criteria and it has been used both as a screening tool and a measure of response to treatment for 
depression. The severity of the PHQ-9 is categorized as follows: None-minimal (0-4), Mild 
(5-9), Moderate (10-14), Moderately Severe (15-19) and Severe (20 -27). PHQ-9 was only 
collected for subjects enrolled prior to implementation of Amendment 3 of the protocol.
5.3.6.2.
Analysis Methods
For the PHQ-9 total score, descriptive statistics of actual values and changes from baseline will 
be provided at each time point for the double-blind and follow-up phases. Frequency 
distributions by severity will be provided at each assessment time point during the double-blind 
and follow-up phases.
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6.
SAFETY
All safety summaries for the double-blind induction phase will be based on the Safety analysis 
set. Safety summaries for the follow-up phase will be based on the Follow-up analysis set.
6.1.
Adverse Events
The Medical Dictionary for Regulatory Activities (MedDRA) (version 18.1 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 study phase 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 will be summarized by system organ class and preferred term. 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 study phase:

TEAEs in Double-Blind induction phase:
a.
If AE onset time is not missing: 
i.
If intranasal study medication was started on the same day as the oral 
antidepressant: DB start date/time <= AE onset date and time <= DB end date 
ii.
If intranasal study medication was not taken or was started after oral 
antidepressant: DB start date <= AE onset date <= DB end date
b.
If AE onset time is missing: DB start date <= AE onset date <= DB end date

AEs in Follow-up phase: F/U start date <= AE onset date <= F/U end date 

For the AEs that have both day and month missing, treatment-emergent flag is assigned 
based on the rules presented in Section 2.7.
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: 
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
drug abuse, dependence and withdrawal (Dependence, Drug abuse, Drug abuser, Drug 
dependence, Drug detoxification, Drug diversion, Drug rehabilitation, Drug tolerance 
increased, Drug withdrawal convulsions, Drug withdrawal headache, Drug withdrawal 
syndrome, Rebound effect, Substance abuse, Substance abuser, Substance dependence, 
Substance use, Substance-induced mood disorder, 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)

transient dizziness/vertigo (Dizziness, Dizziness exertional, Dizziness postural, Dizziness 
procedural, Vertigo, Vertigo labyrinthine, Vertigo positional, Vertigo CNS origin);

impaired cognition (Cognitive disorder, Minor cognitive motor disorder); 

cystitis (Allergic cystitis, Chemical cystitis, Cystitis, Cystitis erosive, Cystitis haemorrhagic, 
Cystitis interstitial, Cystitis noninfective, Cystitis ulcerative, Cystitis-like symptom); 

anxiety (Anticipatory anxiety, Anxiety, Anxiety disorder).
The number and percentage of subjects taking concomitant medication for dissociation events 
(preferred term of Dissociation) at any time during the double-blind phase will be provided.
6.2.
Clinical Laboratory Tests
Descriptive statistics (N, mean, median, minimum, and maximum) for values and changes from 
baseline will be provided for clinical laboratory tests (hematology, chemistry and urinalysis) at 
each scheduled time point in the double-blind induction and follow-up phases. Baseline 
laboratory result is defined as the last result collected prior to Day 1 predose. This will be used to 
calculate change for the double-blind induction phase summary. Changes from baseline for the 
follow-up phase will also be calculated using the double-blind baseline.
Clinical laboratory tests that meet the criteria for markedly abnormal will be listed by subject for 
the double-blind induction phase. The incidence of treatment-emergent markedly abnormal
(TEMA) laboratory values that occurred at any time during the double-blind induction phase will 
be presented. Clinical laboratory test values will be considered TEMA using the criteria defined 
by the Sponsor (Janssen Research & Development, LLC) listed in Attachment 1. The 
identification of TEMA laboratory values is based on the postbaseline value being out of range 
while the baseline value is either missing or within the range given in Attachment 1. If post-
baseline laboratory results are above the upper limit and the baseline value is below the lower 
limit, then the post-baseline abnormality will also be considered TEMA. The same applies to the 
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 study phase. Additionally, incidence of hepatic toxicity (Hy’s Law14) defined as ALT 
values >3*ULN AND total bilirubin values >2*ULN will be presented for the double-blind 
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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.
6.3.
Vital Signs, Weight, and BMI
Descriptive statistics for values and changes from baseline at each scheduled time-point during 
the double-blind induction phase will be presented for temperature, systolic blood pressure, 
diastolic blood pressure, pulse rate, respiratory rate, oxygen saturation, weight, and BMI. In 
addition, descriptive statistics of pulse rate and blood pressure (systolic and diastolic) values,
changes and percent changes from predose will be provided for each dosing day. These 
summaries will be also be provided by hypertension status (history of hypertension recorded in 
medical history or concomitant use of antihypertensive medications, Yes/No). 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 6
below, during the double-blind induction phase will be presented. Both the double-blind baseline 
and the predose assessment will be used to determine abnormal values. A listing of subjects 
meeting any of the criteria will also be provided for the double-blind induction phase.
Table 6:
Treatment-Emergent Abnormality Categories for Vital Signs
Vital Parameter
Post-baseline value outside of normal limit if:
Abnormally low
Abnormally high
Pulse (bpm)
A decrease from baseline of 15 to a 
value 50
An increase from baseline of 15 to a 
value 100
Systolic BP (mmHg)
A decrease from baseline of 20 to a 
value 90
An increase from baseline of 20 to a 
value 180
Diastolic BP (mmHg)
A decrease from baseline of 15 to a 
value 50
An increase from baseline of 15 to a 
value 105
BP = blood pressure
The proportion of subjects who experienced acute hypertension (systolic BP≥180 or diastolic 
BP≥100) at any time during the double-blind induction phase will be summarized by treatment 
group and hypertension status.
Mean (+/-SE) values for systolic BP, diastolic BP and heart rate will be presented graphically 
over the double-blind 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.
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6.4.
Electrocardiogram
ECG variables that will be analyzed include heart rate, RR, PR interval, QRS interval, QT
interval and QTc intervals. The corrected QT (QTc) intervals will include QTcB (Bazett) and 
QTcF (Fridericia).
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 (either intranasal or oral AD). The maximum post-baseline 
value during the double-blind 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 at 
each scheduled time point during the double-blind induction and follow-up phases.
The frequency of treatment-emergent abnormalities will be tabulated and presented for the 
double-blind induction phase. The identification of treatment-emergent abnormal ECG values is 
based on the post-baseline value (a value occurring after the first study drug administration) 
being out of range while the baseline value is either missing or within the limits given in Table 7. 
If post-baseline ECG results are above the upper limits (abnormally high) and the baseline value 
is below the lower limits (abnormally low), then the post-baseline abnormality will also be 
considered treatment-emergent. The same applies to the post-baseline value being below the 
lower limits (abnormally low) with the baseline value being above the upper limits (abnormally 
high). The average predose value will be used as baseline for the double-blind induction 
summary. Abnormal ranges for the HR, PR, QRS and QT intervals are given in Table 7.
Table 7:
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 the double-blind induction phase 
(separate for each QTc correction) the incidence of abnormal QTc values and changes from 
average predose will be summarized by treatment group. Criteria for abnormal corrected QT 
intervals and changes from baseline are given in Table 8 and are derived from the ICH E14 
Guidance7 (the same criteria apply to all QT corrections).
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Table 8:
Criteria for Abnormal QTc Values and Changes From Baseline
Parameter
Classification
Criteria
Clinically Significant QTc Value
No
500
Yes
>500
QTc change from baselinea
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 Day 1 predose value for the double-blind induction phase.
The proportion of subjects with treatment emergent abnormalities will be presented for the 
double-blind induction phase. A listing of subjects with abnormalities will also be provided.
6.5.
Nasal Examination
Targeted nasal examinations (including the upper respiratory tract/throat) will be conducted by a 
qualified healthcare practitioner. The objective of the examination at Screening is to rule out any 
subjects with anatomical or medical conditions that may impede drug delivery or absorption.
Subsequent examinations will consist of a visual inspection of the nostrils, nasal mucosa, and 
throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption and epistaxis and 
graded as follows: absent, mild, moderate, or severe. Any treatment-emergent change or 
worsening from baseline examination will be recorded as an AE.
Changes in findings from the double-blind baseline for each examination (including the upper 
respiratory tract/throat) will be listed for the double-blind and follow-up phases by treatment 
group.
6.5.1.
Nasal Symptom Questionnaire
Subjects will complete a nasal symptom questionnaire on every dosing day at predose and again 
at 1 hour postdose. The questionnaire was developed to assess nasal tolerability following 
intranasal administration of study drug. Subjects will rate nasal symptoms as none, mild, 
moderate, or severe for the following items: stuffy nose, blocked nose, runny nose, itching nose, 
crusting discharge in or on nose, dryness of nose, burning sensation in the nose, discomfort of 
nose, bleeding from the nose, postnasal drip, cough, sore throat, taste disturbance and sneezing.
Frequency distributions will be provided for each of the items at each time point during the 
double-blind induction phase. Shift from predose to postdose questionnaires during each time 
point throughout the study will be provided by treatment group to see if there is any change after 
repeated administrations of study drug. Frequency of subjects who report moderate or severe 
symptoms at any postdose time point during the double-blind induction phase will be presented 
by treatment group. In addition, a listing of severe symptoms will also be presented. 
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6.6.
Other Safety Parameters
6.6.1.
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 treatment12. It is a semi structured clinician-administered questionnaire designed to 
solicit the occurrence, severity, and frequency of suicide-related ideation and behaviors during 
the assessment period. Using the C-SSRS, potentially suicide-related events will be categorized 
using the following scores:
Suicidal Ideation (1-5)
1: Wish to be Dead
2: Non-specific Active Suicidal Thoughts
3: Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
4: Active Suicidal Ideation with Some Intent to Act, without Specific Plan
5: Active Suicidal Ideation with Specific Plan and Intent
Suicidal Behavior (6-10)
6: Preparatory Acts or Behavior
7: Aborted Attempt
8: Interrupted Attempt
9: Actual Attempt (non-fatal)
10: Completed Suicide
If no events qualify for a score of 1 to 10, a score of 0 will be assigned (0=“no event that can be 
assessed on the basis of C-SSRS”). Higher scores indicate greater severity.
The summaries of the C-SSRS outcomes will be based on the Safety analysis set for subjects 
who have at least 1 post-baseline C-SSRS measurement and a pre-treatment C-SSRS assessment 
(assessment at Baseline visit).
A frequency distribution at each scheduled time point by treatment will be provided. Shifts from 
the baseline visit to the most severe/maximum score during the double-blind induction and 
follow-up phases will be summarized by treatment.
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). 
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Shifts from the baseline visit to the maximum category during the double-blind induction and 
follow-up phases will be summarized by treatment.
6.6.2.
Clinician Administered Dissociative States Scale (CADSS)
The CADSS (Clinician Administered Dissociative States Scale) is an instrument for the 
measurement of present-state dissociative symptoms2, and is administered to assess treatment-
emergent dissociative symptoms. The CADSS comprises 23 subjective items and participant’s 
responses are coded on a 5-point scale (0 = “Not at all”, 1 = “Mild”, 2 = “Moderate”, 3 = 
‘Severe” and 4 = “Extreme”). The CADSS is divided into 3 components using the following 
scoring method: 
Component
Questions
Range
Depersonalization
Sum of 3, 4, 5, 6, 7, 20, 23
0-28
Derealization
Sum of 1, 2, 8, 9, 10, 11, 12, 13, 16, 17, 18, 19, 21
0-52
Amnesia
Sum of 14, 15, 22
0-12
Total Score
Sum of 1 through 23
0-92
For the total score and each component, a higher score represents a more severe condition. If any 
response is missing the total score is set to missing. The CADSS is measured prior to each dose, 
at 40 minutes, and at 1.5 hours postdose.
Descriptive statistics (N, median, minimum, and maximum) of the total scores and component 
scores at each time point and visit, changes from predose and proportion of subjects with an 
increase in CADSS total score from the predose value at any time during the study will be 
summarized. Mean (SD) CADSS values will be presented graphically for each dosing day.
6.6.3.
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 
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 the 
double-blind induction phase.
Descriptive statistics (N, median, minimum, and maximum) of the total scores at each time point, 
change from the predose time point within each visit, and the proportion of subjects with an 
increase in BPRS+ from the predose value at any time during the study will be provided. The 
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proportion of subjects with a total score of 3 or more at any time during the study will also be 
provided. Mean (SD) BPRS+ values will be presented graphically for each dosing day.
6.6.4.
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.

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 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 
scheduled time point. 
Mean MOAA/S values will be presented graphically for each dosing day.
6.6.5.
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. 
The clinician will answer “Yes” or “No” to the question “Is the subject considered ready to be 
discharged based on their overall clinical status (e.g., 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 during the double-blind induction phase.
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6.6.6.
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 to establish a baseline prior to discontinuation of esketamine treatment (in the 
event a subject does not continue into ESKETINTRD3004).
The proportion of subjects with withdrawal symptoms at the end of double-blind induction 
therapy or during the follow-up phase will be presented by treatment. In addition, symptoms at 
follow-up will be compared to the end of therapy visit and will be summarized using the 
following categories: new or worsened symptoms, symptoms present and unchanged, no 
symptoms, and improved.
6.6.7.
Computerized Cognitive Battery and Hopkins Verbal Learning 
Test-Revised (HVLT-R)
The effect of intranasal esketamine on cognition over the 4-week double-blind induction phase 
will be assessed using the computerized cognitive battery and the HVLT-R.
The computerized cognitive battery provides assessment of multiple cognitive domains,
including attention, visual learning and memory, and executive function. The tests use culture-
neutral stimuli, enabling use in multilingual/multicultural settings. The HVLT-R is a measure of 
verbal learning and memory and is a 12-item word list recall test. The total number of correct 
responses are captured for 4 trials as well as the number of true-positive responses and false-
positive errors in Trial 4 (Delayed Recall). The Total Recall will be derived as the sum of trials 
1, 2 and 3. Retention % will be derived as (the number of correct responses in Trial 4)/(higher 
score of Trials 2 and 3) X 100. Recognition Discrimination Index will be derived as the total 
number of true-positives – the total number of false-positives.
The computerized cognitive battery and HVLT-R will be assessed at Day 1 predose and 
Day 28/EW of the double-blind induction phase. It will also be assessed again at 2 weeks post-
treatment during the follow-up phase.
See Attachment 2 for details of the analysis.
6.6.8.
University of Pennsylvania Smell Inventory Test (UPSIT)
The UPSIT is a 40-item standardized test to assess a subject’s ability to identify odors. The 
UPSIT will be administered bilaterally (i.e., both nostrils at the same time); testing will occur 
during screening to establish a subject’s baseline sensitivity.
The UPSIT total score is defined as the total number of correct responses; therefore, the total 
score ranges from 0-40, where higher scores indicate greater smell function. Descriptive statistics 
of the observed values for UPSIT total score (%) and percent changes from screening Week 2 
(SC) will be summarized at each scheduled time point during the double-blind induction phase.
UPSIT total score (%) will be defined as [(# correct responses)/(# completed responses)]*100.
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7.
PHARMACOKINETICS/PHARMACODYNAMICS
Details of the pharmacokinetic and pharmacodynamic analysis are provided in a separate 
document.
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REFERENCES
1.
Brannath W, Konig F, Bauer P. Estimation in flexible two stage designs. Statistics in Medicine 2006; 25:3366-3381.
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.
Cui L, Hung HMJ, Wang S-J. Modification of sample size in group sequential clinical trials. Biometrics. 
1999 Sept; 55:853-857.
4.
EuroQol Group. About EQ-5D. http://www.euroqol.org/about-eq-5d.html (accessed 18 June 2014).
5.
EuroQol Group. EQ-5D-5L User Guide: basic information on how to use the EQ-5D-5L instrument. Version 
2.0; October 2013. 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/UserGuide_EQ-5D-
5L_v2.0_October_2013.pdf (accessed 6 August 2014)
6.
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. Department of Health, 
Education, and Welfare; 1976.
7.
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.
8.
Lehmacher W, Wassmer G. Adaptive sample size calculations in group sequential trials. Biometrics 
1999;55:1286–1290.
9.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 
1979;134:382-389.
10.
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
11.
Permutt, T. Sensitivity analysis for missing data in regulatory submissions. Stat Med. 2015; Nov 15 
(Epub ahead of print)
12.
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.
13.
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.
14.
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 [mol/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 [mol/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
Erythrocytes (RBC) [x1012/L] -- female
3.0
5.5
                                                   -- male
3.0
6.4
Leukocytes(WBC) [x109/L]
2.5
15.0
Hy’s Law criteria:
Alanine transaminase (SGPT) [U/L]
>3X ULN
AND
Bilirubin, total [mol/L]
>2X ULN
Note: The same limits apply to both males and females unless gender is indicated; 
N/A = Not applicable.
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Attachment 2: Statistical Analysis Plan for Cogstate
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