A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects With Treatment-resistant Depression
Phase: PHASE3
Conditions: Treatment-resistant Depression
Sponsor: Janssen Research & Development, LLC

Status: Approved, Date: 31 May 2016
1
Janssen Research & Development*
Clinical Protocol
A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the 
Efficacy, Safety, and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral 
Antidepressant in Adult Subjects with Treatment-resistant Depression
Trial of Rapid-acting Intranasal Esketamine for Treatment-resistant Major Depressive Disorder 
(TRANSFORM-1)
Protocol ESKETINTRD3001; Phase 3
AMENDMENT 2
JNJ-54135419 (esketamine)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc.; Janssen Sciences Ireland UC; or Janssen 
Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent these 
various legal entities; the sponsor is identified on the Contact Information page that accompanies the 
protocol.
This compound is being investigated in Phase 3 clinical studies.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2014-004584-20
Status:
Approved
Date:
31 May 2016
Prepared by:
Janssen Research & Development, LLC
EDMS number and version:
EDMS-ERI-93094731, 3.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 29
TIME AND EVENTS SCHEDULE (Screening/Prospective Observational Phase and Double-
blind Induction Phase).............................................................................................................................. 41
TIME AND EVENTS SCHEDULE (Follow-up Phase) .............................................................................. 48
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................................................................................................................. 65
1.2.
Active Comparators in Double-blind Induction Phase ................................................................... 65
1.2.1.
Selective Serotonin Reuptake Inhibitors..................................................................................... 65
1.2.1.1.
Escitalopram............................................................................................................................ 65
1.2.1.2.
Sertraline ................................................................................................................................. 66
1.2.2.
Serotonin and Norepinephrine Reuptake Inhibitors ................................................................... 67
1.2.2.1.
Duloxetine................................................................................................................................ 67
1.2.2.2.
Venlafaxine Extended-release................................................................................................. 67
1.3.
Overall Rationale for the Study...................................................................................................... 68
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 68
2.1.
Objectives ...................................................................................................................................... 68
2.2.
Hypothesis ..................................................................................................................................... 70
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 70
3.1.
Overview of Study Design.............................................................................................................. 70
3.2.
Study Design Rationale.................................................................................................................. 73
3.2.1.
Study Population......................................................................................................................... 73
3.2.2.
Study Phases.............................................................................................................................. 74
3.2.3.
Blinding and Randomization....................................................................................................... 75
3.2.4.
Treatment Groups and Dose Selection ...................................................................................... 75
3.2.5.
Efficacy Measures ...................................................................................................................... 77
3.2.6.
Safety Evaluations...................................................................................................................... 78
3.2.7.
Medical Resource Utilization ...................................................................................................... 79
3.2.8.
Other Assessments .................................................................................................................... 79
3.2.9.
Pharmacokinetic Assessments................................................................................................... 79
3.2.10.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations .............................. 80
4.
STUDY POPULATION ...................................................................................................................... 80
4.1.
Inclusion Criteria ............................................................................................................................ 80
4.2.
Exclusion Criteria ........................................................................................................................... 84
4.3.
Prohibitions and Restrictions ......................................................................................................... 89
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5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 89
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 91
6.1.
Screening/Prospective Observational Phase ................................................................................ 91
6.2.
Double-Blind Induction Phase........................................................................................................ 92
6.2.1.
Guidance on Blood Pressure Monitoring on Intranasal Treatment Session Days ..................... 94
6.3.
Follow-up Phase ............................................................................................................................ 95
7.
TREATMENT COMPLIANCE............................................................................................................ 95
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 95
9.
STUDY EVALUATIONS .................................................................................................................... 97
9.1.
Study Procedures........................................................................................................................... 97
9.1.1.
Overview..................................................................................................................................... 97
9.1.2.
Screening/Prospective Observational Phase ............................................................................. 98
9.1.3.
Double-Blind Induction Phase .................................................................................................. 100
9.1.4.
Follow-up Phase....................................................................................................................... 101
9.2.
Efficacy......................................................................................................................................... 102
9.2.1.
Evaluations ............................................................................................................................... 102
9.2.1.1.
Primary Efficacy Evaluation................................................................................................... 102
9.2.1.2.
Key Secondary Efficacy Evaluation (Clinician-completed).................................................... 102
9.2.1.3.
Key Secondary Efficacy Evaluation (Patient-reported Outcome).......................................... 103
9.2.1.3.1.
SDS .................................................................................................................................... 103
9.2.1.3.2.
PHQ-9 ................................................................................................................................ 103
9.2.1.4.
Other Secondary Efficacy Evaluations (Clinician-completed)............................................... 103
9.2.1.4.1.
CGI-S ................................................................................................................................. 103
9.2.1.5.
Other Secondary Efficacy Evaluations (Patient-reported Outcomes) ................................... 103
9.2.1.5.1.
GAD-7 ................................................................................................................................ 103
9.2.1.5.2.
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......................................................................................................................... 105
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................................ 106
9.6.
Medical Resource Utilization........................................................................................................ 106
9.7.
Safety Evaluations ....................................................................................................................... 107
9.8.
Other Evaluations......................................................................................................................... 114
9.9.
Sample Collection and Handling.................................................................................................. 116
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........................................................... 118
11.
STATISTICAL METHODS............................................................................................................... 118
11.1.
Subject Information ...................................................................................................................... 118
11.2.
Sample Size Determination ......................................................................................................... 118
11.3.
Interim Analysis for Sample Size Re-estimation or Stopping for Futility...................................... 119
11.4.
Efficacy Analyses ......................................................................................................................... 119
11.5.
Pharmacokinetic Analyses........................................................................................................... 121
11.6.
Pharmacokinetic/Pharmacodynamic Analyses............................................................................ 122
11.7.
Biomarker and Pharmacogenomic Analyses............................................................................... 122
11.8.
Medical Resource Utilization Analyses........................................................................................ 122
11.9.
Safety Analyses ........................................................................................................................... 122
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11.10.
Independent Data Monitoring Committee .................................................................................... 124
12.
ADVERSE EVENT REPORTING .................................................................................................... 124
12.1.
Definitions .................................................................................................................................... 125
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 125
12.1.2.
Attribution Definitions................................................................................................................ 126
12.1.3.
Severity Criteria ........................................................................................................................ 127
12.2.
Special Reporting Situations........................................................................................................ 127
12.3.
Procedures................................................................................................................................... 127
12.3.1.
All Adverse Events.................................................................................................................... 127
12.3.2.
Serious Adverse Events ........................................................................................................... 129
12.3.3.
Pregnancy................................................................................................................................. 130
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 131
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 131
13.1.
Procedures................................................................................................................................... 131
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 131
14.
STUDY DRUG INFORMATION....................................................................................................... 131
14.1.
Physical Description of Study Drug(s) ......................................................................................... 131
14.2.
Packaging .................................................................................................................................... 132
14.3.
Labeling........................................................................................................................................ 133
14.4.
Preparation, Handling, and Storage............................................................................................. 133
14.5.
Drug Accountability ...................................................................................................................... 133
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 134
16.
ETHICAL ASPECTS ....................................................................................................................... 135
16.1.
Study-specific Design Considerations ......................................................................................... 135
16.2.
Regulatory Ethics Compliance..................................................................................................... 137
16.2.1.
Investigator Responsibilities ..................................................................................................... 137
16.2.2.
Independent Ethics Committee or Institutional Review Board (IEC/IRB)................................. 137
16.2.3.
Informed Consent ..................................................................................................................... 139
16.2.4.
Privacy of Personal Data .......................................................................................................... 139
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 140
16.2.6.
Country Selection ..................................................................................................................... 140
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 140
17.1.
Protocol Amendments.................................................................................................................. 140
17.2.
Regulatory Documentation .......................................................................................................... 141
17.2.1.
Regulatory Approval/Notification .............................................................................................. 141
17.2.2.
Required Prestudy Documentation........................................................................................... 141
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 142
17.4.
Source Documentation................................................................................................................. 142
17.5.
Case Report Form Completion .................................................................................................... 143
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 143
17.7.
Record Retention ......................................................................................................................... 144
17.8.
Monitoring .................................................................................................................................... 144
17.9.
Study Completion/Termination..................................................................................................... 145
17.9.1.
Study Completion ..................................................................................................................... 145
17.9.2.
Study Termination..................................................................................................................... 145
17.10.
On-site Audits............................................................................................................................... 145
17.11.
Use of Information and Publication.............................................................................................. 146
REFERENCES.......................................................................................................................................... 148
INVESTIGATOR AGREEMENT ............................................................................................................... 160
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Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
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LIST OF ATTACHMENTS
Attachment 1:
Prohibited Concomitant Medications with Intranasal Study Medication 
(Esketamine or Placebo) .......................................................................................... 153
Attachment 2:
New York Heart Association Classification of Cardiac Disease............................... 156
Attachment 3:
Oral Antidepressant Titration Schedule for Double-Blind Induction Phase.............. 157
Attachment 4:
Anticipated Events.................................................................................................... 158
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 ........................................... 61
Table 2:
Intranasal Treatment Administration during the Double-blind Induction Phase ....................... 92
Table 3:
Volume of Blood to Be Collected From Each Subject .............................................................. 98
FIGURES
Figure 1:
Study Design for ESKETINTRD3001 ...................................................................................... 72
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JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
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PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
10 March 2015
Amendment 1
07 January2016
Amendment 2
31 May 2016
Amendments below are listed beginning with the most recent amendment.
Amendment 2 (31 May 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: Based on feedback received from Investigators involved in the study, the 
subject entry criteria are being revised to improve recruitment.
Applicable Section(s)
Description of Change(s)
Rationale: To improve recruitment, the antidepressant treatment requirements at study entry (ie, time of signing the 
ICF) in inclusion criterion no. 3.1 were changed. In addition, the definition of nonresponse at the end of the 
screening/prospective observational phase was revised.
4.1. Inclusion Criteria
Inclusion criterion no. 3.1 was revised as follows (bold text added):
At the start of the screening/prospective observational phase, subject must have had non-
response (≤25% improvement) to ≥12 but ≤5 (if current episode is > 2 years, upper limit is
applicable to only the last 2 years) oral antidepressant treatments in the current episode of 
depression, assessed using the MGH-ATRQ and confirmed by documented records (eg, 
medical/pharmacy/prescription records/ or a letter from a treating physician, etc.,). In 
addition, the sSubject must beis taking one of thea different oral antidepressant 
treatment(s) with nonresponse that is documented (on the MGH-ATRQ) for at least the 
previous 2 weeks (ie, this oral antidepressant treatment must have been taken for at least 
6 weeks at or above the minimal therapeutic dose with a lack of clinically meaningful 
improvement) at the start of the screening/prospective observational phase.
-
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 have beenbe adherent to the continued oral antidepressant 
treatment 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 non-responders to their current oral antidepressant 
medication(s) from the screening/prospective observational phase (as assessed by 
independent, remote raters) may be eligible for randomization if all other entry 
criteria are met. Non-response at the end of the screening/prospective 
observational phase is defined as ≤25% improvement in the MADRS total score 
for 2 consecutive visits from Week 1 to Week 4 and a MADRS total score of 
≥28 for 2 consecutive visits on Week 2 and Week 4.  
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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
Text regarding antidepressant treatment during the screening/prospective observational 
phase was revised as follows (bold text added):
“…the subject must have had documented non-response to at least 1 antidepressant 
treatment (based on MGH-ATRQ criteria) in the current episode of depression, and
the subject isbe taking one of thea different oral antidepressant treatment(s) with 
nonresponse (≤25% improvement) that will be documented (on the MGH ATRQ) for at 
least the previous 2 weeks (ie, this oral antidepressant treatment must have been taken
for at least 6 weeks at or above the minimum therapeutic dosewith a lack of clinically 
meaningful improvement). This antidepressant treatment, as well as any other ongoing 
medications being taken for depression (including adjunctive/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. 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.”
Synopsis, Study 
Population; 3.2.1. 
Study Population; 
9.1.2. 
Screening/Prospective 
Observational Phase
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 was revised from ≥2 to ≥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
Criteria for non-response at the end of the screening/prospective observational phase was 
revised as follows (bold text added):
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 from Week 1 to 
Week 4 and a MADRS total score of ≥ 28 for 2 consecutive visitson Week 2 and Week 4.
3.1. Overview of 
Study Design
Figure 1 was revised to correspond with the changes in the text regarding the subject 
selection criteria for the screening/ prospective observational phase.
16.1. Study-specific 
Design Considerations
Text was revised as follows (bold text added):
For eligibility, subjects must have had non-response to at least 1 prior antidepressant 
treatment and TRD and be currently taking non-responders to their current an
antidepressant treatment with non-response being observed with at the start of the 
screening/prospective observational phase that will be continued as prospective 
treatment in the screening/prospective observational phase. Only subjects with non-
response to their current antidepressant treatment after 4 weeks of prospectively observed 
treatment (for a total duration of antidepressant treatment of at least 10 6 weeks by the end 
of the screening/prospective observational phase), will be eligible to proceed to the 
double-blind induction phase, whenre all subjects will receive a new oral antidepressant in 
addition to intranasal esketamine or placebo.
Rationale: The list of key secondary objectives, evaluations, and endpoints has been reordered to correspond to the 
revised order of the planned analysis.
Synopsis, Objectives 
and Hypothesis; 2.1. 
Objectives
Key secondary objectives reordered to show “Depressive symptoms (subject-reported)” as 
the third key secondary objective.
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Status: Approved, Date: 31 May 2016
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Applicable Section(s)
Description of Change(s)
Synopsis, Efficacy 
Evaluations/Endpoints
Under the “Key Secondary Evaluations and Endpoints” heading, text describing the onset 
of clinical response was moved to the first key secondary evaluation, text describing the 
SDS was moved to second, and text describing PHQ-9 was moved to third. Numbering 
described in the text was revised accordingly.
Synopsis, Statistical 
Methods; 9.2.2.2. 
Secondary Endpoints; 
11.4. Efficacy 
Analyses
Text revised to indicate that analysis of key secondary efficacy endpoints will be analyzed 
in the following order: first, onset of clinical response results; second, SDS results, and 
third, PHQ-9 results.
The detailed description of the efficacy analyses in Section 11.4 has been revised to reflect 
changes in the order of analysis and adjustments to the testing procedure.
9.2.1.3. Key 
Secondary Efficacy 
Evaluation (Patient-
reported Outcome)
Order of key secondary patient-reported outcome efficacy evaluations was revised to 
show description of SDS before that of PHQ-9.
Rationale: Analysis of onset of clinical response revised to indicate that subjects are allowed one excursion.
Synopsis, Efficacy 
Evaluations/Endpoints; 
Synopsis, Statistical 
Methods; 3.2.5. 
Efficacy Measures; 
9.2.1.2. Key 
Secondary Efficacy 
Evaluation (Clinician-
completed); 9.2.2.2. 
Secondary Endpoints; 
11.4. Efficacy 
Analyses
The description of the onset of clinical response was revised as follows (bold text added):
Clinical response is defined as ≥50% improvement in MADRS total score by Day 2 (ie, 
the day after taking the first dose of double-blind intranasal medication) that continues 
through the end of the double-blind phase with one excursion allowed. 
Rationale: Inclusion criterion no. 11.1 was revised to specify the same requirements for contraception for female 
partners of male subjects as specified for female subjects and to remove numbering that was added in error.
4.1. Inclusion Criteria
The text of inclusion criterion no. 11.1 has been changed 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, in addition to the user 
independent highly effective method of contraception, a man who is sexually active with 
a woman of childbearing potential
-
must be practicing a highly effective method of contraception with his 
female partner from those listed above (see examples of highly effective 
methods of contraception provided for female subjects). who is sexually 
active with a woman 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 if his 
partner is pregnant.
-
must agree not to donate sperm.
12. 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 childbearing potential 
changes after start of the study, a female partner of a male study subject, must begin a 
highly effective method of birth control, as described above.
4.1. Inclusion Criteria
The numbering of the last 2 inclusion criteria has been corrected.
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Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
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Applicable Section(s)
Description of Change(s)
Rationale: Exclusion criterion no. 11.1 was revised to delete the exclusion for first degree atrioventricular (AV) 
block as the analyses of PR intervals from subjects in Phase 1 and Phase 2 esketamine studies showed no impact of 
esketamine on PR interval.
4.2. Exclusion Criteria
Exclusion criterion no. 11.1 was revised as follows (bold text added):
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 ECG’s, recorded 4 minutes apart, must not be ≥450 msec.
-
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 ECG’s, recorded 4 minutes apart, 
must not be ≥450 msec.
-
Evidence of 2nd and 3rd degree AV block, or 1st degree AV block with PR 
interval >200 msec (may repeat ECG once, and use average of both readings, if 
the initial PR interval is <240 msec), complete left bundle branch block (LBBB), 
or complete right bundle branch block (RBBB). 
-
Features of new ischemia.
-
Arrhythmia (except premature atrial contractions [PACs] and premature 
ventricular contractions [PVCs]).
Rationale: Exclusion criterion no. 14.1 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. 14.1 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 subjects who have a positive test result at screening due to 
prescribed/over-the-counter opiates, or barbiturates, or amphetamines 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.
o Retesting is not permitted for positive test result(s), except for reasons stated 
above.
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
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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
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.
Attachment 1
For antidepressants, changed 3rd bullet to read “Even if used for other indications (eg, 
trazodone primarily for sleep), trazodonethe use of any medication listed on the ATRQ
is not permitted during the treatment phase” 
For corticosteroids, changed “oral” to “systemic”; allowed episodic use (previously 
prohibited); added that intermittent IM/IV corticosteroids are permitted (chronic use 
prohibited). 
For pseudoephedrine, clarified that is an orally administered agent (not intranasal).
For psychostimulants, allowed continuous use (previously prohibited); added that 
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. 
For ADHD medications, allowed continuous use (previously prohibited); added that these 
medications 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.
Rationale: In Amendment 1, 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 from Amendment 1. This has been corrected in Amendment 2.
4.1 Inclusion Criteria
The bullets in inclusion criterion no. 7.1 were revised as follows:
-
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 and must have thyroid-
stimulating hormone (TSH) within normal range in 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 is normal, the subject can be enrolled. If the FT4 value is abnormal 
and considered to be clinically significant (after discussion with the medical 
monitor) out of range, the subject is not eligible.
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
11
Applicable Section(s)
Description of Change(s)
Rationale: Add MADRS assessment at Visit 3.2 during the follow-up phase and provide clarification in the 
footnotes regarding antidepressant treatment in the screening/prospective observational phase and guidance on 
repetition of the MADRS assessment.
Time and Events 
Schedule, Screening 
and Induction Phase
Footnote “a” revised to state (bold text added): Subjects who do not require a taper and 
are thus eligible to immediately proceed to the double-blind induction phase canwill have 
Visit 1.3 and Visit 2.1 occurring on the same day or within 1 week of each other (if not 
occurring the same day, the antidepressant treatment regimen should be continued 
and discontinued prior to Visit 2.1).
Deleted “only” from footnote “d”.
Footnote “p” revised to state (bold text added): The MADRS should be administered no 
more than 2 days prior to the subject’s scheduled targeted (not actual) clinic visit date 
(except Visit 2.10, which is within 1 day prior). If performed on the day of the 
scheduled clinic visit for an intranasal treatment session, the MADRS must be performed 
prior to the intranasal treatment session.
Time and Events 
Schedule, Follow-up 
Phase
A MADRS assessment was added to Visit 3.2.
Rationale: Revise the visit window for Day 28 of the double-blind  induction phase to allow more flexibility for 
conducting the visit.
Time and Events 
Schedule, Screening 
and Induction Phase
For Visit 2.10 during the induction phase, the visit window was revised to ±1 day (rather 
than -1 day). 
Rationale: To obtain AE and concomitant therapy data in between clinic visits.
Time and Events 
Schedule, Follow-up 
Phase
The following statement was added as footnote “f” to each remote assessment during the 
follow-up phase:
At each “Remote Assessment ” visit, site staff will contact the subject by telephone to 
obtain information regarding adverse events and concomitant therapies
Rationale: To add information about 54135419TRD3008, an open-label safety extension study, which may be 
available for eligible subjects participating in ESKETINTRD3001.
Synopsis, Overview of 
Study Design; 3.1. 
Overview of Study 
Design; 9.1.4. Follow-
up Phase
The following text was added:
An open-label safety extension study, 54135419TRD3008, may be available (pending 
country and site approval) for eligible subjects participating in the ESKETINTRD3001 
study. Please refer to the 54135419TRD3008 protocol for full details when available.
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.
9.7. Safety Evaluations
Any arterial oxygen saturation (SpO2) <93% should beand lasting for more than 
2 minutes, and confirmed by an additional measurement on another part of the body, will 
be reported as an adverse event.
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.
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
12
Applicable Section(s)
Description of Change(s)
Rationale: The maximum sertraline dose was changed from 150 mg/day to 200 mg/day as the maximum dose 
allowed by product labelling is 200 mg/day.   
1.2.1.2. Sertraline; 
Attachment 3 
Maximum dose of sertraline changed from 150 mg/day to 200 mg/day. Titration schedule 
adjusted accordingly. 
Rationale: Revise text regarding uptitration of duloxetine dose, which referred to an incorrect phase of the study.
1.2.2.1. Duloxetine
Text revised to state that certain subjects may be started on a 30 mg dose of duloxetine 
and up-titrated to the therapeutic range of 60 mg by the start of Week 2 of the double-
blind induction phase (not the screening/prospective observational phase).
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
Under “Withdrawal of Consent”, the following text was revised to state (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.
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):
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, 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.
Cover page
Updated Sponsor Statement to remove Janssen Infectious Diseases BVBA. 
Time and Events 
Schedule, Screening 
and Induction Phase
Footnote “p” was added to the MADRS assessment (7-day recall) at Visit 1.2.
4.1. Inclusion Criteria
The following text was added to inclusion criterion no. 9.1:
Contraceptive use by men or women should be consistent with local regulations regarding 
the use of contraceptive methods for subjects participating in clinical studies.
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
13
Applicable Section(s)
Description of Change(s)
9.3. Pharmacokinetics
To correct an error, the text was revised as follows (bold text added): Plasma Serum
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
Deleted text stating “All data relating to the study must be recorded in CRF.”
References 
Removed edition number and date from reference 42. 
Deleted references to Wiens BL (2003) as well as Wiens BL and Dmitrienko A (2005) as 
these are not referenced in the document due to text revisions.
Investigator 
Agreement Page
Removed the “LAST PAGE” designation.
Amendment 1 (07 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 this 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: Clarify that “at least 7 treatments with unilateral ECT” encompasses bilateral ECT treatments as well. 
Synopsis, Study Population;
4.2. Exclusion Criteria
Exclusion criteria no.1 now states “unilateral/bilateral” rather than only 
“unilateral.” 
Rationale: Indication that subjects who received vagal nerve stimulation in the current depressive episode are 
excluded.
4.2. Exclusion Criteria
The current exclusion criteria no. 2 has now been changed, to exclude a subject 
who has received vagal nerve stimulation (VNS) in the current depressive 
episode.
It previously stated subjects with vagal nerve stimulation (VNS) implant were 
excluded.
Rationale: Exclusion criteria expanded to include additional DSM-5 diagnostic codes (317, 318.0, 318.1, 318.2, 
315.8, and 319) for intellectual disability, and autism spectrum disorder.
Synopsis, Study Population;
4.2. Exclusion Criteria
Exclusion criteria no. 3 expanded to include additional intellectual disability 
DSM-5 diagnostic codes (317, 318.0, 318.1, 318.2, 315.8, and 319), and autism 
spectrum disorder.
Rationale: Clarification of the description of MDD and obsessive compulsive disorder, under criteria for subject 
exclusion. 
Synopsis, Study Population;
4.2. Exclusion Criteria
The text of the current exclusion criteria no.3. was modified: 
-
“MDD with psychosis” was revised to “MDD with psychotic features” 
-
“Only” subjects with “current” obsessive compulsive disorder will be 
excluded.
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
14
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of the conditions for exclusion of subjects with coronary artery disease.
4.2. Exclusion Criteria
The text of exclusion criteria 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 the current exclusion criteria no. 9. will now state:
antihypertensive “medication(s)” rather than “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
The text of the current exclusion criteria no.11 was modified as follows:

The first subbullet, was separated into 2 separate bullets, and the following 
bold text was added:
-
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 ECG’s, recorded 4 minutes apart, 
must not be ≥450 msec.
-
-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 
ECG’s, recorded 4 minutes apart, must not be ≥450 msec.

In the second subbullet, the following bold text was added:
-
Evidence of 2nd or 3rd degree AV block, or 1st degree AV block with PR 
interval ˃200 msec “[may repeat the ECG once, and use average of both 
readings, if the initial PR interval is <240 msec]”
-
“complete” was added to LBBB and RBBB.
Rationale: The use of concomitant medications that prolong the QT interval/corrected QT (QTc) are no longer 
excluded, as there is no known increase in QTc signal associated with esketamine; extensive ECG monitoring is in 
place, and precautions in case of increase in QTc added.”
4.2. Exclusion Criteria
The current exclusion criteria no. 12 has been modified:
The following text has been deleted, as:
The “use of concomitant medication that prolong the QT interval/corrected QT (QTc) 
interval” no longer excludes a subject from study enrollment.  
Rationale: Inclusion of a repeat screening test for abnormal ALT and AST values during the screening/prospective 
observational phase.
4.2. Exclusion criteria 
The current exclusion criteria no. 13 has been modified:
Where the subject has a history of, or symptoms and signs suggestive for liver 
cirrhosis/alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
values ≥2x the upper limit (normal), the following is applicable:
“Repeat of screening test for abnormal ALT and AST is permitted once  
during the screening period provided per investigator discretion and provided 
that there is an alternative explanation for the out of range value.”
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
15
Applicable Section(s)
Description of Change(s)
Rationale: Clarification that a positive test for cannabinoids on Day 1 is exclusionary, but not at screening. 
4.2. Exclusion Criteria
The text of the current exclusion criteria no. 14 was modified:
Clarification that “a positive test for cannabinoids at the start of the 
screening/prospective phase is not exclusionary, however a positive test result for 
cannabinoids on Day 1 (predose) of the double-blind-treatment phase is 
exclusionary”.
Rationale: The term “secondary diabetes” was removed from the exclusion criterion because, as stated in the 
criterion, any uncontrolled diabetes mellitus is exclusionary.
4.2. Exclusion Criteria
The text of the current exclusion criteria no. 15 was modified to delete the terms 
“secondary diabetes”.
Rationale: Provide clarification that investigator’s clinical judgment based on the assessment will be used to 
exclude subjects on the basis of any anatomical or medical condition that may impede delivery or absorption of 
intranasal study drug.
4.2. Exclusion Criteria
The text of exclusion criteria no. 17 was modified to indicate that the 
‘investigator’s clinical judgment based on the assessment’ will be used to 
determine eligibility.
Text that is redundant (ie, examples of structural or functional abnormalities) has 
been deleted.
Rationale: Exclusion criteria no. 18 is no longer required as it is covered as part of exclusion criteria no. 17.
4.2. Exclusion Criteria
The text of exclusion criteria no. 18 has been deleted.
Rationale: Clarification that a subject is excluded if currently enrolled in an investigational study, which is 
interventional, and clarification that the limit for participation in 2 or more MDD or other psychiatric condition 
clinical interventional studies in the previous 1 year is based on studies with different investigational medications..
4.2. Exclusion Criteria
The text of exclusion criteria no. 24 has been modified to include:
-
Subject who has participated in 2 or more MDD or other psychiatric 
condition clinical interventional studies “(with different investigational 
medication)” in the previous 1 year.
-
Subject 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. 30), as a safety precaution, since the effect of impaired renal clearance on the PK of intranasal 
esketamine is not fully known and subjects may be more vulnerable to blood pressure increases.
4.2. Exclusion Criteria
Added exclusion criteria no. 30 for all subjects: Severe renal impairment 
(creatinine clearance < 30 ml/min)
Rationale: Clarification to inclusion criterion regarding nonresponse to oral antidepressant treatments in current 
episode of depression was added. 
Synopsis, Study Population;
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 the current inclusion criteria no. 3 was modified :

At the start of the screening/prospective observational phase, subject must 
have had non-response (≤ 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, assessed using the MGH-ATRQ
and confirmed by documented records (eg, medical/pharmacy/prescription 
records or a letter from a treating physician e.t.c.). 

Subject must be taking one of the oral antidepressant treatment(s) with 
nonresponse that is documented on the MGH-ATRQ (ie, this oral 
antidepressant treatment must be taken for at least 6 weeks at the minimal 
therapeutic dose with a lack of clinically meaningful improvement) at the 
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
16
Applicable Section(s)
Description of Change(s)
start of the screening/prospective observational phase.
-
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. 

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.
Rationale: Indicate that the severity of a subject’s depressive symptoms in their current major depressive episode is 
also being 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 the current inclusion criteria no. 5 was modified:
The subject’s current major depressive episode, “depression symptom severity 
(Week 1 MADRS total score ≥ 28 required)”, and antidepressant treatment 
response in the current depressive episode, must be confirmed using a Site 
Independent Qualification Assessment. 
Rationale: Inclusion of an additional lab test which measures levels of free thyroxine (FT4), in the event that TSH 
values are out of range.
4.1. Inclusion Criteria
The text of the inclusion criteria no. 7 was modified to include an additional lab
test for assessing levels of free thyroxine:
-
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.
Rationale: Clarification of the criteria for assessing pregnancy in women of childbearing potential.
4.1. Inclusion Criteria
The text of the current inclusion criteria no.10 now states that:
•
A woman of childbearing potential must have a negative “highly sensitive”
serum (β-human chorionic gonadotropin [β-hCG]) at the start of the 
screening/prospective observational phase.
•
A negative urine pregnancy test “must be obtained before the first dose of 
study drug” on Day 1 of the double-blind induction phase prior to 
randomization.
Rationale: Inclusion criteria for methods of birth control were updated per new Sponsor protected template 
requirements.
4.1. Inclusion Criteria
The text of the current inclusion criteria no. 11 was modified:
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
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
17
Applicable Section(s)
Description of Change(s)
4.1. Inclusion Criteria
The text of the current inclusion criteria no. 9 was also modified:
A woman must be either:
a.
Not of childbearing potential defined as:
o
postmenopausal
A postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause. A high follicle stimulating hormone (FSH) 
level (˃40 IU/L or mIU/ml in the postmenopausal range) will be used to 
confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy, however in the 
absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.
o
permanently sterile 
Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, bilateral tubal occlusion/ligation procedures, and 
bilateral oophorectomy.
b.
Of childbearing potential and
o
practicing a highly effective method of contraception (failure rate of 
<1% per year when used consistently and correctly).
Examples of highly effective contraceptives include 
-user-independent methods:
implantable progestogen-only hormone contraception associated 
with inhibition of ovulation; intrauterine device (IUD); 
intrauterine hormone-releasing system (IUS); vasectomized 
partner; sexual abstinence (sexual abstinence is considered a 
highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk 
associated with the study drug. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the subject.)
-user-dependent methods:
combined (estrogen-
and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation: oral, 
intravaginal, 
and 
transdermal; 
progestogen-only 
hormone 
contraception associated with inhibition of ovulation: oral and 
injectable
Typical use failure rates may differ from those when used consistently 
and correctly. Use should be consistent with local regulations regarding 
the use of contraceptive methods for subjects participating in clinical 
studies.
Hormonal contraception may be susceptible to interaction with the 
study drug, which may reduce the efficacy of the contraceptive method.
o
agrees to use a highly effective method throughout the study and for at 
least 6 weeks after the last dose of study drug.
1.
Note: If the childbearing potential changes after start of the study or the risk 
of pregnancy changes (eg, a woman who is not heterosexually active 
becomes active), a woman must begin a highly effective method of 
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
18
Applicable Section(s)
Description of Change(s)
contraception, as described throughout the inclusion criteria.
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
19
Applicable Section(s)
Description of Change(s)
Rationale: Allow option for subjects who have in the past shown increased sensitivity towards SSRI/SNRIs to start 
at a 30 mg dose of duloxetine in the oral antidepressant titration schedule.
1.2.2.1. Duloxetine;
Attachment 3,
Legend ‘a’
Deletion of text in Section 1.2.2.1. stating: ‘Although not in the US prescribing 
information, an initial starting dose of 30 mg/day has also been evaluated’.
The following text has been added, as the US prescribing information 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.”
“In the current study, subjects should be initiated with 60 mg/day. Subjects that
have in the past shown increased sensitivity towards SSRI/SNRIs can, at the 
discretion of the treating physician, be started on 30 mg dose and up-titrated into 
the therapeutic range of 60 mg by the start of Week 2 of the 
screening/prospective observational phase”.
Rationale: Update to align with new protocol template text regarding data being collected for medical resource 
utilization
9.6. Medical Resource 
Utilization

Deleted text that specified “including surgeries and other selected procedures; 
“number and character of diagnostic and therapeutic tests and procedures”, 
and “outpatient medical encounters and treatments (including physician or 
emergency room visits, tests and procedures, and medications)”.
Rationale: Total bilirubin was omitted in error from the serum chemistry panel in the prior protocol.
9.7. Safety Evaluations
Total bilirubin was added to the serum chemistry panel.
Rationale: Clarify that in the event that an intranasal treatment session is postponed/delayed (within a visit window)
due to a predose vital sign assessment (e.g., blood pressure), on the actual day of the intranasal treatment session, 
specific assessments (including predose) must be performed/repeated, as specified in the T&E Schedule.
9.7. Safety Evaluations;
Time & Events Schedule
Where a decision has been made to postpone/delay the intranasal treatment 
session within the visit window, all time points (including predose) of the 
following assessments listed in the Time & Events Schedule, 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.
A footnote ‘q’ was added to the following assessments in the double-blind 
induction phase to indicate what needs to be performed/repeated for a postponed 
(within the visit window) intranasal dosing visit:
Vital signs, 12-lead ECG, C-SSRS, MOAA/S, pulse oximetry, BPRS+, and 
CADSS.
Rationale: Add recommendation for rescheduling smell test assessments if a subject has significant nasal 
congestion on the day of a scheduled smell test(s).
Time & Events Schedule;
9.7. Safety Evaluations
A footnote ‘o’ was added to UPSIT and Smell Threshold Test to note that the 
smell test assessment(s) should be rescheduled for the next clinic visit if the 
subject has nasal congestion.
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 that menstrual cycle tracking will be documented for women with a menstrual cycle only.
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
20
Applicable Section(s)
Description of Change(s)
Time & Events Schedule;
9.8. Other Evaluations
A footnote ‘n’ was added to menstrual cycle tracking in the double-blind 
induction phase of the Time & Events Schedule to indicate it is only applicable to 
women with a menstrual cycle.
Rationale: Footnote corrected to specify at which clinic visit a predose and/or postdose 12-lead ECG will be 
performed. 
Time & Events Schedule
The footnote ‘f’ was corrected to indicate that:
Twelve-lead ECG will be performed at t = 1 h postdose “only (ie, no predose 
ECG required)” at Visits 2.4, 2.6, and 2.9. 
Rationale: The Time and Events Schedule row that provided the assessment windows for MADRS was removed 
due to misunderstandings it was creating relative to the clinic visit windows.
Time & Events Schedule
The row for MADRS assessment windows was deleted and a footnote ‘p’ was 
added, with the same guidance as previously stated in the row, to indicate that the 
MADRS should be administered no more than 2 days prior to the subject’s 
scheduled clinic visit, and that 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: Clarify arterial oxygen saturation level that requires further monitoring.
9.7. Safety Evaluations
The symbol “<” was added to this sentence to clarify that additional assessments 
are required when the level is < 93%: 
“If oxygen saturation levels are < 93% at any time during the 1.5 hour postdose 
interval, pulse oximetry will be recorded every 5 minutes until levels return to ≥ 
93%.”
Rationale: Add an additional Sheehan Disability Scale (SDS) assessment between Day 1 and Day 28.
Time & Events Schedule
An SDS assessment was added on Day 15 (Week 2) of the Double-blind 
Induction Phase, as indicated.
Rationale: The PWC-20 assessment is to be performed for all subjects on Day 25 of the Double-blind Induction 
Phase (last planned intranasal treatment session) because sites will not know at that time whether or not a subject 
will be continuing into ESKETINTRD3003.
Time & Events Schedule
Footnote “j” was removed from the Day 25 PWC-20 assessment.
Rationale: The scoring of the PAQ assessment was revised.
9.8. Other Evaluations
Text describing scoring of the PAQ was revised to indicate:

The total score is based on the response selected for Question 1 (previously 
stated it was calculated by adding response choices for questions 1c through 
1f), and

A score of 0-1 = adherent (previously stated 0 = adherent) and 2 or more is 
nonadherent (previously stated 1 or more = nonadherent).
Rationale: Clarification of the description for the HVLT-R recall test.
9.7. Safety Evaluations
Changes added to the description of the HVLT-R recall test:

Administration includes a delayed recall (20 minute) trial and a 24-word 
recognition list.

The test administrator reads instructions and word lists aloud, and records 
words recalled/recognized by the subjects.

Scores include learning, delayed recall, and recognition.

Additional text added stating that “All subjects will complete a practice 
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
21
Applicable Section(s)
Description of Change(s)
session for the computerized cognitive battery during the 
screening/prospective observational phase. There is no practice session for 
the HVLT-R.”
Rationale: Alert site staff to ECG readings that would raise safety concerns and necessitate subject withdrawal and 
study discontinuation
9.7. Safety Evaluations;
10.2. Withdrawal from the 
Study
The following text was added:
-The subject must be discontinued at any time point after baseline (Day 1, 
predose), if:

QTcF change from baseline is ≥ 60 msec and QTcF > 480 msec, or 

QTCF > 500 msec.
Rationale: Indicate biomarkers will be protein and RNA and provide the rationale for recommendation of subject 
adherence to a low fat diet on the day of sample collection.
3.2.10. Biomarker, 
Pharmacogenomic (DNA), and 
Expression (RNA) Evaluations;
Synopsis
Added text to indicate that biomarkers will be assessed at both the protein and 
RNA level.
Addition of sentence stating that ‘On the day of biomarker sample collection, it is 
preferred that subjects adhere to a low fat diet (as an alternative to fasting) to 
reduce the level of postprandial lipemia in blood samples, since moderately or 
grossly lipemic specimens may interfere with assay results.
Rationale: Blood volume table updated to include tricyclic antidepressant and free thyroxine (FT4) blood level 
testing, if required, as well as changes in blood volumes for biomarker (protein/DNA) assessment.
9.1.1. Overview, 
Table 3 legend e) and f)
Table 3. 
Screening/Prospective Observational Phase:
- Row added to blood volume table to include:
-
a single 6 mL sample per subject for analysis of blood levels of tricyclic 
antidepressant, if required. 
-
a single 3.5 mL sample per subject for analysis of blood levels of FT4, if 
required.
- Addition of footnote ‘e)’”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 antidepressant treatment”.
- Addition of footnote ‘f)’ “for any subject (regardless of thyroid history), if the 
TSH value is out of range, a free thyroxine (FT4) will be conducted”
Double-blind Induction Phase:
- Merge the two rows for ‘Biomarker: protein visits’ to a single row, that will 
now state: “Biomarker: protein (at Visits 2.1, 2.4, and 2.9). The volume of 
sample collected at each visit is 10 mL. The number of samples per subject is 
now 3.
All study phases:
- Volume of blood sample for Biomarker: protein is now 10 mL
- Volume of blood sample for Biomarker: DNA is now 6 mL
- Delete footnote ‘d)’ Blood volume listed under protein biomarkers 
represents the combined volume of several different collection tubes.
Total Volume of Blood to be collected per subject is now 116 mL. 
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
22
Applicable Section(s)
Description of Change(s)
Rationale: Provide further clarification on how the current oral antidepressant treatment 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;
Dosage and Administration;
Study Population;
3.1. Overview Study Design;
3.2.1. Study Population;
6.1.Screening/Prospective 
Observational Phase;
9.1.2. Screening/Prospective 
Observational Phase
Subject’s current oral antidepressant treatment regimen should remain unchanged 
and at the same dosage for the 4-week screening/prospective observational phase.

At the start of the screening/prospective observational phase. the subject must 
be taking one of the oral antidepressant treatment(s) with nonresponse (≤ 
25% improvement) that will be documented on the MGH-ATRQ (ie, this oral 
antidepressant treatment must have been taken for at least 6 weeks at the 
minimum therapeutic dose with
a lack of clinically meaningful 
improvement). This antidepressant treatment, as well as any other ongoing 
medications being taken for depression at screening (including adjunctive/ 
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.
After 4 weeks, subjects who are non-responders to the current oral antidepressant 
treatment may be eligible to proceed to the double-blind induction phase. 
Nonresponse 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.
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. 
-
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 lorazepam, or new 
benzodiazepines 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.
Rationale: Clarification on the mandatory use of oral antidepressant dosing titration schedule.
Synopsis, Dosage and 
Administration;
3.2.4. Treatment Groups and 
Dose Selection;
6.2. Double-Blind Induction 
Phase, 
Oral Antidepressant 
Medication;
9.1.3 Double-Blind Induction 
Phase
-
Use of the titration schedule provided in Attachment 3 is mandatory.
-
Text regarding the use of local prescribing information and “maximum 
tolerated dose” has been deleted.
-
“Doses are not to exceed the maximum dose defined in the titration schedule” 
has been added.
Rationale: Clarification of guidance on blood pressure monitoring on intranasal treatment session days.
6.2.1. Guidance on Blood 
Pressure Monitoring on 
Intranasal Treatment Session 
Days
Clarification of guidance on blood pressure monitoring;
predose blood pressure monitoring:
If subsequent to fulfilling the inclusion and exclusion criteria on Day 1 
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
23
Applicable Section(s)
Description of Change(s)
“(ie, applicable to all other intranasal treatment session days after Day 1)”, 
a subject’s pre-dose systolic blood pressure “(SBP) is ˃140 mmHg and/or 
diastolic blood pressure (DBP) is ˃90 mmHg”, it is recommended to repeat the 
blood pressure measurement after subject rests in sitting or recumbent position.
-
“If after rest and repeated measurements, pre-dose SBP is ˃140 mmHg and/or 
DBP is ˃90 mmHg”, then dosing should be postponed and the subject 
scheduled to return on the following day or within the given visit window.
-
If the blood pressure elevation still persists on the next visit, the subject will 
be scheduled for a consultation by cardiologist, “other specialist” or primary 
care physician, prior to further dosing”
postdose blood pressure monitoring:
If at any postdose time point on the dosing day, the SBP is ≥180 mmHg but 
<200 mmHg and/or the DBP is ≥110 mmHg but <120 mmHg, further intranasal 
dosing should be interrupted and the subject should be referred to a cardiologist, 
“other specialist”, or primary care physician for a follow-up assessment.”
-
After the assessment by a cardiologist, “other specialist” or primary care 
physician, “if recommended by the referring doctor and considered  
appropriate according to the clinical judgment” for the subject to continue in 
the study, the subject may continue with intranasal dosing, if the predose 
blood pressure, at the next scheduled visit is within the acceptable range (see 
bullet point above).
If at any postdose time point on the dosing day the SBP is ≥200 mmHg and/or 
the DBP is ≥120 mmHg, the subject “must” discontinue from further dosing and 
the subject should be referred to a cardiologist, “other specialist”, or primary care 
physician for a follow-up assessment.
Addition of the following criteria for discharge based on post-dose blood 
pressure assessments during the double-blind induction phase:
During the double-blind induction phase, at 1.5 hours postdose, if the SBP is 
≥160 mmHg and/or the DBP ≥100 mmHg, assessments should continue every 
30 minutes until:
the blood pressure is <160 mmHg SBP and <100 mmHg DBP, or 
“in the investigator’s clinical judgment, the subject 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 mmHg SBP and/or / ≥110 mmHg DBP, 
2 hours after dosing, the subject should be referred for immediate medical 
treatment”.
Rationale: Clarification of the language regarding subjects meeting blood pressure criteria on intranasal treatment 
session days for discontinuation from further dosing, to indicate that the discontinuation of such subjects is 
mandatory.
6.2.1. Guidance for Blood 
pressure Monitoring on 
Intranasal Treatment Session 
Days
Updated the text in the section “Guidance for Blood Pressure Monitoring on 
Intranasal Treatment Session Days” to indicate that:

If at any postdose time point on the dosing day the SBP is ≥200 mmHg 
and/or the DBP is ≥120 mmHg, the subject “must” discontinue from further 
dosing (rather than ‘should’ discontinue), and the subject should be referred 
to a cardiologist, “other specialist”, or primary care physician for a follow-up 
assessment..
Rationale: Clarifications for the use of prestudy and concomitant therapies.
8. Prestudy and Concomitant 
Therapy;
Clarification of the following:
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
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Applicable Section(s)
Description of Change(s)
4.3. Prohibitions and 
Restrictions
Concomitant Therapy
Antidepressant treatments which are not listed on the MGH-ATRQ, but were 
used, or are currently being used as antidepressant treatments in the current 
depressive episode must be recorded in ‘Concomitant Therapy’ eCRF.
Concomitant therapies must be recorded from signing of the informed consent 
and continuing up the last visit.
If a subject has routinely taken his/her oral antihypertensive medications in the 
morning on dosing days, the morning dose should be taken prior to intranasal 
dosing.
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.
Rescue Medications
Clarification of text: “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.
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;
9.7. Safety Evaluations
Updated/ added the 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: Provide further clarification to site staff requirements for intranasal treatment sessions. 
Synopsis;
6.2. Double-blind Induction 
Phase, Intranasal Study Drug
The text now states: 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.
Rationale: Inclusion of tests for measuring free thyroxine (FT4) and for determining rates of creatinine clearance
9.7. Safety Evaluations
Inclusion of the following tests at time points specified in the Time & Events 
Schedule:

Free thyroxine (FT4), if applicable

Calculation of creatinine clearance
Rationale: Changes to Attachment 1, including the table listing of Prohibited Concomitant Medications:
Attachment 1
Inclusion of 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 (i.e., start of 
screening/prospective observational phase), it must be continued unchanged until 
the end of Week 4 of the screening/prospective observational phase, therefore 
this requirement is not applicable. In such cases the investigator may choose to 
taper the relevant medication during the 3-week taper period based on their 
clinical judgment”.
-
Deletion of row referring to CYP3A4 inhibitors as prohibited concomitant 
medication.
-
Additional example of anorexiants (eg, phendimetrazine) that are prohibited 
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
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Applicable Section(s)
Description of Change(s)
as concomitant medication for reasons of safety.
-
An additional example of anticonvulsants (eg, pregabalin) that are permitted 
as concomitant medication when used for indications other that seizures was 
added.
-
Methylphenidate, modafinil, and armodafinil, were added as additional 
examples of prohibited psychostimulants. 
-
A new row was added for prohibited non-stimulant ADHD medications (eg, 
.atomoxetine, guanfacine).
-
Addition of new text to comments on the use of antidepressants in this study, 
stating that ”Even if used primarily for sleep, trazodone use is not permitted 
during the treatment phase”.
-
Deletion of text in comments on the use of Non-benzodiazepine sleeping 
medication.
-
Clarification that benzodiazepine medication should be taken at dosages 
equal to or less than the equivalent of 6 mg/day of lorazepam.
-
Addition of new text to comments on the use of Cough/cold 
preparations/nasal solutions containing vasoconstrictors, decongestants 
“pseudoephedrine – containing products should not be used within 12 hours 
prior to an intranasal treatment session”. This is for reasons of safety and due 
to potential PD interactions.
-
Added row for non-vitamin K antagonist oral anticoagulant agents (eg, 
dabigatran, rivaroxaban, apixaban).
-
Deletion of text in comments on the use of thyroid hormone supplements.
Rationale: Clarification of procedures that need to be followed with respect sample collection and handling, on 
withdrawal of a subject from the study.
10.2. Withdrawal from the 
study
Addition of new text specifying that:

When a subject withdraws before completing the study, the reason for 
withdrawal must be documented in the CRF and in the source document.

Subjects who withdraw will not be replaced.

If a subject withdraws before the end of the double-blind induction phase, an 
early withdrawal visit is to be performed.
Deletion of the following text:

Study drug assigned to the withdrawn subject may not be assigned to another 
subject.
Rationale: Update and clarification to prohibited medications, substances, and restrictions during the double-blind 
induction phase.
Synopsis, Overview of Study 
Design,
Double-Blind Induction Phase;
3.1. Overview Study Design;
4.3. Prohibitions and 
Restrictions
Restrictions on the use of benzodiazepines during the double-blind induction 
phase:
- 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.
- 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.
Removal of the following restriction: ‘Subjects should not ingest grapefruit juice, 
Seville oranges, or quinine for 24 hours before an intranasal dose of study 
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
26
Applicable Section(s)
Description of Change(s)
medication is to be administered.
An additional criterion has been added: A positive urine drug test for “lysergic 
acid diethylamide (LSD)” from Day 1 through to the final visit in the double-
blind induction phase will lead to discontinuation.
Rationale: Provide clarification that all medication(s) being used for depression must be discontinued after 
completion of the 4-week prospective observational phase
Synopsis, Dosage and 
Administration
Text was clarified to indicate that “all medication(s) being used for depression” will 
be discontinued for subjects eligible to enter the double-blind induction phase.
Rationale: A diary has been added to record oral antidepressant use.  
Time & Events Schedule;
Synopsis, Dosage and 
Administration;
6.2. Double-Blind Induction 
Phase;
7. Treatment Compliance;
15. Study-Specific Materials
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.
Rationale: Update list of study-specific materials
15. Study-Specific Materials
Guidance document for the use of the MGH-ATRQ and subject diary have been 
added.
Rationale: Clarification of criteria for withdrawal of consent.
10.2. Withdrawal from the 
Study
For clarification the following additions to the text were made:
Withdrawal of consent:
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.
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 the 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 site personnel should attempt to obtain both primary and secondary 
telephone contact numbers (eg, home, work, and mobile numbers), as well as 
other contact information
(eg, email addresses) from subjects before 
randomization. In addition, the study site should emphasize the importance of 
follow-up information to the subject before randomization. The measures taken 
to follow up must be documented.
Subjects who withdraw will not be replaced.
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 (e.g. 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 study with the reason noted as 
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
27
Applicable Section(s)
Description of Change(s)
“Other” and will specify the reason why. For a subject who “withdraws consent”, 
it is recommended that the subject withdraw consent in writing; if the subject 
refuses or is physically unavailable, the study site should document and sign the 
reason for the subject’s failure to withdraw consent in writing and maintain it 
with the subjects source records.
-
The investigator will be responsible for making all required notifications to 
the Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC).
Rationale: Clarification of study site personnel availability for on-site monitoring visits.
17.8. Monitoring
Revision of text, which now states that;
‘It is expected that study-site personnel will be available to provide an update on 
the progress of the study at the study site’
Rationale: Clarification of the content of electronic case report form(s) (eCRF)
17.11. Use of Information and 
Publication
It is now stipulated 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: Clarification of procedures for correcting data entries in the eCRF
17.5. Case Report Form 
Completion
Clarification that: “All data relating to the study must be recorded in CRF. 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”.
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.
Deletion of the following text: ‘Clinical data manager can generate a query for 
resolution by the study site personnel’.
Rationale: Drug accountability (oral antidepressant) , to be performed on visit 3.7 of the Follow-up Phase
Time & Event Schedule
Drug accountability for oral study medication is to be performed on visit 3.7 
(Week 12 after last intranasal dose) of the Follow-up Phase.
Legend ‘e)’, which is applicable to this assessment was added:
e) For any remaining oral antidepressant study medication.
Rationale: Indicate that there is a required order of administration for intranasal devices.
6.2. Double-blind Induction 
Phase, 
Table 2
A footnote ‘c)’ added, which states that ‘The 3 intranasal devices for each 
intranasal treatment session should be administered in the medication kit order 
provided by the IWRS.”
Rationale: Include published data 
1.1.2.3. Safety and Tolerability, 
Adverse events associated with 
short-term use of intranasal 
esketamine in patients with 
MDD
Summary introduction paragraph: Additional text added to include published 
data relating summarize to adverse events associated with short-term use of 
intranasal esketamine in patients with MDD.
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
28
Applicable Section(s)
Description of Change(s)
Rationale: Minor errors and clarification were noted.
Throughout the protocol
Grammatical, formatting, or spelling changes were made.
10.3. Withdrawal from the use 
of Samples in Future Research
New section 10.3. designated
Attachment 3
Global titration schedule: list of countries that are exempt (ie, Japan, Taiwan, 
South Korea, and Malaysia) is no longer applicable.
Tine & Events Schedule
Changes to the text:

Study Drug: distinguish between study visits during the double-blind 
induction phase in which the subject diary is to be dispensed, reviewed, and 
returned to the subject. 

Cognition tests: clarification that the “practice sessions for computerized test 
battery” are distinct from the actual sessions in which the “Computerized test 
battery and the HVLT-R” recall cognition tests are performed.

Added foonote “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.
Synopsis, Oral Antidepressant 
Study Medication
Text added to clarify that:
The subjects maximum tolerated dose of oral antidepressant, should not be lower 
than the minimum therapeutic dose “at the end of the induction phase”
4.2. Exclusion Criteria
9.3. Pharmacokinetics
The following text: “(ie, AHI<30)” was added to exclusion criterion no. 23, to 
clarify the meaning of ‘effective’ treatment of sleep apnea.
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.”
9.2.1.1 Primary Efficacy 
Evaluation
Text was added to indicate that the MADRS will be administered using the 
structured interview guide for the MADRS (SIGMA).
9.2.1.1. Primary Efficacy 
Evaluation
“(interest level)” was added after the MADRS item description of “inability to 
feel” to describe what this item will be assessing.
Synopsis, Primary and Key 
Secondary Efficacy Analyses;
11.4. Efficacy Analyses
The third key secondary efficacy endpoint, change from baseline in SDS total 
score at week 4 in the double-blind-induction-phase, will be analyzed using the 
same models described for the MADRS total score, and not using the ANOVA, 
as originally stated.
9.7. Safety Evaluations
9.7. Safety Evaluations
The following correction was made to Clinical Laboratory Tests:
Urine Drug Screen: cannabinoids (cannabinoids are only “exclusionary on” Day 
1 predose).
Administrative error corrected to lipid panel which previously listed high density 
lipoprotein (HDL)-cholesterol twice. Text was updated to clarify it includes low 
density lipoprotein (LDL) and high density lipoprotein (HDL)-cholesterol. 
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
29
SYNOPSIS
A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, 
and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult 
Subjects with Treatment-resistant Depression
Study Acronym: TRANSFORM-1
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.
Ketamine and esketamine (S-ketamine, the S enantiomer of ketamine) are approved and widely used for 
the induction and maintenance of anesthesia via intramuscular (IM) or intravenous (IV) administration. 
The desired analgesic-anesthetic effects of ketamine and esketamine are attributed to the blockade of 
ionotropic N-methyl-D-aspartate (NMDA) glutamate receptors. The mechanism of action of ketamine and 
esketamine are distinct from conventional monoaminergic antidepressant treatments, in that they 
profoundly affect fast excitatory glutamate transmission, increases in brain-derived neurotrophic factor 
(BDNF) release, and stimulate synaptogenesis.
Janssen Research & Development (JRD) is developing intranasal esketamine as an antidepressant 
therapy.A higher NMDA receptor affinity of esketamine allows a lower volume of medication to be 
administered via the non-invasive, rapidly absorbed intranasal route.
The current study is being conducted to evaluate the efficacy, safety, and tolerability of 2 fixed doses of 
intranasal esketamine plus a newly initiated oral antidepressant in adult 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 adult subjects with TRD from 
a prior antidepressant treatment (to which they have not responded) to intranasal esketamine (56 mg or 
84 mg) plus a newly initiated oral antidepressant, compared with switching to a newly initiated oral 
antidepressant (active comparator) plus intranasal placebo, in improving depressive symptoms, as 
assessed by the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS)
total score from Day 1 (pre-randomization) to the end of the 4 week double-blind induction phase.
Key Secondary Objectives

The key secondary objectives are to assess the effect of intranasal esketamine plus a newly initiated 
oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus 
intranasal placebo on the following parameters in adult subjects with TRD:

Onset of clinical response by Day 2

Functioning and associated disability

Depressive symptoms (subject-reported)
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Other Secondary Objectives

To assess the effect of intranasal esketamine plus a newly initiated oral antidepressant compared 
with a newly initiated oral antidepressant (active comparator) plus intranasal placebo on the 
following parameters in adult subjects with TRD:

Depression response rates

Depression remission rates

Overall severity of depressive illness

Anxiety symptoms

Health-related quality of life and health status

To investigate the safety and tolerability of intranasal esketamine plus a newly initiated oral 
antidepressant compared with a newly initiated oral antidepressant (active comparator) plus 
intranasal placebo in adult subjects with TRD, including the following:

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

To assess the pharmacokinetics (PK) of intranasal esketamine in adult 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 adult subjects with TRD

To assess the potential relationship of biomarkers with response/non-response to intranasal 
esketamine or oral antidepressants in adult subjects with TRD

To assess medical resource utilization
Hypothesis
The hypothesis for this study is that, in adult subjects with TRD, switching from a failed antidepressant 
treatment to intranasal esketamine plus a newly initiated oral antidepressant is superior to switching to a
newly initiated oral antidepressant treatment (active comparator) plus intranasal placebo in improving 
depressive symptoms.
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OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, active-controlled, multicenter study in male and female adult subjects 
with TRD to assess the efficacy, safety, and tolerability of fixed dosed intranasal esketamine (56 mg or 
84 mg) plus a newly initiated oral antidepressant compared with a newly initiated oral antidepressant 
(active comparator) plus intranasal placebo. 
The study has 3 phases 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 non-
response to at least 1 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 weeks, subjects who are non-responders 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 ≥ 28 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 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.
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 348 subjects will be randomly assigned at a 1:1:1 ratio to receive double-blind intranasal 
treatment with either esketamine 56 mg, esketamine 84 mg, or placebo. 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 non-response to in the 
current depressive episode, has not been previously intolerant to (lifetime), and is available in the 
participating country.
Subjects who were taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of 
lorazepam) and/or permitted non-benzodiazepine sleep medications (e.g., zolpidem, zaleplon) during the 
screening/prospective observational phase can continue these medications during the induction phase. No 
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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, subjects who are responders (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) may be eligible to participate in the subsequent study ESKETINTRD3003 if they meet 
all other study entry criteria (ESKETINTRD3003 is a longer-term efficacy maintenance 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.
Follow-up phase (24-week duration)
This phase will include all subjects who are not eligible or who choose to not participate in the 
maintenance of effect study ESKETINTRD3003 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. 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 at least the first 2 weeks of the follow-up phase unless determined as 
not clinically appropriate.
The follow-up phase will also allow collection of additional informative data to assess the course of the 
subject’s major depressive episode over a 6-month period.
An open-label safety extension study, 54135419TRD3008, may be available (pending country and site 
approval) for eligible subjects participating in the ESKETINTRD3001 study. Please refer to the 
54135419TRD3008 protocol for full details when available.
Taking into consideration the optional taper period of up to 3 weeks, the maximum duration of a subject’s 
study participation
in the current study
will be
11 weeks (for subjects continuing into 
ESKETINTRD3003) or 35 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 adult men and women, 18 (or older if the minimum legal age of consent 
in the country in which the study is taking place is >18) to 64 years of age (inclusive), who meet the 
Diagnostic and Statistical Manual of Mental Disorders (5th Edition; DSM-5) diagnostic criteria for 
single-episode MDD (if single-episode MDD, the duration of the episode must be 2 years) or recurrent 
MDD without psychotic features, based upon clinical assessment, and confirmed by the 
Mini-International Neuropsychiatric Interview (MINI). In addition, the subject must have an Inventory of 
Depressive Symptomatology-Clinician rated, 30-item (IDS-C30) total score of 34, which corresponds to 
moderate to severe depression.
At the start of the screening/prospective observational phase, subjects must have had non-response (ie, 
lack of clinically meaningful improvement, defined as ≤25% improvement) to 1 but 5 (if current 
episode is > 2 years, upper limit is only applicable to the last 2 years) oral antidepressant treatments taken 
at adequate dosage and for adequate duration, as assessed using the Massachusetts General 
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Hospital -Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and documented by records 
(eg, medical/pharmacy/prescription records or a letter from treating physician, etc.) for the current 
episode of depression. In addition, the subject must currently be taking 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 antidepressant 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 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 ≥28 on 
Week 2 and Week 4. 
Treatment-resistant depression is defined as a lack of clinically meaningful improvement after treatment 
with at least 2 different antidepressant agents prescribed in adequate doses for adequate duration.
The subject’s current major depressive episode, depression symptom severity (Week 1 MADRS total 
score ≥ 28 required), and antidepressant treatment response in their current depressive episode 
(retrospectively assessed) must be deemed valid for participation in the clinical study based on a 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 
non-response of depressive symptoms to esketamine or ketamine in the current major depressive episode,
or to all 4 of the oral antidepressant treatment options available for the double-blind 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. Subjects,
who in the current depressive episode have received vagal nerve stimulation (VNS) or deep brain 
stimulation (DBS), 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 psychosis, bipolar or related disorders (confirmed by the 
MINI), obsessive compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes 317, 
318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, borderline personality disorder, antisocial 
personality disorder, histrionic personality disorder, or narcissistic personality disorder; if they have 
homicidal ideation/intent or suicidal ideation with some intent to act within 6 months prior to the start of 
the screening/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 subject must have had documented non-
response to at least 1 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 antidepressant 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 prospective observation of response or non-response.
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.
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The sponsor will not supply these antidepressant medications. Antidepressant treatment adherence during 
this phase will be assessed using the Patient Adherence Questionnaire (PAQ).Eligible subjects who are 
entering the double-blind induction phase, after completion of 4 weeks of prospective antidepressant 
treatment and assessment of the antidepressant treatment response, will discontinue all of their current
medication(s) being used for depression treatment, including adjunctive/augmentation 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 
(e.g., 
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 benzodiazepines or non-benzodiazepine sleep 
medications are permitted during the screening/prospective observational phase. If clinically indicated 
(eg, antidepressant treatments with short half-lives, such as paroxetine and venlafaxine XR; or tolerability 
concerns), the antidepressant medication(s) may be tapered off and discontinued 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 medication(s) can proceed 
immediately into the double-blind induction phase.
Double-blind induction phase
During this phase, subjects will be randomized to 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.
All subjects randomized to intranasal esketamine (56 mg or 84 mg) will start at 56 mg on Day 1. In a 
blinded manner, if a subject is randomly assigned to 84 mg, he or she will receive an 84-mg dose on 
Day 4 and for all subsequent intranasal treatment sessions. Subjects who are randomly assigned to 56 mg 
will remain on that dose for all subsequent intranasal treatment sessions. No adjustment to the intranasal 
esketamine dose is permitted for the duration of the double-blind induction phase.
On all intranasal treatment session days, a site staff member with training in cardiopulmonary 
resuscitation (eg, Basic Life Support course or equivalent course) that is up to date per local regulations,
must be present with the subject during the intranasal treatment sessions and the postdose observation 
period. In addition, equipment for supportive ventilation and resuscitation needs to be present. Subjects 
must remain at the site until study procedures have been completed and the subject is ready for discharge. 
At the time of discharge, subjects should be accompanied by a responsible adult when released from the 
clinical site. Subjects must not drive a car or work with machines for 24 hours after receiving intranasal 
study drug.
Oral Antidepressant Study Medication
Starting on Day 1, a new, open-label oral antidepressant treatment will be initiated in all subjects. The 
oral antidepressant will be 1 of 4 oral antidepressant medications (duloxetine, escitalopram, sertraline, or 
venlafaxine XR). The antidepressant medication will be assigned by the investigator based on review of 
MGH-ATRQ and relevant prior antidepressant medication information, and will be one that the subject 
has not previously had a non-response to in the current depressive episode, has not been previously 
intolerant to (lifetime), and is available in the participating country.
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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. If higher 
doses are not tolerated, a down-titration is permitted based on clinical judgment. However, the subject’s 
dose should not be lower than the following minimum therapeutic doses at the end of the induction phase: 
Sertraline (50 mg/day), venlafaxine XR (150 mg/day), escitalopram (10 mg/day), and duloxetine 
(60 mg/day). While subjects requiring lower doses can continue in the study and complete the double-
blind induction phase, such subjects will not be eligible to participate in the maintenance of effect study 
ESKETINTRD3003 and will proceed to the follow-up phase after completion of the induction phase.
All subjects will be provided with an additional 4 week supply of the oral antidepressant medication to 
ensure that there is no interruption of oral antidepressant therapy during the transition to 
ESKETINTRD3003 or 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 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 at least the first 2 weeks of the 
follow-up phase unless determined as not clinically appropriate.
EFFICACY EVALUATIONS/ENDPOINTS
Primary Efficacy Evaluation and Endpoint
The primary efficacy evaluation will be the MADRS total score. The MADRS will be performed by 
independent remote raters during the study. The MADRS is a clinician-rated scale designed to measure 
depression severity and detects changes due to antidepressant treatment.
The primary efficacy endpoint will be change from baseline in MADRS total score from Day 1 
pre-randomization to the end of the 4-week double-blind induction phase.
Key Secondary Efficacy Evaluations and Endpoints
1.
MADRS: The first key secondary endpoint is the onset of clinical response by Day 2 that is 
maintained for the duration of the double-blind induction phase (50% improvement in MADRS 
total score by the day after taking the first dose [ie, Day 2] of double-blind intranasal medication that 
continued through the end of the 4 week double-blind induction phase with one excursion allowed).
Subjects who discontinue the study prior to end of the double-blind induction phase will not be 
considered to have maintained clinical response.
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2.
Sheehan Disability Scale (SDS): The SDS is a subject-reported outcome measure that will be used to 
assess functional impairment and associated disability. The second key secondary endpoint is the 
change in SDS total score as measured by the change from baseline (Day 1 prior to randomization) 
to the end of the 4-week double-blind induction phase.
3.
Patient Health Questionnaire 9-item (PHQ-9): The PHQ-9 is a subject-reported outcome measure 
that will be used to assess depressive symptoms. The scale scores each of the 9 symptom domains of 
the DSM-5 MDD criteria and it has been used both as a screening tool and a measure of response to 
treatment for depression. The third key secondary endpoint is the change from baseline (Day 1 prior 
to randomization) to the end of the 4 week double-blind induction phase in the subject-reported 
depressive symptoms, using the PHQ-9 total score.
Other Secondary Efficacy Evaluations and 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:

Severity of depressive illness, using the Clinical Global Impression – Severity (CGI-S);

Anxiety symptoms, using the Generalized Anxiety Disorder (GAD-7), and 

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 and their potential relationship to the different treatment groups and to 
maintenance/stabilization of response, non-response, and relapse will be explored. Blood samples will be 
collected to measure genetic and epigenetic markers (including but not limited to BDNF allelic variants)
and protein markers (including but not limited to growth factors, inflammation, endocrine, or metabolic
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.
MEDICAL RESOURCE UTILIZATION
Medical resource utilization data, associated with medical encounters, will be collected using the 
Healthcare Resource Use Questionnaire (HRUQ) during the follow-up phase. The HRUQ includes 
information regarding utilization of healthcare services (including the timing and type of services), 
enabling changes in level and quantity of services to be considered as a variable in economic models.
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SAFETY EVALUATIONS
Safety evaluations will include:

Monitoring of TEAEs, including TEAEs of special interest, clinical laboratory tests (including 
hematology, serum chemistry, and urinalysis), pregnancy testing (for women of childbearing 
potential), 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

Clinician Administered Dissociative States Scale (CADSS), to assess 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) and Smell Threshold Test 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 for the 
double-blind induction phase of 6.5 points in MADRS total score between any dose of esketamine and the 
active comparator, a standard deviation of 12, a 1-sided significance level of 0.0125, and a drop-out rate 
of 25%. A maximum of about 116 subjects will need to be randomized to each treatment group to achieve 
90% power for comparison of each esketamine dose plus oral antidepressant arm with oral antidepressant 
(active comparator) plus intranasal placebo arm using a fixed design with no interim analysis. The 
treatment difference and standard deviation used in this calculation were based on results from Panel A of 
the ESKETINTRD2003 study and on clinical judgment.
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Interim Analysis for Sample Size Re-Estimation or Stopping for Futility
One unblinded interim analysis will be performed 4 weeks after randomizing 120 subjects in the study 
(approximately 40 subjects per treatment group). It is projected that at that time approximately 90 subjects 
in the full analysis set would have completed the double-blind induction phase of the study
(approximately 30 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 116 per treatment group. If the study is not stopped for futility, sample size re-estimation 
will be conducted for both doses of esketamine; ie, the analysis does not allow for stopping a dose based 
on the results of the interim analysis. 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 of the decision made at the interim analysis so that only the required amount of study 
medication will be packaged.
Primary and Key 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 
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 each
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 each esketamine plus oral antidepressant arm versus intranasal placebo plus oral 
antidepressant will be performed using the appropriate contrast.
For the analysis of the first of 3 key secondary efficacy endpoints, the proportion of subjects showing 
onset of clinical response (by Day 2 that is maintained for the duration of the double-blind induction 
phase) in the esketamine plus oral antidepressant arm will be compared with the oral antidepressant plus 
intranasal placebo arm using a Cochran-Mantel-Haenszel chi-square test adjusting for country and class 
of antidepressant (SNRI or SSRI). Clinical response is defined as 50% improvement in MADRS total 
score by Day 2 (ie, the day after taking the first dose of double-blind intranasal medication) that continues
through the end of the double-blind phase with one excursion allowed. Subjects who discontinue the 
study prior to end of the double-blind induction phase will not be considered to have maintained clinical 
response.
The second and third key secondary efficacy endpoints, change from baseline in SDS total score at 
Week 4 and change from baseline in PHQ-9 total score at Week 4 (subject to regulatory acceptance of 
PHQ-9) in the double-blind induction phase, will be analyzed using the same models described above for 
the MADRS total score. 
To strongly control Type I error across the primary and the 3 key secondary efficacy endpoints (change in 
MADRS total score, onset of clinical response, change in SDS, and change in PHQ-9 total score), and 
across the 2 esketamine dose-placebo comparisons, a truncated fixed sequence parallel gatekeeping test 
procedure will be applied between families of hypotheses corresponding to the endpoints and between 
two dose-placebo comparisons within each family (where, 84 mg esketamine dose group will be tested 
first, and 56 mg esketamine dose group will be tested only if the 84 mg dose group is shown to be 
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
39
significant). The 2 dose-placebo comparisons corresponding to each efficacy endpoint are considered as a 
family of hypotheses. Further details of this approach will be provided in the statistical analysis plan 
(SAP).
Response and remission rates will be summarized at each visit.
Change from baseline in GAD-7 total scores and 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 respective baseline score 
(unranked score in the case of CGI-S) as the covariate. 
Dimension scores of the EQ-5D-5L descriptive system, the health status index, and the EQ visual 
analogue 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 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 comparison 
of biomarker measures between the treatment groups, correlation with efficacy and other measures, and 
relationship with clinical response, relapse, and non-response. The analysis plan and summarized results
from both biomarker and pharmacogenomics analyses will be reported separately.
Medical Resource Utilization Analyses
Medical resource utilization data will be descriptively summarized.
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 
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
40
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. AEs 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 Bazett’s formula (QTcB) and QT corrected according to 
Fridericia’s formula (QTcF).
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.
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, and Smell Threshold Test 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.
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
41
TIME AND EVENTS SCHEDULE (Screening/Prospective Observational Phase and Double-blind Induction Phase)
Screening/ Prospective 
Observational Phase
Double-blind Induction Phase
Visit number
1.1
1.2
1.3 a
2.1 a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10
EW b
Week
Week 1
End of 
Week 2
End of 
Week 4
1
2
3
4
—
Study day
—
—
—
1
(baseline)
2
4
8
11
15
18
22
25
28
EW
Clinic visit window (in days)
—
±2
±2
—
—
±1
±1
±1
±1
±1
±1
±1
±1
—
Clinic visit (C) or remote MADRS 
interview only (RM)
C
C
C
C
RM
C
C
C
C
C
C
C
C
C
Screening/Administrative
Informed consent (ICF)
X
Medical history, psychiatric 
history, demographics, 
employment status
X
MINI
X
MGH-ATRQ
X
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
MGH-Female RLHQ: Module I
X
IDS-C30
X
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
42
Screening/ Prospective 
Observational Phase
Double-blind Induction Phase
Visit number
1.1
1.2
1.3 a
2.1 a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10
EW b
Week
Week 1
End of 
Week 2
End of 
Week 4
1
2
3
4
—
Study day
—
—
—
1
(baseline)
2
4
8
11
15
18
22
25
28
EW
Clinic visit window (in days)
—
±2
±2
—
—
±1
±1
±1
±1
±1
±1
±1
±1
—
Clinic visit (C) or remote MADRS 
interview only (RM)
C
C
C
C
RM
C
C
C
C
C
C
C
C
C
Study Drug
Randomization
X
Dispensing of new oral 
antidepressant (duloxetine, 
escitalopram, sertraline, or 
venlafaxine XR)
X
Xj
X
Practice session for use of 
intranasal device
X c
Intranasal esketamine or placebo 
X
X
X
X
X
X
X
X
Drug accountability
(intranasal study medication)
X
X
X
X
X
X
X
X
X
Drug accountability (oral 
antidepressant study medication)
X
X
X
Dispense subject diary for oral 
antidepressant
X
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 examination c
X
X
X
X
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
43
Screening/ Prospective 
Observational Phase
Double-blind Induction Phase
Visit number
1.1
1.2
1.3 a
2.1 a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10
EW b
Week
Week 1
End of 
Week 2
End of 
Week 4
1
2
3
4
—
Study day
—
—
—
1
(baseline)
2
4
8
11
15
18
22
25
28
EW
Clinic visit window (in days)
—
±2
±2
—
—
±1
±1
±1
±1
±1
±1
±1
±1
—
Clinic visit (C) or remote MADRS 
interview only (RM)
C
C
C
C
RM
C
C
C
C
C
C
C
C
C
Vital signs: blood pressure, pulse, 
respiratory rate, temperature c,q
X
X
X
X
X
X
X
X
X
X
Vital signs (postdose): blood 
pressure, pulse, respiratory rate e,q
X
X
X
X
X
X
X
X
Weight
X
X
X
X
12-lead ECG f,q
X
X
X
X
X
X
C-SSRS: Baseline/Screening 
version
X
C-SSRS: Since last visit versionq
X
X
Xr
X
X
X
X
X
X
X
X
X
MOAA/S and pulse oximetry g,q
X
X
X
X
X
X
X
X
X
BPRS+ h,q
X
X
X
X
X
X
X
X
CADSS h,q
X
X
X
X
X
X
X
X
CGADR i, 
X
X
X
X
X
X
X
X
PWC-20
X
X
Safety Assessments (Subject-completed)
Nasal symptom questionnaire k
X
X
X
X
X
BPIC-SS c
X
X
X
X
Assessment of Sense of Smell
UPSIT c, o 
X
X
X
X
Smell Threshold Test c, o
X
X
X
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
44
Screening/ Prospective 
Observational Phase
Double-blind Induction Phase
Visit number
1.1
1.2
1.3 a
2.1 a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10
EW b
Week
Week 1
End of 
Week 2
End of 
Week 4
1
2
3
4
—
Study day
—
—
—
1
(baseline)
2
4
8
11
15
18
22
25
28
EW
Clinic visit window (in days)
—
±2
±2
—
—
±1
±1
±1
±1
±1
±1
±1
±1
—
Clinic visit (C) or remote MADRS 
interview only (RM)
C
C
C
C
RM
C
C
C
C
C
C
C
C
C
Efficacy Assessments (Clinician)
MADRS (7-day recall; performed 
by independent, remote raters)
X
Xp
Xp
X d
Xp
Xp
Xp
Xp
X
MADRS (24-hr recall; performed 
by independent, remote raters)
X
CGI-S c
X
X
X
X
X
X
X
X
Subject-completed Assessments
PAQ
X
X
X
PHQ-9 c
X
X
X
X
X
SDS c
X
X
X
X
X
GAD-7 c
X
X
X
X
EQ-5D-5L c
X
X
X
X
X
Cognition Testing
Practice sessions for computerized 
test battery
X
Computerized test battery and 
HVLT-R
X
X
X
Clinical Laboratory Assessments
TSH, HbA1c
X
Lipid panel (fasting)
X
Hematology, chemistry c
X
X
X
X
Urine drug screen c
X
X
X
X
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
45
Screening/ Prospective 
Observational Phase
Double-blind Induction Phase
Visit number
1.1
1.2
1.3 a
2.1 a
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10
EW b
Week
Week 1
End of 
Week 2
End of 
Week 4
1
2
3
4
—
Study day
—
—
—
1
(baseline)
2
4
8
11
15
18
22
25
28
EW
Clinic visit window (in days)
—
±2
±2
—
—
±1
±1
±1
±1
±1
±1
±1
±1
—
Clinic visit (C) or remote MADRS 
interview only (RM)
C
C
C
C
RM
C
C
C
C
C
C
C
C
C
Alcohol breath test
X
X
Urinalysis c
X
X
X
X
X
Serum pregnancy test
X
Urine pregnancy test c
X
X
X
X
Pharmacokinetics
Blood collection l
X
X
Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations
Blood sample collection 
(protein) c, m
X
X
X
X
X
Blood sample collection 
(DNA) c, m
X
X
X
Blood sample collection 
(RNA) c, m
X
X
X
X
X
Ongoing Subject Review
Concomitant therapy
Ongoing
Adverse events
Ongoing
Other
Menstrual cycle tracking
(start date of last menstrual period 
prior to study visit)
Xn
Xn
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
46
Footnotes:
Abbreviations: BMI, body mass index; BPIC-SS, Bladder Pain/Interstitial Cystitis Symptom Score; BPRS+, 4-item positive symptom subscale of the Brief Psychiatric 
Rating Scale; C, clinic visit; 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; GAD-7, Generalized Anxiety Disorder, 7-item scale; HbA1c test, glycated hemoglobin test;  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; MGH-Female RLHQ, Massachusetts General Hospital - Female 
Reproductive Lifecycle and Hormones Questionnaire; MINI, Mini-International Neuropsychiatric Interview; MOAA/S, Modified Observer’s Assessment of 
Alertness/Sedation; PAQ, Patient Adherence Questionnaire; PHQ-9, Patient Health Questionnaire – 9; PWC-20, Physician Withdrawal Checklist, 20-item scale; 
RNA, ribonucleic acid; SDS, Sheehan Disability Scale; STOP-Bang, Snoring, Tired, Observed Apnea, High Blood Pressure, Body mass index, Age, Neck Size, Gender 
(a questionnaire); TSH, thyroid-stimulating hormone
Note: On intranasal dosing days, time 0 is defined as the time of the first intranasal spray. Therefore, postdose time points are referenced from this.
a) An additional, optional period of up to 3 weeks is permitted to taper and discontinue current antidepressant treatment(s) after completion of the Week 
4 (Visit 1.3) assessments, per the local prescribing information or clinical judgment. Subjects who do not require a taper and are thus eligible to 
immediately proceed to the double-blind 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 the same day, the antidepressant treatment regimen should be continued and discontinued prior to Visit 2.1).
b) If a subject withdraws before the end of the double-blind induction phase (ie, before completing Visit 2.10/Day 28) for reasons other than withdrawal 
of consent, an early withdrawal visit should be conducted within 1 week of the date of discontinuation, followed by the follow-up phase. If the early 
withdrawal visit is conducted on the same day as a scheduled visit, duplicate assessments are not required.
c) Predose (if/when performed on intranasal dosing days). Predose subject-reported outcome assessments should be administered before all other study-
related procedures during a clinic visit.
d) Performed for subjects requiring a taper period during the screening/prospective observational phase; the result will be considered as the subject’s 
baseline MADRS for the double-blind 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.
e) Postdose vital signs will be performed at 40 minutes, 1 hour, and 1.5 hours postdose. Please refer to Section 6.2.1 for guidance for blood pressure 
monitoring on intranasal 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 only (ie,
no predose ECG required) at Visits 2.4, 2.6, and 2.9. A time window of ±15 minutes is permitted.
g) The MOAA/S will not be performed at Visit 1.1 (pulse oximetry only). The MOAA/S will be performed every 15 minutes from predose to 
t=+1.5 hours postdose (please refer to Section 9.7 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 9.7 for further guidance on timing of pulse oximetry assessments).
h) The BPRS+ and CADSS to be performed predose and at 40 minutes and 1.5 hours postdose. 
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
47
i) CGADR to be performed at 1 hour and 1.5 hour postdose; if the response is not “Yes” at 1.5 hour postdose, the assessment will be repeated every 
15 minutes until a “Yes” response is achieved or until the subject is referred for appropriate medical care if clinically indicated. A subject should not 
be discharged prior to the 1.5 hour time point.
j) Performed only if the subject is not continuing into Study ESKETINTRD3003.
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 applicable to women with a menstrual cycle.
o) If the subject has significant nasal congestion on the day of a scheduled assessment, the site should consider postponing the smell test assessment(s) to 
the next scheduled clinic visit.
p) The MADRS should be administered no more than 2 days prior to the subject’s targeted (not actual) clinic visit date (except Visit 2.10, which is 
within 1 day prior). If performed on the day of the scheduled clinic visit for an intranasal treatment session, the MADRS must be performed prior to 
the intranasal treatment session.
q) If intranasal dosing is postponed (but occurs within visit window) due to vital sign results (eg, blood pressure elevation), all assessment time points 
(including predose) must be performed on the actual intranasal dosing day.
r) Performed only if Visit 1.3 and Visit 2.1 do not occur on the same day.
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
48
TIME AND EVENTS SCHEDULE (Follow-up Phase)
Follow-up Phase
Visit number
3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
3.10
3.11
3.12
3.13
Weeks after last intranasal dose
1
2
4
6
8
10
12
14
16
18
20
22
24
Visit window for clinic visit or remote assessments only (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Clinic visit (C) or remote assessments only (RA)
RAf
C
RAf
RAf
RAf
RAf
C
RAf
RAf
RAf
RAf
RAf
C
Oral antidepressant compliance a 
Oral antidepressant compliance check
X
Drug accountability
Drug accountability (oral antidepressant study medication)
X
Xe
Return of subject diary
X
Safety Assessments (Clinician-completed)
Physical examination
X
X
Nasal examination
X
Vital signs: Blood pressure, pulse, respiratory rate, temperature
X
X
12-lead ECG
X
C-SSRS: Since last visit version
X
X
X
PWC-20
X c
X
Safety Assessments (Subject-completed)
BPIC-SS
X
Efficacy Assessments (Clinician-completed)
MADRS (performed by independent, remote raters)
X
X
CGI-S 
X
X
X
Efficacy Assessments (Subject-completed)
PHQ-9
X
X
X
X
X
X
X
SDS
X
X
X
X
X
X
X
GAD-7
X
X
X
X
X
X
X
EQ-5D-5L
X
X
X
X
X
X
X
NCT02417064

JNJ-54135419 (esketamine)
Clinical Protocol ESKETINTRD3001 Amendment 2
Status: Approved, Date: 31 May 2016
49
Follow-up Phase
Visit number
3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
3.10
3.11
3.12
3.13
Weeks after last intranasal dose
1
2
4
6
8
10
12
14
16
18
20
22
24
Visit window for clinic visit or remote assessments only (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Clinic visit (C) or remote assessments only (RA)
RAf
C
RAf
RAf
RAf
RAf
C
RAf
RAf
RAf
RAf
RAf
C
Cognition testing
Computerized test battery and HVLT-R
X
Medical Resource Utilization
HRUQ b
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Laboratory Assessments
Hematology, chemistry
X
Urinalysis
X
Serum pregnancy test
X
Urine pregnancy test
X
X
Biomarker and Expression (RNA) Evaluations
Blood sample collection (protein) d
X
Blood sample collection (RNA) d
X
Ongoing Subject Review
Concomitant therapy
Ongoing
Adverse events
Ongoing
Footnotes:
Abbreviations: BPIC-SS, Bladder Pain/Interstitial Cystitis Symptom Score; C, clinic visit; CGI-S, Clinical Global Impression – Severity; C-SSRS, Columbia Suicide 
Severity Rating Scale; ECG, electrocardiogram; EQ-5D-5L, EuroQol-5D, 5-level; GAD-7, Generalized Anxiety Disorder, 7-item scale; HRUQ, Healthcare Resource 
Use Questionnaire; HVLT-R, Hopkins Verbal Learning Test-Revised; PHQ-9, Patient Health Questionnaire – 9; PWC-20, Physician Withdrawal Checklist, 20-item 
scale; RA, remote assessments only; RNA, ribonucleic acid; SDS, Sheehan Disability Scale.
Note: No intranasal study medication will be administered during the follow-up phase.
a) In order to better assess potential withdrawal symptoms from intranasal study medication, the oral antidepressant medication should be continued for 
at least the first 2 weeks of the follow-up phase unless determined to be not clinically appropriate.
b) For the HRUQ, a clinician-completed assessment may be required (based on subject-responses).
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c) Performed by telephone by qualified site staff.
d) It is preferred that subjects adhere to a low fat diet the day of sample collection.
e) For any remaining oral antidepressant study medication.
f) At each “Remote Assessment ” visit, site staff will contact the subject by telephone to obtain information regarding adverse events and concomitant 
therapies.
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ABBREVIATIONS
AHI
ANCOVA
Apnea-hypopnea index
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
Brief Psychiatric Rating Scale
BPRS+
4-item positive symptom subscale of the Brief Psychiatric Rating Scale
C
clinic visit
CADSS
Clinician Administered Dissociative States Scale
CGADR
Clinical Global Assessment of Discharge Readiness
CGI-S
Clinical Global Impression – Severity
Cmax
maximum plasma concentration
CRF
C-SSRS
Case report form
Columbia Suicide Severity Rating Scale
CYP
cytochrome P450, with any appended letters (2B6, 3A4, etc.) indicating subtypes
DBP
diastolic blood pressure
DBS
deep brain stimulation
DNA
deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders (5th Edition)
ECG
electrocardiogram
eCRF
electronic case report form
ECT
electroconvulsive therapy
eDC
Electronic Data Capture
EQ-5D-5L
European Quality of Life (EuroQol)-5 dimension-5 level
EQ-VAS
EuroQol group: Visual Analogue Scale
EU
European Union
EW
Early Withdrawal
FDA
United States Food and Drug Administration
FT4
Free thyroxine
GAD-7
Generalized Anxiety Disorder 7-item scale
GCP
Good Clinical Practice
HbA1c test
glycated hemoglobin test
HPA
hypothalamic pituitary adrenal
HRUQ
Healthcare Resource Use Questionnaire
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
ITT
IV
Intent-to-treat
intravenous
IWRS
interactive web response system
LOCF
last observation carried forward
MADRS
Montgomery-Asberg Depression Rating Scale
MAOI
monoamine oxidase inhibitor
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MGH-ATRQ
Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire
MGH-Female RLHQ
Massachusetts General Hospital - Female Reproductive Lifecycle and Hormones 
Questionnaire
MINI
Mini-International Neuropsychiatric Interview (mental status questionnaire)
MOAA/S
Modified Observer’s Assessment of Alertness/Sedation
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MMRM
mixed-effects model for repeated measures
NMDA
N-Methyl-D-Aspartate
PAQ
Patient Adherence Questionnaire
PCP 
phencyclidine
PCP
PD
Primary care physician
pharmacodynamics
PHQ-9
Patient Health Questionnaire – 9
PK
pharmacokinetics
PQC
product quality complaint
PWC-20
Physician Withdrawal Checklist; 20-item
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
SDS
Sheehan Disability Scale
SmPC
Summary of Product Characteristics
SMQ
standardized MedDRA queries
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
SBP
systolic blood pressure
TEAEs
treatment-emergent adverse events
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
MDD 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.91,94 About 30% 
of patients fail to achieve remission despite treatment with multiple antidepressant medications,
and are considered to have treatment-resistant depression (TRD).31, 75 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.75,78 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.16,24
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.  
52,66,97
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.24 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, increases BDNF release, 
and stimulates synaptogenesis.24
Most literature reports of the antidepressant effects of ketamine describe studies using IV 
administration of the racemate, with a few exceptions.14,60 Janssen Research & Development 
(JRD) is developing intranasal esketamine as an antidepressant therapy because it has higher 
NMDA receptor affinity which allows a lower volume to be administered via the intranasal 
route.51,62,67  
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.
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1.1.
Background
1.1.1.
Summary of Nonclinical Findings
Safety Pharmacology
The following text, quoted from the United States (US) prescribing information for anesthetic 
Ketalar® (ketamine hydrochloride 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 to 72 mg/day. Heart rate was 
slightly increased. 
Further details can be found in the Investigator's Brochure.42
Genetic Toxicity
A series of in vitro and in vivo genotoxicity studies was conducted with ketamine and 
esketamine. The weight of evidence indicates that esketamine poses no genotoxic risk to 
humans.42
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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 adult subjects. Moreover, the large dosages and prolonged treatment durations 
associated with neurotoxicity in juvenile animals do not suggest a concern.
Chronic treatment with ketamine at high dose levels affected the brain of adolescent monkeys, as 
evidenced by histopathologic lesions and functional impairment. 
The neurotoxicity of ketamine in adult animals is also associated with high dose levels, in 
contrast to the relatively low dose levels of esketamine associated with antidepressant efficacy in 
humans. In single-dose and 14-day repeated-neurotoxicity studies with intranasally administered 
esketamine in rats, no histopathologic brain lesions were noted even upon high exposures, as 
achieved at 54 mg/day in the 14-day study. In the 6-month rat and 9-month dog repeat-dose 
toxicology studies with intranasally administered esketamine, where the animals were of 
adolescent age at initiation of treatment, and in the pre- and post-natal developmental toxicity 
study in rats, no evidence of neurotoxicity was found. Consequently, the risk of neurotoxicity 
associated with intranasal administration of esketamine to adult and adolescent patients is 
considered low.42
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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.26 The inhibitory action on membrane 
currents may partly explain the species and tissue differences in inotropic responses to ketamine.
Blood pressure responses to ketamine also vary with the laboratory species and with 
experimental conditions. Blood pressure is increased in normotensive and renal hypertensive rats 
with and without adrenalectomy and under pentobarbital anesthesia. The US prescribing 
information for the anesthetic Ketalar® (ketamine hydrochloride [HCl] for injection) provides the 
following guidance. 
Intravenous Ketalar produces a fall in arterial blood pressure in the Rhesus monkey and a rise in 
arterial blood pressure in the dog. In this respect the dog mimics the cardiovascular effect 
observed in man. The pressor response to Ketalar injected into intact, unanesthetized dogs is 
accompanied by a tachycardia, rise in cardiac output and a fall in total peripheral resistance. It 
causes a fall in perfusion pressure following a large dose. The tachycardia and increase in 
myocardial contractile force seen in intact animals does not appear in isolated hearts. These 
observations support the hypothesis that the hypertension produced by Ketalar is due to selective 
activation of central cardiac stimulating mechanisms leading to an increase in cardiac output. 
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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
Ketamine (and esketamine) undergoes extensive metabolism by hepatic cytochrome P450 
(CYP). In humans, N-demethylation to norketamine is the major route of metabolism, which can 
undergo further metabolism to form hydroxynorketamine. Ketamine and norketamine are 
extensively 
hydroxylated 
to 
a 
series 
of 
6 
hydroxynorketamine 
metabolites 
and 
2 hydroxyketamine metabolites.93 Like ketamine, norketamine is a noncompetitive antagonist at 
the NMDA receptor.25 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 
CYP3A4.38,68,95 The CYP enzymes responsible for the formation of norketamine metabolites 
include CYP2A6 and CYP2B6.68 Published results of a clinical pharmacokinetics (PK) study 
indicate that esketamine does not invert to the R-enantiomer.34
Excretion
Racemic ketamine and its metabolites have been previously shown to be predominantly excreted 
in the urine. An average of 91% and 3% of a tritium-labeled dose (1 mg/kg) administered to 
6 healthy subjects was recovered in urine and feces, respectively.5 Less than 3% of an 
administered dose was excreted in urine as parent drug.92
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 ESKTIVTRD2001.10 Maximum concentrations of esketamine were observed at the 
end of the infusion. Mean values for maximum plasma concentration (Cmax) and area under the 
concentration-time curve (AUC) increased with an increase in the esketamine dose administered 
(80.9 and 135 ng/mL, respectively, and 150 and 218 ng*h/mL, respectively, for 0.2 mg/kg and 
0.4 mg/kg esketamine). The mean plasma clearance of esketamine was high (109 L/h and 
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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.10 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.7 The intranasal esketamine treatments were self-administered under the direct 
supervision of the investigator or designee. Subjects in Cohorts 1 and 3 received esketamine 
doses that ranged from 28 to 112 mg. The regimens were self-administered in the upright 
position. No instructions were given with regards to sniffing after administration. The reported 
median time of 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, whereas mean 
AUC∞values ranged from 164 to 565 ng*h/mL. Mean Cmax and AUC values of esketamine 
increased in a less than dose-proportional manner across the dose regimens. Furthermore, there 
was substantial overlap in the range of individual Cmax and AUC values among the 3 doses. The 
mean terminal half-life of esketamine ranged from 5.86 to 9.83 hours across all treatments.
Subjects in Cohort 2 received 84 mg in a semi-reclined position and were instructed to sniff after 
each spray. Higher mean Cmax and AUC∞values were observed in this cohort (174 ng/mL and 
437 ng*h/mL, respectively) compared with the same esketamine dose self-administered by 
subjects in Cohort 1 (107 ng/mL and 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.
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.8 On 
average, plasma esketamine Cmax and AUC values were up to 48% higher in Japanese subjects 
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).9 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 Cmax and area under the plasma 
concentration-time curve from time 0 to infinite time, AUC∞, for esketamine were approximately 
21% and 17% higher, respectively, in the elderly compared with younger adult subjects.
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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 (data on file). The mean 
esketamine concentrations in plasma samples collected on Days 1 and 11 were similar,
suggesting that the PK are consistent after repeated administration.
1.1.2.2.
Pharmacodynamics and Efficacy
The efficacy of subanesthetic doses (0.5 mg/kg IV administered over 40 minutes) of IV ketamine 
has been evaluated in approximately 192 subjects with MDD (cases and controls), and 2 studies 
in bipolar depressed subjects (meta-analyses).32 This recent 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).10 The intent-to-treat (ITT) analysis of the 
primary efficacy variable (change in Montgomery-Asberg Depression Rating Scale [MADRS]
total score from baseline Day 1 to Day 2) indicated that the improvement in both 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. 
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.11
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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) (data on file). 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 effect sizes in Period 1 for esketamine compared with placebo were:

Esketamine 28 mg:
0.43 (CI -0.259-1.118)

Esketamine 56 mg:
0.92 (CI 0.201-1.621)

Esketamine 84 mg:
1.19 (CI 0.473-1.883)
The duration of effect with the 28 mg dose appears to be shorter, with the MADRS total score 
higher on Day 8 than on Day 2. The duration of effect for the 56 mg 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 depression, that it has rapid onset of effect within 2 hours, and that 
multiple repeated sessions dose-dependently show sustained response throughout the study 
duration. A clear dose response was seen in the double-blind data in Panel A, and the point 
estimates and confidence intervals suggest a high effect size (Cohen’s D) with the 56 mg and 
84 mg dose groups, supporting further development.
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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® Summary of Product 
Characteristics [SmPC] 2011; Ketanest®S SmPC 2011).36 44
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.
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 restlessness c
Cardiac 
disorders
Blood pressure and pulse rate were frequently 
elevated after administration. However, 
hypotension and bradycardia have been 
observed. Arrhythmia has also occurred.
Common occurrences were temporary 
tachycardia and increase in blood pressure and 
heart rate (approximately 20% of the initial value 
was typical).
Respiratory, 
thoracic, and 
mediastinal 
disorders
Although stimulation of respiration was a 
frequently observed effect, severe depression 
of respiration or apnea also could occur after 
rapid intravenous administration of high doses.
Common effects were increase in vascular 
resistance in pulmonary circulation and increase 
in mucus secretion. Increased oxygen 
consumption, laryngospasms, and temporary 
respiratory depression were common; the risk of 
respiratory depression was noted to depend on 
dose and injection speed.
Gastro-
intestinal 
disorders
No gastrointestinal effects were listed as 
frequent, but the USPI stated that anorexia,
nausea, and vomiting have been observed.
Common effects included nausea and vomiting.
Abbreviations: SmPC, Summary of Product Characteristics; USPI, United States Prescribing Information
a) "Frequent" was not defined numerically, except in the case of emergence reactions (12%). The terms "very 
common" and "common" did not appear in the adverse effects section of the USPI.
b) "Very common" was defined in the SmPC as 1/10 and "common" was defined as 1/100 to <1/10.
c) The incidence of these events can be greatly reduced by the administration of a benzodiazepine.
Source: Investigator's Brochure for esketamine (JNJ-54135419).42
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Adverse Events Associated with Short-term Use of Intranasal Esketamine in Patients with 
MDD
According to the SmPC for esketamine,46 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. In Panel A 
of the Phase 2 study with intranasal esketamine (ESKETINTRD2003), the most common 
treatment-emergent adverse events (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.76 Dissociative 
symptoms were the most typical of these adverse events observed post dose and were 
characterized by feeling unreal or detached from reality or by perceptual changes. Transient 
perceptual changes (dissociation), dizziness, and nausea were typically seen immediately after 
drug administration, resolving by 2 hours. No deaths were reported in ESKETINTRD2003 study 
during the double-blind phase. One subject experienced a serious adverse event 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.76
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.
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The mean (standard deviation; SD) peak systolic blood pressure after the first administration in 
each dose group 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) mmHg
Mean (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
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.58 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.57
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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.13,56 ,58 ,61 Overall, infrequent or recreational 
ketamine use does not appear to be associated with long-term cognitive impairment.58 The most 
robust findings are that frequent ketamine users (more than 5 times a week) exhibit impairments in 
both short- and long-term memory.56 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.57,58
Ketamine-induced ulcerative cystitis is a recently identified complication.57 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 
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 literature41,43,55 ,65 but no large-scale 
studies, and so the incidence of ketamine dependence is largely unknown.57 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.82 There is conflicting evidence 
of the existence of a "withdrawal syndrome" after cessation of ketamine use.57 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.57 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.12,50 However, a specific ketamine withdrawal syndrome has not yet been described.57
Please refer to the Investigator's Brochure for a summary of the adverse events reported in 
ketamine and esketamine studies.42
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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 fixed doses of intranasal esketamine (56 mg or 84 mg) plus a newly 
initiated oral antidepressant compared with a newly initiated oral antidepressant (active 
comparator) plus intranasal placebo.
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 
US prescribing information.22,27,79,87 For further information, please refer to the appropriate 
package insert applicable to the local country in which the study is being conducted.
In the US, all 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 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.22,27,79 ,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.27
The starting dosage for MDD in the US prescribing information 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.
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 
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of stopping escitalopram]); concomitant use with pimozide; and known hypersensitivity to 
escitalopram or citalopram or any of the inactive ingredients.
As with most SSRIs, a gradual reduction in the dosage rather than abrupt cessation of 
escitalopram treatment is recommended whenever possible.
1.2.1.2.
Sertraline
Sertraline hydrochloride is indicated in adults for the treatment of MDD, obsessions and 
compulsions in patients with obsessive compulsive disorder, panic disorder (with or without 
agoraphobia), post-traumatic stress disorder, premenstrual dysphoric disorder, and social anxiety 
disorder.79
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 
therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose increases up to 
a maximum of 200 mg/day. Given the 24-hour elimination half-life of sertraline, dose changes 
should not occur at intervals of less than 1 week. The maximum dose of sertraline in the current 
study is 200 mg/day.
Contraindications to the use of sertraline include serotonin syndrome and MAOI use 
(concomitant use with MAOIs intended to treat psychiatric disorders, linezolid, or IV methylene 
blue; use within 14 days of stopping treatment with an MAOI intended to treat psychiatric 
disorders); concomitant use with pimozide; and known hypersensitivity to sertraline or any of the 
inactive ingredients. 
In adult subjects, the most common TEAEs associated with the use of sertraline (incidence of at 
least 5% for sertraline or at least twice that for placebo within at least one of the indications) 
were ejaculation failure, dry mouth, increased sweating, somnolence, tremor, dizziness, fatigue, 
pain, malaise, abdominal pain, anorexia, constipation, diarrhea/loose stools, dyspepsia, nausea, 
agitation, insomnia, and decreased libido.
As with most SSRIs, a gradual reduction in the dosage rather than abrupt cessation treatment is 
recommended whenever possible.
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1.2.2.
Serotonin and Norepinephrine Reuptake Inhibitors
1.2.2.1.
Duloxetine
Duloxetine is indicated in adults for MDD, generalized anxiety disorder, diabetic peripheral 
neuropathic pain, fibromyalgia, and chronic musculoskeletal pain.22
The starting dosage for MDD in the US prescribing information is 40 to 60 mg/day. The dosage 
for acute treatment is 40 to 60 mg/day, with maintenance treatment at 60 mg/day. For some 
patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to 
the medication before increasing to 60 mg once daily.91
In the current study, subjects should be initiated with 60 mg/day. Subjects that have in the past 
shown increased sensitivity towards SSRI/SNRIs can, at the discretion of the treating physician,
be started on a 30 mg dose and up-titrated to the therapeutic range of 60 mg by the start of 
Week 2 of the double-blind induction phase.
The maximum dosage is 120 mg/day, although there is no evidence that dosages greater than 
60 mg/day confer any additional benefits. The maximum dose to be used in this study is 
60 mg/day.
For pooled studies for all approved indications, the most commonly observed adverse reactions 
in duloxetine-treated subjects (incidence of at least 5% and at least twice the incidence in 
placebo subjects) were nausea, dry mouth, somnolence, fatigue, constipation, decreased appetite, 
and hyperhidrosis. As observed in diabetic peripheral neuropathy studies, duloxetine treatment 
worsens glycemic control in some subjects with diabetes.
Contraindications to the use of duloxetine include use of an MAOI concomitantly or within 
2 weeks of MAOI use; and use in patients with uncontrolled narrow-angle glaucoma.
A gradual reduction in the dosage rather than abrupt cessation is recommended whenever 
possible.
1.2.2.2.
Venlafaxine Extended-release
Venlafaxine XR is indicated in adults for MDD and social anxiety disorder.87
The starting dosage for MDD in the US prescribing information is 75 mg/day (in some patients, 
37.5 mg/day for 4 to 7 days), with a dosage increase by 75 mg/day at intervals of 4 days or 
longer, and a maximum dosage of 225 mg/day. 
Dosage reductions are recommended for hepatic impairment (including mild) and renal 
impairment.
Contraindications to the use of venlafaxine XR include serotonin syndrome and MAOI use 
(concomitant use with MAOIs intended to treat psychiatric disorders, linezolid, or IV methylene 
blue; use within 14 days of stopping treatment with an MAOI intended to treat psychiatric 
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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 hydrochloride XR capsules and at a rate at least twice that of 
the placebo group were abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, 
and anorexia), central nervous system complaints (dizziness, somnolence, and abnormal dreams), 
and sweating.
Sustained hypertension is noted within the Warnings and Precautions section. Preexisting 
hypertension should be controlled before treatment with venlafaxine XR. It is recommended that 
patients receiving venlafaxine XR tablets have regular monitoring of blood pressure. For patients 
who experience a sustained increase in blood pressure while receiving venlafaxine XR, either 
dosage reduction or discontinuation should be considered.
Across most indications, a dose-related increase in supine systolic and diastolic blood pressure 
was evident in venlafaxine XR-treated patients. Across all clinical studies, 1.4% of subjects in 
the venlafaxine XR-treated groups experienced a 15-mmHg increase in supine diastolic blood 
pressure, with blood pressure 105 mmHg, compared with 0.9% of subjects in the placebo 
groups. Similarly, 1% of subjects in the venlafaxine XR-treated groups experienced a 
20 mmHg increase in supine systolic blood pressure, with blood pressure 180 mmHg,
compared with 0.3% of subjects in the placebo groups. 
A gradual dosage reduction, individualized as necessary, is recommended to avoid 
discontinuation symptoms.
1.3.
Overall Rationale for the Study
This study is being conducted to evaluate the efficacy, safety, and tolerability of 2 fixed doses of 
intranasal esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant in adult 
subjects with TRD. The study will serve as a 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 adult subjects with 
TRD from a prior antidepressant treatment (to which they have not responded) to intranasal 
esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant compared with switching 
to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in improving 
depressive symptoms, as assessed by the change from baseline in the MADRS total score from 
Day 1 (pre-randomization) to the end of the 4-week double-blind induction phase.
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Key Secondary Objectives

The key secondary objectives are to assess the effect of intranasal esketamine plus a newly
initiated oral antidepressant compared with a newly initiated oral antidepressant (active 
comparator) plus intranasal placebo on the following parameters in adult subjects with TRD:
-
Onset of clinical response by Day 2
-
Functioning and associated disability
-
Depressive symptoms (subject-reported)
Other Secondary Objectives

To assess the effect of intranasal esketamine plus a newly initiated oral antidepressant 
compared with a newly initiated oral antidepressant (active comparator) plus intranasal 
placebo on the following parameters in adult subjects with TRD:
-
Depression response rates
-
Depression remission rates
-
Overall severity of depressive illness
-
Anxiety symptoms
-
Health-related quality of life and health status

To investigate the safety and tolerability of intranasal esketamine plus a newly initiated oral 
antidepressant compared with a newly initiated oral antidepressant (active comparator) plus 
intranasal placebo in adult subjects with TRD, including the following parameters:
-
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 

To assess the PK of intranasal esketamine in adult 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 adult subjects with TRD
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
To assess the potential relationship of biomarkers with response/non-response to intranasal 
esketamine or oral antidepressants in adult subjects with TRD

To assess medical resource utilization
2.2.
Hypothesis
The hypothesis for this study is that, in adult subjects with TRD, switching from a failed 
antidepressant treatment to intranasal esketamine plus a newly initiated oral antidepressant is 
superior to switching to a newly initiated oral antidepressant treatment (active comparator) plus 
intranasal placebo in improving depressive symptoms.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind, active-controlled, multicenter study in male and female adult 
subjects with TRD to assess the efficacy, safety, and tolerability of fixed dosed intranasal 
esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant compared with a newly 
initiated oral antidepressant (active comparator) plus intranasal placebo. 
The study has 3 phases 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 non-response to at least 1 antidepressant treatment (based on MGH-ATRQ) in the 
current episode of depression, and subject is taking a different oral antidepressant treatment (on 
the MGH-ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose . 
This antidepressant treatment, as well as any other ongoing medications being taken for 
depression at screening (including adjunctive/augmentation therapies), will continue from the 
start of Week 1 through the end of Week 4 of the screening/prospective observational phase.
Dose adjustment is permitted per clinical judgment, but the oral antidepressant treatment is to 
remain at or above the minimum therapeutic dose (per the MGH-ATRQ) through the end of 
Week 4.
After 4 weeks, subjects who are non-responders to their current oral antidepressant treatment 
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 ≥ 28 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) 
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during the screening/prospective observational phase can continue these medications. No dose 
increases beyond the equivalent of 6 mg/day lorazepam, or new benzodiazepine 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.
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 treatments) 
can proceed immediately into the double-blind induction phase.
Double-blind induction phase (4-week duration)
Approximately 348 subjects will be randomly assigned at a 1:1:1 ratio to receive double-blind 
intranasal treatment with either esketamine 56 mg, esketamine 84 mg, or placebo. 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 non-response 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 induction phase, subjects who are responders (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) may be eligible to participate in the subsequent study 
ESKETINTRD3003 if they meet all other study entry criteria (ESKETINTRD3003 is a 
longer-term efficacy maintenance 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.
Follow-up phase (24-week duration)
This phase will include all subjects who are not eligible or who choose to not participate in the 
maintenance of effect study ESKETINTRD3003 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.
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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. 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 at least the first 
2 weeks of the follow-up phase unless determined as not clinically appropriate.
The follow-up phase will also allow collection of additional informative data to assess the course 
of the subject’s major depressive episode over a 6 month period.
An open-label safety extension study, 54135419TRD3008, may be available (pending country 
and site approval) for eligible subjects participating in the ESKETINTRD3001 study. Please 
refer to the 54135419TRD3008 protocol for full details when available.
Taking into consideration the optional taper period of up to 3 weeks, the maximum duration of a 
subject’s study participation in the current study will be 11 weeks (for subjects continuing into 
ESKETINTRD3003) or 35 weeks (for subjects completing the follow-up phase).
A diagram of the study design is provided in Figure 1.
Figure 1:
Study Design for ESKETINTRD3001
Abbreviations: AD, antidepressant; D/C, discontinued; 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.
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An Independent Data Monitoring Committee (IDMC) will be commissioned for this study. 
Please refer to Section 11.10, Independent Data Monitoring Committee, for details.
3.2.
Study Design Rationale
3.2.1.
Study Population
The study population will include adult men and women, therefore the age range of18 (or older if 
the minimum legal age of consent in the country in which the study is taking place is >18) to 64 
years of age (inclusive) is considered appropriate.
The subjects will meet the Diagnostic and Statistical Manual of Mental Disorders (5th Edition; 
DSM-5) diagnostic criteria for single-episode MDD (if single-episode MDD, the duration of the 
episode must be 2 years) or recurrent MDD, without psychotic features, based upon clinical 
assessment, and confirmed by the Mini-International Neuropsychiatric Interview (MINI). In 
addition, the subject must have an Inventory of Depressive Symptomatology-Clinician rated, 30-
item (IDS-C30) total score of 34, 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 non-response (defined as 
≤25% improvement) to 1 but 5 (if current episode is > 2 years, upper limit is applicable to 
only the last 2 years) oral antidepressant treatments taken at adequate dosage and for adequate 
duration, as assessed on the Massachusetts General Hospital – Antidepressant Treatment 
Response 
Questionnaire 
(MGH-ATRQ)
and 
documented 
by 
records 
(eg, 
medical/pharmacy/prescription records / or 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) to an antidepressant treatment will not be 
considered to have failed that antidepressant treatment. The use of historical data to define 
non-response to treatment prior to patient enrollment in a treatment study is considered practical 
and valid. The MGH-ATRQ is a validated tool assessing treatment response. 
In addition, at the start of the screening/prospective observational phase, 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 ≥ 
28 on Week 2 and Week 4.
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The subject’s current major depressive episode, depression symptom severity (Week 1 MADRS
total score ≥28 required), and antidepressant treatment response in their current depressive 
episode (retrospectively assessed) must be deemed valid for participation in the clinical study 
based on a 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 non-response to the current antidepressant treatment(s) that is 
continued for the duration of this phase. This method of recruitment allows subjects to enter the 
study on a variety of different antidepressant medications that they had been taking, which 
mimics clinical practice and yet allows for prospective demonstration of treatment resistance to 
the current antidepressant treatment. Even though there is no depression rating score available at 
the start of the antidepressant treatment, 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 non-response 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. Non-responders 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 
period of up to 3 weeks is expected to provide an adequate amount of time for taper and 
discontinuation.
As described in Section 1.1.2, the duration of the 4 week double-blind induction phase was 
selected based upon the onset of effect of typical antidepressant treatments and the duration is 
considered to be sufficiently long to show the antidepressant effects of the 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.48,96 Similarly, it has been demonstrated that improvement of 25% on the 
Hamilton Depression 17-item rating scale on Day 14 was a significant cutoff value to predict 
response after 5 weeks of treatment and a lack of improvement (ie, <25%) by Day 14 predicted 
poor response after 5 weeks of treatment.63 All together, these results suggest that a 4 week 
duration should be adequate to assess antidepressant response.
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For subjects entering the follow-up phase, the 24 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 
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. In addition, this phase will allow 
collection of additional informative data to assess the course of the subject’s major depressive 
episode over a 6 month period.
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 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 1:1:1 to intranasal 
placebo, intranasal esketamine 56 mg, or intranasal esketamine 84 mg. The stratification is aimed 
at balancing treatment groups across country and class of antidepressant.
3.2.4.
Treatment Groups and Dose Selection
The 3 treatment groups in the double-blind induction phase are:

Intranasal esketamine (56 mg)

Intranasal esketamine (84 mg)

Intranasal placebo
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 
2 fixed doses of intranasal esketamine plus a newly initiated oral antidepressant as compared 
with a newly initiated oral antidepressant treatment (active comparator) plus intranasal placebo 
in adult subjects with TRD.
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Intranasal Study Drug
The dose selection (56 mg and 84 mg) and administration interval (2 treatment sessions per week 
for 4 weeks) for this study were based on the sponsor’s previous clinical data, in particular the 
results from Studies ESKETIVTRD2001, KETIVTRD2002, ESKETINTRD1001, and Panel A 
of Study ESKETINTRD2003, described above in Section 1.1.2. 
The data from Study ESKETINTRD2003 Panel A support the hypotheses that both the 56 mg 
and 84 mg doses are effective as a treatment for depression in subjects with TRD, that they have 
a rapid onset of effect, and that 2 treatment sessions per week can sustain the response 
throughout the 4 week duration of the double-blind induction phase. In addition, the 56 mg and 
84 mg dosages were generally well tolerated by subjects.
To improve tolerability, subjects who will be randomly assigned to esketamine 84 mg will start 
at 56 mg on Day 1 and then, in a blinded manner, increase to 84 mg on Day 4. The rationale for 
this approach is that using the lower dose (56 mg) initially, and then increasing to 84 mg, may 
allow subjects to adjust to the effects of the lower dose before going to the higher dose (84 mg). 
Thereafter, no further dose adjustments will be permitted. For example, internal data from the 
CADSS suggest a dose response, with the greatest effect seen initially on the 84 mg dose 
(ESKETINTRD2003). However, on subsequent repeated dosing, dissociative symptoms lessen. 
Starting with a lower dose may therefore limit the number of subjects discontinuing the study 
treatment because of intolerability in the 84 mg dose group.
Oral Antidepressant
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 antidepressant medication will be assigned by the investigator based on review of 
MGH-ATRQ and relevant prior antidepressant medication 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 non-response to in the current 
depressive episode, has not been previously intolerant to (lifetime), and is available in the 
participating country. Dosing of the oral antidepressant will begin on Day 1. A mandatory 
titration schedule is provided in Attachment 3. Doses are not to exceed the maximum dose 
defined in the titration schedule, 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 ESKETINTRD3003 study).
If 
higher doses are not tolerated, a down-titration is permitted based on clinician’s judgment. 
However, the subject’s dose should not be lower than the following minimum therapeutic doses
at the end of the induction phase: Sertraline (50 mg/day), venlafaxine XR (150 mg/day), 
escitalopram (10 mg/day), and duloxetine (60 mg/day). While subjects requiring lower doses can 
continue in the study and complete the double-blind induction phase, such subjects are not 
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eligible to participate in the ESKETINTRD3003 study and will proceed to the follow-up phase 
after completion of the double-blind induction phase.
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 any of the 3 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.
In addition to being the primary efficacy measure, the MADRS will also be used to evaluate the 
key secondary efficacy endpoint of onset of clinical response (ie, antidepressant effect) by Day 2
that is maintained for the duration of the double-blind induction phase. Onset of clinical response 
is defined as 50% improvement in MADRS total score by Day 2 (ie, the day after taking the 
first dose of double-blind intranasal medication) that continues through the end of the 
double-blind phase with one excursion allowed.
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.
Patient Health Questionnaire – 9 (PHQ-9)
The PHQ-9 will be used as a subject-reported outcome measure of depressive symptomatology.84
Please refer to Section 9.2.1.3.2 for additional information regarding PHQ-9.
SDS
The Sheehan Disability Scale (SDS) is a subject-reported outcome measure and is included as an
assessment of functional impairment and associated disability.49,81
Please refer to 
Section 9.2.1.3.1 for additional information regarding SDS.
Clinical Global Impression – Severity (CGI-S)
The CGI-S is included to rate the severity of the subject’s illness at the time of assessment, 
relative to the clinician’s past experience with subjects who have the same diagnosis and 
improvement with treatment.35 Please refer to Section 9.2.1.4.1 for additional information 
regarding CGI-S.
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Generalized Anxiety Disorder 7-item Scale (GAD-7)
GAD-7 is included as a brief and validated measure of overall anxiety.83 Please refer to 
Section 9.2.1.5.1 for additional information regarding GAD-7.
EuroQol-5 Dimension-5 Level (EQ-5D-5L)
The EQ-5D-5L is included as a standardized subject-completed instrument for use as a measure 
of health-related quality of life and health status.29,30 Please refer to Section 9.2.1.5.2 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 
[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) will be performed to assess suicidal 
ideation and behavior, the CADSS will be administered to assess treatment-emergent 
dissociative symptoms, the Brief Psychiatric Rating Scale (BPRS+; four-item positive symptom 
subscale) 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 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 meeting 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 
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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 the 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) and Smell Threshold Test 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, and should be accompanied by a responsible 
adult when released from the clinical site. Subjects must not drive a car or work with machines 
for 24 hours after receiving intranasal study drug.
A list of prohibited medications is provided in Attachment 1 as general guidance for the 
investigator (but is not all inclusive).
3.2.7.
Medical Resource Utilization 
Superior and sustained response and remission rates to the current antidepressant medication(s) 
are expected to result in low utilization of services, whereas non-response is expected to result in 
higher utilization of healthcare services (such as outpatient visits, emergency room visits, or 
hospitalization), as assessed using the Healthcare Resource Use Questionnaire (HRUQ) during 
the follow-up phase. The HRUQ includes information regarding utilization of healthcare 
services, including the timing of services, enabling changes in level and quantity of services to 
be considered as a variable in economic models.
3.2.8.
Other Assessments
Patient Adherence Questionnaire
During the screening/prospective observational phase, the subject-reported Patient Adherence 
Questionnaire (PAQ) will be used to assess how often the subject has taken, and whether he or 
she has made any changes to, his or her antidepressant treatment regimen in the last 2 weeks. 
This assessment will provide confirmation of medication adherence
when evaluating 
antidepressant treatment response. Subjects who report missing 4 days of antidepressant 
medication treatment(s) during a 2-week recall period will be discontinued because of inadequate 
adherence.
3.2.9.
Pharmacokinetic Assessments
PK samples will be obtained during the study for measurement of the plasma concentrations of 
esketamine, noresketamine, and/or additional metabolites, if warranted.
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3.2.10.
Biomarker, Pharmacogenomic (DNA), and Expression (RNA)
Evaluations
Assessment of biomarkers (protein and RNA) and their potential relationship to the different 
treatment groups and to maintenance/stabilization of response, non-response, and relapse will be 
explored. Blood samples will be collected to measure genetic and epigenetic markers (including 
but not limited to BDNF allelic variants) and protein markers (including but not limited to 
growth factors, inflammation, endocrine, or metabolic). Samples of deoxyribonucleic acid 
(DNA) and biomarkers may be used to help address emerging issues and to enable the 
development of safer, more effective, and ultimately individualized therapies.
Genetic variation can be an important contributory factor to inter-individual differences in drug 
distribution and response and can also serve as a marker for disease susceptibility and prognosis. 
Pharmacogenomic research may help to explain inter-individual variability in clinical outcomes 
and may help to identify population subgroups that respond differently to a drug or subgroups 
that are more susceptible to relapse. In addition, pharmacogenomics research may allow for the 
identification of genetic factors that influence the PK, PD, efficacy, safety, or tolerability of the 
different treatment groups, and for the identification of genetic factors associated with TRD or 
MDD. Specifically, genetic and epigenetic changes in genes known to be in pathways relevant to 
depression (eg, hypothalamic pituitary-adrenal [HPA] axis, inflammation, growth factors, 
monoamine transporters, ion channels, and circadian rhythm) will be evaluated.
Protein, metabolite, and ribonucleic acid (RNA) biomarkers may aid in the elucidation of the 
mechanism of action of the different treatment groups or help to explain inter-individual 
variability in clinical outcomes or may help to identify population subgroups that respond 
differently to a drug or may help to identify subgroups that are more susceptible to relapse. The 
goal of the biomarker analyses is to evaluate the PD of the different treatment groups, and aid in 
evaluating the drug-clinical response relationship.
On the day of biomarker sample collection, it is preferred that subjects adhere to low fat diet (as 
an alternative to fasting) to reduce the level of postprandial lipemia in blood samples, since 
moderately or grossly lipemic specimens may interfere with assay results.
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
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
At the time of signing the informed consent form (ICF), subject must be a man or woman 18 
(or older if the minimum legal age of consent in the country in which the study is taking 
place is >18) to 64 years of age, inclusive.
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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 must be 
2 years) or recurrent MDD, without psychotic features, based upon clinical assessment and 
confirmed by the MINI.
3.
Criterion modified per amendment 1
3.1. Criterion modified per amendment 2
3.2. At the start of the screening/prospective observational phase, subject must have had 
non-response (≤25% improvement) to 1 but 5 (if current episode is > 2 years, upper limit 
is applicable to only the last 2 years) oral antidepressant treatments in the current episode of 
depression, assessed using the MGH-ATRQ and confirmed by documented records (eg, 
medical/pharmacy/prescription records or a letter from a treating physician, etc.). In 
addition, the subject is taking a different oral antidepressant treatment (on the MGH-ATRQ) 
for at least the previous 2 weeks at or above the minimal 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 non-responders to their current oral antidepressant medication(s) from 
the screening/prospective observational phase (as assessed by independent, remote 
raters) may be eligible for randomization if all other entry criteria are met. Non-
response at the end of the screening/prospective observational phase is defined as ≤25% 
improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total 
score of ≥28 on Week 2 and Week 4. 
4.
At the start of the screening/prospective observational phase, subject must have an IDS-C30
total score of 34.
5.
Criterion modified per amendment 1
5.1. The subject’s current major depressive episode, depression symptom severity (Week 1 
MADRS total score ≥28 required), and antidepressant treatment response in the current 
depressive episode, must be confirmed using a 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
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7.2. 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.
9.
Criterion modified per amendment 1
9.1. Criterion modified per amendment 2
9.2. Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical studies.
A woman must be either:
a.
Not of childbearing potential defined as:
o
Postmenopausal
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level 
(>40 IU/L or mIU/mL in the postmenopausal range) will be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy, however in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.
o
permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, 
bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy.
b.
Of childbearing potential and
o
practicing a highly effective method of contraception (failure rate of <1% per year 
when used consistently and correctly).
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Examples of highly effective contraceptives include 

user-independent methods:
implantable progestogen-only hormone contraception associated with inhibition of 
ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); 
vasectomized partner; sexual abstinence (sexual abstinence is considered a highly 
effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study drug. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the subject.)

user-dependent methods:
combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only 
hormone contraception associated with inhibition of ovulation: oral and injectable
Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods 
for subjects participating in clinical studies.
Hormonal contraception may be susceptible to interaction with the study drug, which 
may reduce the efficacy of the contraceptive method.
o
agrees to use a highly effective method throughout the study and for at least 6 
weeks after the last dose of study drug
Note: If the childbearing potential changes after start of the study or the risk of pregnancy 
changes (eg, a woman who is not heterosexually active becomes active,) a woman must 
begin a highly effective method of contraception, as described throughout the inclusion 
criteria.
10. Criterion modified per amendment 1
10.1. A woman of childbearing potential must have a negative highly sensitive serum 
(β-human chorionic gonadotropin [β-hCG]) at the start of the screening/prospective 
observational phase and a negative urine pregnancy test must be obtained before the first 
dose of study drug on Day 1 of the double-blind induction phase prior to randomization.
11. Criterion modified per amendment 1
11.1. Criterion modified per amendment 2
11.2. 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).
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
must use a condom if his partner is pregnant.

must agree not to donate sperm.
Note: If the childbearing potential changes after start of the study, a female partner of a male 
study subject, must begin a highly effective method of birth control, as described above.
12. Subject must be willing and able to adhere to the prohibitions and restrictions specified in 
this protocol.
13. 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
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.
1.
Criterion modified per amendment 1
1.1. 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 1
2.1. Subject has received vagal nerve stimulation (VNS) or has received deep brain 
stimulation (DBS) in the current episode of depression.
3.
Criterion modified per amendment 1
3.1. Subject has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with 
psychotic features bipolar or related disorders (confirmed by the MINI), obsessive 
compulsive disorder (current only), intellectual disability (DSM-5 diagnostic codes 317, 
318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, borderline personality 
disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic 
personality disorder.
4.
Subject has homicidal ideation/intent, per the investigator’s clinical judgment, or has
suicidal ideation with some intent to act within 6 months prior to the start of the 
screening/prospective observational phase, per the investigator’s clinical judgment or based 
on the C-SSRS, corresponding to a response of “Yes” on Item 4 (active suicidal ideation 
with some intent to act, without specific plan) or Item 5 (active suicidal ideation with 
specific plan and intent) for suicidal ideation on the C-SSRS, or a history of suicidal 
behavior within the past year prior to the start of the screening/prospective observational 
phase. Subjects reporting suicidal ideation with intent to act or suicidal behavior prior to the 
start of the double blind induction phase should be excluded.
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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 is exclusionary.
6.
Subject has a current or past history of seizures (uncomplicated childhood febrile seizures 
with no sequelae are not exclusionary).
7.
Subject has an UPSIT total score 18, indicative of anosmia, in the screening/prospective 
observational phase.
8.
Criterion modified per amendment 1
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. 

New York Heart Association (NYHA) Class III-IV heart failure of any etiology (refer 
to Attachment 2).
9.
Criterion modified per amendment 1
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) >140 mmHg or diastolic blood pressure (DBP)
>90 mmHg 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 >140 mmHg or DBP >90 mmHg is 
exclusionary.

A potential subject may have his/her current antihypertensive medication(s) adjusted 
during the screening/prospective observational phase and be re-evaluated to assess their 
blood pressure control. The subject must be on a stable regimen for at least 2 weeks 
before Day 1 of the double-blind induction phase.
10. Subject has a current or past history of significant pulmonary insufficiency/condition or with 
an arterial blood oxygen saturation (SpO2) of <93% at the start of the screening/prospective 
observational phase or Day 1 prior to randomization. 
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11. Criterion modified per amendment 1
11.1. Criterion modified per amendment 2
11.2. 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 4 minutes apart, must not be ≥450 msec.

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 4 minutes apart, must not be 
≥450 msec.

Evidence of 2nd and 3rd degree AV block, complete left bundle branch block (LBBB),
or complete right bundle branch block (RBBB).

Features of new ischemia.

Arrhythmia (except premature atrial contractions [PACs] and premature ventricular 
contractions [PVCs]).
12. Criterion modified per amendment 1
12.1. Subject has a history of additional risk factors for Torsades des Pointes (eg, heart 
failure, hypokalemia, family history of Long QT Syndrome).
13. Criterion modified per amendment 1
13.1 Subject has a history of, or symptoms and signs suggestive of, liver cirrhosis (eg,
esophageal varices, ascites, and increased prothrombin time) OR alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) values 2x the upper limit of normal or total 
bilirubin >1.5 times the ULN in the screening/prospective observational phase.

Repeat of screening test for abnormal ALT and AST is permitted once during the 
screening period provided per investigator discretion and provide there is an alternative 
explanation for the out of range value.

For elevations in bilirubin if, in the opinion of the investigator and agreed upon by the 
sponsor’s medical officer, the elevation in bilirubin is consistent with Gilbert’s disease, 
the subject may participate in the study.
14. Criterion modified per amendment 1
14.1. Criterion modified per amendment 2
14.2. 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.
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
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.
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. A positive test for cannabinoids at the start of the 
screening/prospective observational phase is not exclusionary; however, a positive test 
result for cannabinoids predose on Day 1 of the double-blind induction phase is 
exclusionary.
15. Criterion modified per amendment 1
15.1. 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.
16. Subject has untreated glaucoma, current penetrating or perforating eye injury, brain injury, 
hypertensive encephalopathy, intrathecal therapy with ventricular shunts, or any other 
condition associated with increased intracranial pressure or increased intraocular pressure or 
planned eye surgery.
17. Criterion modified per amendment 1
17.1 Subject has any anatomical or medical condition that, per the investigator’s clinical 
judgment based on assessment, may impede delivery or absorption of intranasal study drug
18. Criterion deleted per amendment 1
19. 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).
20. 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.
21. 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.
22. Subject is taking a total daily dose of benzodiazepines greater than the equivalent of 
6 mg/day of lorazepam at the start of the screening/prospective observational phase.
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23. 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] must be <30). A subject with 
obstructive sleep apnea can be included if he or she is using a positive airway pressure 
device or other treatment/therapy that is effectively treating (ie, AHI<30) his or her sleep 
apnea.
24. Criterion modified per amendment 1
24.1. 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 
medication) in the previous 1 year before the start of the screening/prospective observational 
phase, or is currently enrolled in an investigational interventional study.
25. Subject is a woman who is pregnant, breast-feeding, or planning to become pregnant while 
enrolled in this study or within 6 weeks after the last dose of intranasal study drug.
26. Subject has a diagnosis of acquired immunodeficiency syndrome (AIDS). Human 
immunodeficiency virus (HIV) testing is not required for this study.
27. 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.
28. Subject has had major surgery, (eg, requiring general anesthesia) within 12 weeks before the 
start of the screening/prospective observational phase, or will not have fully recovered from 
surgery or has surgery planned during the time the subject is expected to participate in the 
study. 
Note: Subjects with planned surgical procedures to be conducted under local anesthesia may 
participate.
29. Subject is an employee of the investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study site, as well 
as family members of the employees or the investigator.
30. Subject has severe renal impairment (creatinine clearance <30 ml/min).
NOTE: Investigators should ensure that all study enrollment criteria have been met. If a subject's 
status changes (including laboratory results or receipt of additional medical records) before the 
first dose of study drug is given such that he or she no longer meets all eligibility criteria, then 
the subject should be excluded from participation in the study. Section 17.4, Source 
Documentation, describes the required documentation to support meeting the enrollment criteria.
The sponsor will evaluate and approve/reject requests to rescreen an individual subject on a 
case-by-case basis.
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4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:

Refer to Section 4.1(Inclusion Criteria) and Section 4.2 (Exclusion Criteria) for information 
regarding contraception requirements.

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 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. Benzodiazepines and non-benzodiazepine sleeping medication (e.g., 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 for use of phencyclidine (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 start of the screening/prospective observational phase. With the 
exception of new CBT, which is prohibited, new psychotherapy is allowed during this study. 
Any change in existing therapy or new therapy must be documented on the concomitant 
therapies form.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation and Randomization
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 3 treatment groups in a 1:1:1 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 
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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 by the electronic case report form (eCRF) and in the source document. The 
documentation received from the IWRS indicating the code break must be retained with the 
subject's source documents in a secure manner.
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled early withdrawal and follow up visits.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. For interim analysis, the randomization codes and, if required, the 
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.
At the end of the double-blind induction phase the database will be locked for the analysis and 
reporting of this phase. The subject treatment assignment will be revealed only to sponsor’s 
study staff. The investigators and the site personnel will be blinded to the treatment assignment 
until all subjects have completed study participation through the follow-up phase.
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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 is to 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 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, to confirm 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 medication(s).
During this phase, antidepressant treatment adherence will be assessed using the PAQ.
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 ≥ 28 on Week 2 and Week 4.
After the completion of 4 weeks of prospective antidepressant treatment and assessment of the 
antidepressant treatment response, eligible subjects who are entering the double-blind induction 
phase will discontinue all of their medication(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 lorazepam or new benzodiazepine medications are 
permitted during the screening/prospective observational phase. If clinically indicated, the 
antidepressant medication may be tapered and discontinued over a period of up to 3 weeks per 
the local prescribing information or clinical judgment (eg, antidepressant treatments with short 
half-lives, such as paroxetine and venlafaxine XR; or tolerability concerns). Eligible subjects 
who do not require a tapered discontinuation of their antidepressant treatment(s) can proceed 
immediately 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 
esketamine (56 mg or 84 mg) or placebo twice per week for 4 weeks as a fixed 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 course) that is up to date per local 
regulations must be present with the subject during the intranasal treatment session and the 
postdose observation period. In addition, equipment for supportive ventilation and resuscitation 
needs to be present.
Table 2 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 2:
Intranasal Treatment Administration during the Double-blind Induction Phase
Intranasal Treatment
Time of Intranasal Device Administrationc
0 a
5 minutes
10 minutes
Intranasal device b
1st
2nd
3rd
Placebo
1 spray of placebo to 
each nostril
1 spray of placebo to 
each nostril
1 spray of placebo to 
each nostril
Esketamine 56 mg 
1 spray of esketamine to 
each nostril 
1 spray of esketamine to 
each nostril
1 spray of placebo to 
each nostril
Esketamine 84 mg
1 spray of esketamine to 
each nostril
1 spray of esketamine to 
each nostril
1 spray of esketamine to 
each nostril
a) Time 0 is defined as the time of administration of the first intranasal spray to one nostril from the first intranasal 
device. 
b) One device will be used at each time point. Each individual intranasal device contains 2 sprays. The intranasal 
devices containing esketamine deliver 14 mg per spray, for a total of 28 mg per individual device (ie, 2 sprays)
c) The 3 intranasal devices for each intranasal treatment session should be administered in the medication kit order 
provided by the IWRS
Instructions for use documents (subject and healthcare provider versions) for intranasal study 
drug administration will be provided as separate documents. Details regarding study drug 
administration will be recorded in the source documents and the eCRF.
Prior to the first intranasal dose on Day 1, subjects will practice spraying (into the air, not 
intranasally) a demonstration intranasal device that is filled with placebo solution.
All subjects will self-administer the intranasal study drug (esketamine or placebo) at treatment 
sessions twice a week for 4 weeks at the study site. The first treatment session will be on Day 1. 
Intranasal treatment sessions should not take place on consecutive days.
All subjects randomized to intranasal esketamine (56 mg or 84 mg) will start at 56 mg on Day 1. 
In a blinded manner, if a subject is randomly assigned to 84 mg, he or she will receive an 84 mg 
dose on Day 4 and for all subsequent intranasal treatment sessions. Subjects who are randomly 
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assigned to 56 mg will remain on that dose for all subsequent intranasal treatment sessions. No 
further adjustment to the intranasal esketamine dose is permitted for the duration of the 
double-blind induction phase.
Food will be restricted for at least 2 hours before each administration of study drug. Drinking of 
any fluids will be restricted for at least 30 minutes before the first nasal spray.
If the subject has nasal congestion on the dosing day, an intranasal decongestant can be used to 
reduce congestion or the dosing day be delayed (per the permitted visit window; see the Time 
and Events Schedule). If an intranasal decongestant is used to reduce congestion, it cannot be 
used within 1 hour prior to intranasal study drug dosing.
On all intranasal treatment sessions, subjects must remain at the clinical site until study 
procedures have been completed and the subject is ready for discharge. 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 the intranasal treatment session.
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 
MGH-ATRQ and relevant information regarding prior antidepressant treatments, and will be one
that the subject has not previously had a non-response to in the current depressive episode, has 
not been previously intolerant to (lifetime), and is available in the participating country. 
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. If higher doses are not tolerated, a down-titration is permitted based on clinical 
judgment. However, the subject’s dose should not be lower than the following minimum 
therapeutic doses at the end of the induction phase: Sertraline (50 mg/day), venlafaxine XR 
(150 mg/day), escitalopram (10 mg/day), and duloxetine (60 mg/day). While subjects requiring 
lower doses can continue in the study and complete the double-blind induction phase, such 
subjects will not be eligible to participate in the maintenance of effect study ESKETINTRD3003 
and will proceed to the follow-up phase after completion of the double-blind induction phase.
All subjects will be provided with an additional 4 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.
Study-site personnel will instruct subjects on how to take and store the oral antidepressant
treatments supplied during this study for at-home use. A subject diary to capture oral 
antidepressant study medication use will be provided.
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On intranasal dosing days, it is recommended the oral antidepressant medication not be taken 
until at least 3 hours after an intranasal treatment session. 
6.2.1.
Guidance on Blood Pressure Monitoring on Intranasal Treatment 
Session Days
Given the potential for treatment emergent transient elevation in systolic and diastolic blood 
pressure, the following guidance should be followed on intranasal dosing days:

If subsequent to fulfilling the inclusion and exclusion criteria on Day 1 (ie, applicable for all 
other intranasal treatment session days after Day 1), a subject’s pre-dose systolic blood 
pressure (SBP) is ˃140 mmHg and/or diastolic blood pressure (DBP) is ˃90 mmHg, it is 
recommended to repeat the blood pressure measurement after subject rests in sitting or 
recumbent position. If after rest and repeated measurements, pre-dose SBP is ˃140 mmHg 
and/or DBP is ˃90 mmHg, then dosing should be postponed and the subject scheduled to 
return on the following day or within the given visit window. If the blood pressure elevation 
still persists on the next visit, the subject will be scheduled for a consultation by cardiologist, 
other specialist, or primary care physician, prior to further dosing.

If at any postdose time point on the dosing day, the SBP is 180 mmHg but <200 mmHg 
and/or the DBP is 110 mmHg but <120 mmHg, further intranasal dosing should be 
interrupted and the subject should be referred to a cardiologist, other specialist, or primary 
care physician for a follow-up assessment.
-
After the assessment by a cardiologist, other specialist, or primary care physician, if 
recommended by the referring doctor and considered appropriate according to the clinical 
judgment for the subject to continue in the study, the subject may continue with 
intranasal dosing if the pre-dose blood pressure at the next scheduled visit is within the 
acceptable range (see bullet point above).

If at any postdose time point on the dosing day the SBP is 200 mmHg and/or the DBP is 
120 mmHg, the subject must discontinue from further dosing and the subject should be 
referred to a cardiologist, other specialist, or primary care physician for a follow-up 
assessment.
During the double-blind induction phase, at 1.5 hours postdose, if the SBP is 160 mmHg and/or 
the DBP 100 mmHg, assessments should continue every 30 minutes until:

the blood pressure is <160 mmHg SBP and <100 mmHg DBP, or 

in the investigator’s clinical judgment, the subject it is clinically stable and can be 
discharged from the study site, or 

the subject is referred for appropriate medical care, if clinically indicated.

if the blood pressure remains ≥180 mmHg SBP and/or ≥110 mmHg DBP, 2 hours after 
dosing, the subject should be referred for immediate medical treatment.
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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 maintenance clinical study ESKETINTRD3003, will 
proceed into the 24 week 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.
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 at least 
the first 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. 
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 as inadequate adherence.
Antidepressant treatment compliance 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, 
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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 in ‘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 induction phase.
Concomitant therapies must be recorded throughout the study, beginning with signing of the 
informed consent and continuing up to the last visit. Information on concomitant therapies 
should also be obtained beyond this time only in conjunction with new or worsening adverse 
events until resolution of the event.
Subjects should continue to take their permitted concomitant medications (eg, antihypertensive 
medications) at their regular schedule; however, restrictions as outlined in Section 4.3 and 
Attachment 1 should be taken into account. Of note, if a subject has routinely taken his/her oral 
antihypertensive medications in the morning on dosing days, the morning dose should be taken 
prior to intranasal dosing.
Subjects receiving psychotherapy (including cognitive behavioral therapy; CBT) can continue 
receiving psychotherapy, however, CBT must have been ongoing for the last 3 months prior to 
the start of the screening/prospective observational phase. With the exception of new CBT,
which is prohibited, new psychotherapy is allowed during the study. Any change in existing 
therapy or new therapy must be documented on the concomitant therapies form.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; nonpharmacologic therapies, such as psychotherapy, electrical stimulation, 
acupuncture, special diets, and exercise regimens) different from the study drug must be recorded 
in the eCRF. Modification of an effective preexisting therapy should not be made for the explicit 
purpose of entering a subject into the study, unless permitted by protocol (eg, adjustment of 
blood pressure medications.
Rescue Medications
Rescue medications will not be supplied by the sponsor. In case of treatment-emergent adverse 
events that cannot be resolved by stopping further administration of intranasal 
esketamine/placebo, the following rescue medications may be considered:

For agitation or anxiety: As required, midazolam (maximum dose 2.5 mg orally or IM) or 
short acting benzodiazepine

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.
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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, medical resource utilization, health economic, and safety measurements 
applicable to this study.
With the exception of postdose assessments, visit-specific subject-reported outcomes
assessments should be conducted or completed before any tests, procedures, or other 
consultations for that clinic visit to prevent influencing subject perceptions. A recommended 
order of study procedures will be provided to sites as a separate document.
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 116.0 mL (Table 3). 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. Additional serum or urine pregnancy tests may be performed, as determined necessary 
by the investigator or required by local regulation, to establish the absence of pregnancy at any 
time during the subject's participation in the study.
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Table 3:
Volume of Blood to Be Collected From Each Subject
Type of Sample
Volume per 
Sample (mL)
No. of Samples 
per Subject
Total Volume of 
Blood (mL) a
Screening/Prospective Observational Phase
Serum chemistry b
5
1
5
TSH
3.5
1
3.5
Hematology c
2
1
2
Biomarker: protein
10
1
10
Biomarker: DNA
6
1
6
Biomarker: RNA
2.5
1
2.5
Tricyclic Antidepressant Blood levele
FT4f
6
3.5
1
1
6
3.5
Double-blind Induction Phase
Serum chemistry
2.5
2
5
Hematology
2
2
4
Pharmacokinetics
2
4
8
Biomarker: protein (at Visits 2.1, 2.4, and 2.9)    
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
116.0 mL
Abbreviations: DNA, deoxyribonucleic acid; RNA, ribonucleic acid; TSH, thyroid-stimulating hormone
a) Calculated as number of samples multiplied by amount of blood per sample.
b) Serum chemistry includes serum -hCG pregnancy tests (for women of childbearing potential) and lipid panel.
c) As needed, HbA1c will be measured from the sample collected for hematology.
e) For specific tricyclic antidepressants which are being taken at a dose below the MGH-ATRQ minimum 
therapeutic dose, a blood level that is within therapeutic (antidepressant) range, is acceptable to establish the 
adequacy of the antidepressant treatment.
f) 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 18 
(or older if the minimum legal age of consent in the country in which the study is taking place is 
>18) to 64 years of age (inclusive) will be screened to determine eligibility for study 
participation (please refer to the study entry criteria listed in Section 4). 
Subjects must meet DSM-5 diagnostic criteria for single-episode MDD (if single-episode MDD, 
the duration must be 2 years) or recurrent MDD, without psychotic features, based upon clinical 
assessment and confirmed by the MINI. In addition, at the start of the screening/prospective 
observational phase, the subject must have an IDS-C30 total score 34.
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At the start of this phase, subjects must have had non-response (≤ 25% improvement) to 1 but 
5 (if current episode is > 2 years, upper limit is applicable to only the last 2 years) oral
antidepressant treatments taken at adequate dosage and for adequate duration, as assessed using 
the MGH-ATRQ and documented by records (eg, medical/pharmacy/prescription records or a 
letter from treating physician, etc.), for the current episode of depression. In addition, at the start 
of the screening/prospective observational phase, the subject is taking a different oral
antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or above the 
minimum therapeutic dose. This antidepressant treatment, as well as any other ongoing 
medications being taken for depression (including adjunctive/augmentation therapies), will 
continue from the start of Week 1 through the end of Week 4 of the screening/prospective 
observational phase to confirm non-response prospectively. Dose adjustment is permitted per 
clinical judgment, but the oral antidepressant treatment is to remain at or above the minimum 
therapeutic dose (per the MGH-ATRQ) through the end of Week 4.
Antidepressant treatment adherence will be assessed using the PAQ. 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 ≥28 required), and antidepressant treatment response in the current depressive episode 
must be confirmed using a 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 non-responders 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 ≥ 28 on Week 2 and Week 4. Eligible 
subjects (determined by remote blinded raters) who are entering the double-blind induction phase 
will discontinue all of their current medication(s) being used for depression treatment, including 
adjunctive/augmentative therapies, and any other prohibited psychotropic medications, including 
adjunctive atypical antipsychotics. Subjects who were 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 non-responder 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.
The taper period should not start until after the completion of 4 weeks of prospective 
antidepressant treatment and assessment of the antidepressant treatment response.
9.1.3.
Double-Blind Induction Phase
During this phase, subjects will self-administer double-blind intranasal treatment with 
esketamine (56 mg or 84 mg) or placebo twice per week for 4 weeks as a fixed dose regimen. In 
addition, subjects will simultaneously initiate a new, open-label oral antidepressant (please refer 
to Section 6, Dosage and Administration).
Approximately 348 eligible subjects with TRD will be randomly assigned to 1 of the following 
3 double-blind intranasal treatment groups at a 1:1:1 ratio (approximately 116 subjects per 
group):

Intranasal placebo

Intranasal esketamine (56 mg)

Intranasal esketamine (84 mg)
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 antidepressant medication assigned by the 
investigator (based on review of the MGH-ATRQ and relevant prior antidepressant treatment 
information) will be one that the subject has not previously had a non-response to in the current 
depressive episode, has not been previously intolerant to (lifetime), and is available in the 
participating country. Dosing of the oral antidepressant will begin on Day 1. A mandatory 
titration schedule is provided in Attachment 3. Doses are not to exceed the maximum dose 
defined in the titration schedule.
For information obtained via telephone contact, written documentation of the communication 
must be available for review in the source documents. During telephone contact visits with the 
subject by site personnel, adverse event and concomitant therapy information will be obtained. In 
addition, specified clinician-administered assessments will be performed by appropriately 
qualified staff.
At the end of the double-blind induction phase, subjects who are responders (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) may be eligible to enter the subsequent maintenance 
clinical study (Study ESKETINTRD3003). To maintain study blinding, all responder subjects, 
including responders to the active comparator (ie, oral antidepressant plus intranasal placebo),
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may be eligible to enter Study ESKETINTRD3003. Participation in ESKETINTRD3003 will 
begin immediately after the completion of the double-blind induction phase. Subjects will 
receive oral antidepressant medication and will be instructed to continue taking their oral 
antidepressant medication through their next study visit (ie, first study visit of the stabilization 
phase in Study ESKETINTRD3003).
Those subjects who do not enter Study ESKETINTRD3003 will proceed into the 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.
If applicable, subjects who withdraw early will receive additional oral antidepressant medication 
and it will be recommended that they continue taking the oral antidepressant medication for at 
least the first 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 ESKETINTRD3003 study will 
proceed into the 24-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 addition, data will be collected to assess the course of the 
subject’s current major depressive episode over a 6 month period.
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. In order to better assess potential withdrawal symptoms from the 
intranasal medication, the oral antidepressant medication should be continued for at least the first 
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.
An open-label safety extension study, 54135419TRD3008, may be available (pending country 
and site approval) for eligible subjects participating in the ESKETINTRD3001 study. Please 
refer to the 54135419TRD3008 protocol for full details when available.
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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 various subject-reported outcome assessments be completed prior to 
other procedures.
9.2.1.1.
Primary Efficacy Evaluation
The primary efficacy evaluation will be the MADRS total score. The MADRS will be performed 
by independent remote raters during the study, using the Structured Interview Guide for the 
Montgomery Asberg Depression Rating Scale (SIGMA: Williams 2008).
The MADRS is a clinician-rated scale designed to measure depression severity and detects 
changes due to antidepressant treatment. 53 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.
Key Secondary Efficacy Evaluation (Clinician-completed)
The MADRS will also be administered using a modified recall period of 24 hours for the key 
secondary efficacy evaluation related to onset of clinical response by Day 2 that is maintained 
for the duration of the double-blind induction phase with one excursion allowed.
The MADRS with a 24-hour recall period will be used on Day 2. The feasibility of this shortened 
recall period has been confirmed with patients, and physicians, and there are data supporting the 
psychometric properties of this shortened recall period (data on file). The MADRS with a 7 day 
recall will be used for all subsequent MADRS assessments used for the key secondary efficacy 
evaluation (maintenance of clinical response achieved on Day 2 for duration of double-blind 
induction phase).
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9.2.1.3.
Key Secondary Efficacy Evaluation (Patient-reported Outcome)
9.2.1.3.1.
SDS
The SDS will be used to assess the secondary objective of functional impact and associated 
disability. The SDS is a subject-reported outcome measure and is a 5-item questionnaire which 
has been widely used and accepted for assessment of functional impairment and associated 
disability.49,81 , The first three items assess disruption of (1) work/school, (2) social life, and 
(3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items 
are summed to create a total score of 0-30 where a higher score indicates greater impairment. It 
also has one item on days lost from school or work and one item on days when underproductive. 
The recall period for this study is 7 days.
9.2.1.3.2.
PHQ-9 
The PHQ-9 is a 9-item, subject-reported outcome measure that will be used to assess depressive 
symptoms.84 The scale scores each of the 9 symptom domains of the DSM-5 MDD criteria and it 
has been used both as a screening tool and a measure of response to treatment for depression. 
Each item is rated on a 4-point scale (0=not at all, 1=several days, 2=more than half the days, 
and 3=nearly every day). The subject’s item responses are summed to provide a total score 
(range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. The 
recall period is 2 weeks. 
9.2.1.4.
Other Secondary Efficacy Evaluations (Clinician-completed)
9.2.1.4.1.
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; 
7=among the most extremely ill patients. The CGI-S permits a global evaluation of the subject’s 
condition at a given time.
9.2.1.5.
Other Secondary Efficacy Evaluations (Patient-reported Outcomes)
9.2.1.5.1.
GAD-7 
The 7-item subject-reported GAD-7 will be used to measure the secondary objective of 
symptoms of anxiety. The GAD-7 is a brief and validated measure of overall anxiety. Each item
is rated on a 4-point scale (0=not at all; 1=several days; 2=more than half the days; 3=nearly 
every day). 83 Item responses are summed to yield a total score (range of 0 to 21), with higher 
scores indicating more anxiety. The recall period is 2 weeks.
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9.2.1.5.2.
EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily 
designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and 
the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L descriptive system comprises the 
following 
5 
dimensions: 
Mobility, 
self-care, 
usual 
activities, 
pain/discomfort 
and 
anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems 
(Level 1 indicating no problem, Level 2 indicating slight problems, Level 3 indicating moderate 
problems, Level 4 indicating severe problems, and Level 5 indicating extreme problems).
The subject selects an answer for each of the 5 dimensions considering the response that best 
matches his or her health “today.” The descriptive system can be represented as a health state. 
The EQ-VAS self-rating records the respondent’s own assessment of his or her overall health 
status at the time of completion, on a scale of 0 to 100. 
The time taken to complete the questionnaire varies with age, health status, and setting but is 
likely to be around 1 minute.
9.2.2.
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
The first key secondary endpoint is the proportion of subjects showing onset of clinical response 
by Day 2 that is maintained through the end of the 4 week double-blind induction phase. Onset 
of clinical response is defined as 50% reduction in the MADRS total score by the day after 
taking the first dose of double-blind medication (Day 2) that continued through the end of the 4-
week double-blind induction phase with one excursion allowed. Subjects who discontinue the 
study prior to the end of the double-blind induction phase will not be considered to have 
maintained clinical response.
The second key secondary endpoint is the change in SDS total score as measured by the change 
from baseline (Day 1 prior to randomization) to the end of the 4-week double-blind induction 
phase.
The third key secondary endpoint is the change from baseline (Day 1 prior to randomization) to 
the end of the 4-week double-blind induction phase in subject-reported depressive symptoms, 
using the PHQ-9 total score.
Other secondary efficacy endpoints include:

Proportion of responders (50% reduction from baseline in MADRS total score) at the end 
of the 4 week double-blind induction phase
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
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: 
–
Severity of depressive illness, using the CGI-S
–
Anxiety symptoms, as measured by the GAD-7
–
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.
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 adverse events as additional 
PD parameters) and PK metrics of esketamine may be evaluated. If there is any visual trend in 
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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, hypothalamus pituitary adrenal (HPA) axis activation, 
neurotrophic factors, and metabolic factors will be investigated. Biomarkers may be added or 
deleted based on scientific information or technical innovations under the condition that the total 
volume of blood collected will not be increased.
The biomarker data obtained from this study may also be included in an ongoing cross-study 
analysis to investigate the relationship between depression severity and phenotypes and 
biomarkers.
Blood samples for DNA analyses will be collected at the time points indicated in the Time and 
Events Schedule for the assessment of genetic and epigenetic variation in genes in pathways 
relevant to depression (eg, HPA axis, inflammation, growth factors, monoamine transporters, ion 
channels, and circadian rhythm).
Genotyping will be conducted only on the screening sample; pharmacogenomic and epigenetic 
evaluations may be performed on any/all collected samples.
DNA samples will be used for research related to esketamine, oral antidepressants, TRD, or 
MDD. They may also be used to develop tests/assays related to esketamine, oral antidepressants, 
TRD, or MDD. Pharmacogenomic research may consist of the analysis of 1 or more candidate 
genes or of the analysis of genetic markers throughout the genome (as appropriate) in relation to 
esketamine, oral antidepressants, TRD, or MDD clinical endpoints.
Further information regarding handling, shipment, and labeling of biological samples will be 
provided in a separate laboratory manual.
9.6.
Medical Resource Utilization
Medical resource utilization data, associated with healthcare encounters, will be collected during 
the follow-up phase of the study. Protocol-mandated procedures, tests, and encounters are 
excluded. The data collected may be used to conduct exploratory economic analyses and will 
include:

Number, duration, and type of healthcare encounters (inpatient and outpatient)

Duration of hospitalization (total days length of stay, including duration by wards)
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9.7.
Safety Evaluations
Details regarding the Independent Data Monitoring Committee are provided in Section 11.10.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule.
There may be instances where a subject has started a scheduled clinic visit in which an intranasal 
treatment session is planned, but due to predose vital sign measurements (e.g., blood pressure 
value), a decision has been made to postpone/delay the intranasal treatment session within the 
visit window permitted per protocol. In such cases, all time points (including predose) of the 
following assessments must be repeated on the actual intranasal treatment session day: vital sign 
(ie, blood pressure, pulse, respiratory rate, and temperature), 12-lead ECG, C-SSRS (since last 
visit), 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.
TEAEs of special interest will be examined separately (please refer to Sections 3.2.6 and 11.9).
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and a urine sample for urinalysis will be 
collected. The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the adverse event section of the 
eCRF. The laboratory reports must be filed with the source documents.
The use of local laboratories is allowed in cases where initiation of treatment or safety follow-up 
is time-critical and the central laboratory results are not expected to be available before the need 
to begin dosing or if actions need to be taken for safety reasons.
The following tests will be performed by the central laboratory, unless noted otherwise:

Hematology Panel
-hemoglobin
-platelet count
-hematocrit
-red blood cell (RBC) count
-white blood cell (WBC) count with differential
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
Serum Chemistry Panel
-sodium
-alkaline phosphatase
-potassium
-creatine phosphokinase (CPK)
-chloride
-calcium
-bicarbonate
-phosphate
-blood urea nitrogen (BUN)
-albumin
-creatinine
-total protein
-glucose
-total bilirubin
-aspartate aminotransferase (AST)
-alanine aminotransferase (ALT)
-gamma-glutamyltransferase (GGT)

Urinalysis
Dipstick
Sediment (if dipstick result is abnormal)
-specific gravity
-red blood cells
-pH
-white blood cells
-glucose
-epithelial cells
-protein
-crystals
-blood
-casts
-ketones
-bacteria
-bilirubin
-urobilinogen
-nitrite
-leukocyte esterase
If dipstick result is abnormal, flow cytometry or microscopy will be used to measure 
sediment. In case of discordance between the dipstick results and the flow cytometric 
results, the sediment will be examined microscopically.
The following tests will be done at time points specified in the Time and Events Schedule or as 
required based on subject status (noted below):

Lipid panel: Total cholesterol, low density lipoprotein (LDL)-cholesterol, high density 
lipoprotein (HDL)-cholesterol, and triglycerides

Serum and urine pregnancy testing (for women of childbearing potential only)

Urine Drug Screen: Barbiturates, methadone, opiates, cocaine, cannabinoids (cannabinoids 
are 
only 
exclusionary 
on 
Day 
1 
predose), 
phencyclidine, 
and 
amphetamine/methamphetamine

Alcohol breath test 

Thyroid-stimulating hormone (TSH)

Free thyroxine (FT4), only if required for abnormal TSH (refer to Inclusion 
criteria)Calculation of creatinine clearance

Glycated hemoglobin (HbA1c) test
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
A serum follicle stimulating hormone (FSH) level test, only if required for documentation
that a female subject is not of childbearing potential (refer to Inclusion Criteria No. 9)
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:
-
QTcF change from baseline is ≥ 60 msec and QTcF > 480 msec, or 
-
QTCF > 500 msec.
Vital Signs (temperature, pulse/heart rate, respiratory rate, blood pressure)
Blood pressure and pulse/heart rate measurements will be assessed supine with a completely 
automated device or using manual techniques.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of 
rest in a quiet setting without distractions (eg, television, cell phones).
For further details regarding blood pressure, please see Guidance on Blood Pressure Monitoring 
on Intranasal Dosing Days (Section 6.2.1).
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 (SpO2) <93% 
should be confirmed by an additional measurement on another part of the body.
On intranasal treatment session days, pulse oximetry will be recorded every 15 minutes from 
predose to t=1.5 hours postdose. If oxygen saturation levels are <93% at any time during the 
1.5 hour postdose interval, pulse oximetry will be recorded every 5 minutes until levels return to 
93% or until the subject is referred for appropriate medical care, if clinically indicated.
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Physical Examination, Height, Body Weight, and Neck Circumference
Physical examinations, body weight, and height will be performed/measured as 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. 
Nasal Symptom Questionnaire
Subjects will complete a nasal symptom questionnaire. The nasal symptom questionnaire was 
developed by the sponsor to assess nasal tolerability 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,4 and 
will be administered to assess treatment-emergent dissociative symptoms.
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The CADSS consists of 23 subjective items, divided into 3 components: Depersonalization 
(Items 3 to 7, 20, and 23), derealization (Items 1, 2, 8 to 13, 16 to 19, and 21) and amnesia 
(Items 14, 15, and 22). Participant’s responses are coded on a 5-point scale (0=not at all through 
to 4=extremely). CADSS has excellent inter-rater reliability and internal consistency. 
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.64 It reportedly 
provides a rapid and efficient evaluation of treatment response in clinic drug studies and in 
clinical settings.73
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 
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.
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 dosing 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.
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The clinician will answer “Yes” or “No” to the question “Is the subject considered ready to be 
discharged based on their overall clinical status (eg, sedation, blood pressure, and other adverse 
events)?”
On each intranasal dosing day, the CGADR will be performed at 1 hour and 1.5 hours postdose; 
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 on Day 25 to establish a 
baseline prior to discontinuation of intranasal esketamine treatment. In order to better assess 
potential withdrawal symptoms from the intranasal medication it is recommended that the oral 
antidepressant medication be continued for at least the first 2 weeks of the follow up phase 
unless determined as not clinically appropriate.
The PWC-20 is a 20-item simple and accurate method to assess potential development of 
discontinuation symptoms after stopping of study drug. The PWC-20 is a reliable and sensitive 
instrument for the assessment of discontinuation symptoms.71 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 subject-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.
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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 or cystitis.40
If any items are missing, a total score cannot be calculated.
If a subject has a score greater than 18 on the BPIC-SS scale and urinalysis and microscopy 
indicate no evidence of urinary tract infection, then the subject 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 obtained if the BPIC-SS score on applicable 
study day is greater than 18.
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:

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).3 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. 
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.
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UPSIT and Smell Threshold Test
To assess any potential treatment-emergent effects on the sense of smell, olfactory function will 
be qualitatively and quantitatively assessed using validated standardized olfactory tests prior to 
and at specified time points during the study. The 2 tests to be administered are: 

The UPSIT assesses 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 4 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 >0.90.17,18,19
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 Smell Threshold Test will assess the smell threshold using a forced-choice single 
staircase threshold procedure. This test quantifies a detection threshold for the rose-like 
smelling odorant phenyl ethyl alcohol (PEA). This odorant is used because it has little 
propensity to stimulate the trigeminal nerve within the nose. This test is sensitive to 
olfactory deficits from a wide range of disorders. 
These tests 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. 
If the subject has significant nasal congestion on the day of a scheduled UPSIT and/or Smell 
Threshold Test, the site should consider postponing the smell test assessment(s) to the next 
scheduled clinic visit.
9.8.
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.15
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.
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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 Obstructive Sleep Apnea (apnea hypopnea index of >30).6
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.85
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.74 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
Massachusetts General Hospital Female Reproductive Lifecycle and Hormones 
Questionnaire (MGH-Female RLHQ): Module I and Menstrual Cycle Tracking
The MGH-Female RLHQ Module I (childbearing potential, menopausal status, and menstrual 
cycle) is a brief questionnaire aimed at standardizing the minimal collection of relevant 
information about reproductive hormones and status. It will be completed by a clinician. This 
information may facilitate exploratory analyses of the impact of endogenous and exogenous 
reproductive hormones on the course of treatment of MDD and potentially inform care of women 
with MDD in the future.33
Menstrual cycle tracking (start date of last menstrual period) will be documented at the study 
visits specified in the Time and Events Schedule for women with a menstrual cycle.
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PAQ
Subjects’ 
adherence 
to 
their 
oral 
antidepressant 
treatment 
regimen 
during 
the 
screening/prospective observational phase will be assessed using the PAQ. It is a brief, 2-item 
subject-report outcome measure that was developed at the University of Texas Southwestern 
Medical Center to assess how often the subject has taken, and whether he or she has made any 
changes to his/her antidepressant treatment regimen in the last 2 weeks. The total score is based 
on the response selected to Question 1, and is interpreted as 0-1=adherent and 2 or 
more=nonadherent.
9.9.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. If blood samples are collected via an indwelling cannula, an appropriate 
amount (1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock 
will be removed from the cannula and discarded before each blood sample is taken. After blood 
sample collection, the cannula will be flushed with 0.9% sodium chloride, United States 
Pharmacopeia (USP) (or equivalent) and charged with a volume equal to the dead space volume 
of the lock.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
10.
SUBJECT COMPLETION/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 assessment 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.
Subjects who enter the follow-up phase will be considered to have completed this phase of the 
study if he or she has completed the MADRS assessment at Week 24 of the follow-up phase.
10.2.
Withdrawal from the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up
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
Withdrawal of consent (Note: See “Withdraw of Consent” section below; this should only 
be selected as a reason for withdrawal if the subject does not agree to any further study 
assessments or procedures. If the subject is agreeable to participating in the Early 
Withdrawal visit and the follow-up phase, another reason for withdrawal should be 
selected.)

Violation of protocol procedures (determined on a case-by-case basis)

Blind is broken (double-blind 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.

Subject becomes pregnant

Study is terminated by sponsor for futility

Death
If the subject withdraws from the study before the end of the double-blind induction phase, an 
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), as well as other contact 
information (eg, email addresses) from subjects before randomization. In addition, the study site 
should emphasize the importance of follow-up information to the subject before randomization. 
The measures taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Subjects who withdraw will not be 
replaced.
Withdrawal of Consent
Every effort will be made in the study to ensure withdrawal of consent is not selected as a reason 
for discontinuation when in fact the subject withdrew for an identifiable reason (eg, due to an 
adverse event or 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 
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agreeable to follow-up contact will be withdrawn from the study as “withdrawal of consent.”
Subjects who no longer wish to take study drug but agree to provide follow-up information will 
be withdrawn from the double-blind induction phase with the reason noted as “Other” and will 
specify the reason why.
For a subject who “withdraws consent”, it is recommended that the subject withdraw consent in 
writing; if the subject refuses or is physically unavailable, the study site should document and 
sign the reason for the subject’s failure to withdraw consent in writing and maintain it with the 
subjects source records.
The investigator will be responsible for making all required notifications to the Institutional 
Review Board (IRB) 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.
At the end of the double-blind induction phase the database will be locked for the analysis and 
reporting of this phase. The subject treatment assignment will be revealed only to sponsor’s 
study staff. The investigators and the site personnel will be blinded to the treatment assignment 
until all subjects have completed study participation through the follow-up phase.
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 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 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 
for the double-blind induction phase of 6.5 points in MADRS total score between any dose of 
esketamine and the active comparator, a standard deviation of 12, a 1-sided significance level of 
0.0125, and a drop-out rate of 25%. A maximum of about 116 subjects will need to be 
randomized to each treatment group to achieve 90% power for comparison of each esketamine 
dose plus oral antidepressant arm with oral antidepressant plus intranasal placebo arm (active 
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comparator) 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.
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 120 subjects in the 
study (approximately 40 subjects per treatment arm). It is projected that at that time 
approximately 90 subjects in the full analysis set would have completed the double-blind 
induction phase of the study (approximately 30 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 116 per 
treatment group. If the study is not stopped for futility, sample size re-estimation will be 
conducted for both doses of esketamine, ie, the analysis does not allow for stopping a dose based 
on the results of the interim analysis.
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 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 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.
11.4.
Efficacy Analyses
Efficacy analyses will be performed on the full analysis set, which will include all randomized 
subjects who receive at least 1 dose of intranasal study drug and 1 dose of oral antidepressant 
medication in the double-blind induction phase.
With the exception of 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 each esketamine plus 
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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 each esketamine plus oral antidepressant arm 
versus intranasal placebo plus oral antidepressant will be performed using the appropriate 
contrast.
For the analysis of the first key secondary efficacy endpoints, the proportion of subjects showing 
onset of clinical response by Day 2 that is maintained for the duration of the double-blind 
induction phase in the esketamine plus oral antidepressant arm will be compared with the oral 
antidepressant plus intranasal placebo arm using a Cochran-Mantel-Haenszel chi-square test 
adjusting for country and class of antidepressant (SNRI or SSRI). Clinical response is defined as 
50% improvement in MADRS total score by Day 2 (ie, the day after taking the first dose of 
double-blind intranasal medication) that continues through the end of the double-blind phase
with one excursion allowed. Subjects who discontinue the study prior to end of the double-blind
induction phase will not be considered to have maintained clinical response.
The second and third key secondary efficacy endpoints, change from baseline in SDS total score 
at Week 4 and change from baseline in PHQ-9 total score at Week 4 (subject to regulatory 
acceptance of PHQ-9) in the double-blind induction phase, will be analyzed using the same 
models described above for the MADRS total score. Responses to questions H1 to H3 from the 
SDS will be summarized separately.
To strongly control Type I error across the primary and the 3 key secondary efficacy endpoints 
(change in MADRS total score, onset of clinical response, and change in SDS, change in PHQ-9 
total score), and across the 2 esketamine dose-placebo comparisons, a truncated fixed sequence 
parallel gatekeeping test procedure20,21  will be applied between families of hypotheses 
corresponding to the endpoints, and between the two dose-placebo comparisons within each 
family (where, 84 mg esketamine dose group will be tested first and 56 mg esketamine dose 
group will be tested only if 84 mg is shown to be significant). The 2 dose-placebo comparisons 
corresponding to each efficacy endpoint are considered as a family of hypotheses.  Further 
details of this approach will be provided in the SAP. The following is a high level summary of 
the approach:
Testing will start with the primary endpoint, and will proceed to other endpoints along the 
sequence only if at least 1 esketamine dose-placebo comparison is significant at a pre-specified 
level of significance.
The 84 mg dose comparison will be tested at a 1-sided α = 0.025 for MADRS total score. If this 
dose is significantly different from placebo, then the 56 mg dose of esketamine will be tested 
against placebo at a 1-sided α1 =0.02125. 
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If both dose-placebo comparisons are significant for the MADRS total score, then testing will 
proceed to onset of clinical response. The 84 mg dose comparison will be tested at a 1-sided α = 
0.025. If this dose is significantly different from placebo, then the 56 mg dose of esketamine will 
be tested against placebo at a 1-sided α1 =0.02125. However, if only the 84 mg dose is 
significant for the MADRS total score then testing will proceed to onset of clinical response at a 
1-sided α2=0.00375, where the 84 mg dose will be compared to placebo. The 56 mg dose will 
not be tested for any of the remaining endpoints.
Similarly, if both-dose comparisons are significant for onset of clinical response, then testing 
will proceed to SDS at a 1-sided α = 0.025 for the 84 mg dose and at a 1-sided α1=0.02125 for 
the 56 mg dose in a fixed sequence. However, if only the 84 mg dose is significant for onset of 
clinical response then testing will proceed to SDS at a 1-sided α2=0.00375, where only the 84 mg 
dose will be compared to placebo. The 56 mg dose will not be tested for the remaining 
endpoints.
Finally, if both-dose comparisons are significant for SDS, then testing will proceed to PHQ-9 at 
1-sided α = 0.025 for the 84 mg dose and at a 1-sided α1=0.02125 for the 56 mg dose in a fixed 
sequence. However, if only the 84 mg dose is significant for SDS then testing will proceed to 
PHQ-9 at 1-sided α2=0.00375, where only the 84 mg dose will be compared to placebo.
Response and remission rates will be summarized at each visit.
Change from baseline in GAD-7 total scores and 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 
respective baseline score (unranked score in the case of CGI-S) as the covariate. 
Dimension scores of EQ-5D-5L data, 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 non-response.
Pharmacogenomic analyses may include candidate gene analyses or genome-wide association 
analyses in relation to treatment response, maintenance/stabilization of response, relapse, 
non-response, and MDD/TRD. Expression analyses may include testing of known messenger 
RNA/microRNA (mRNA/miRNA) transcripts or transcriptome-wide analysis in relationship to 
antidepressant treatment response and MDD/TRD.
Details of the analysis plan and summary of results from both biomarker and pharmacogenomics 
analyses will be reported separately.
11.8.
Medical Resource Utilization Analyses 
Medical resource utilization data will be descriptively summarized.
11.9.
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). AEs 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 QTc interval using the following correction methods: QT corrected according to Bazett's 
formula (QTcB) and QTcF.2,39,77
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 score and changes from predose will be summarized at each
scheduled time point.
Clinical Global Assessment of Discharge Readiness, PWC-20, BPIC-SS, UPSIT, and Smell 
Threshold Test
Descriptive statistics of each score and changes and/or percent changes from baseline will be 
summarized at each scheduled time point.
Cognition Testing
Descriptive statistics of the cognitive domain scores and changes from baseline will be 
summarized at each scheduled time point.
11.10. 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 
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be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An 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.22,23,27,28,79,80,87,88
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).
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12.1.3.
Severity Criteria
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure (which may include contact for follow-up of safety), with the exception 
of pregnancy which will be reported up to 6 weeks after the last dose of study medication 
(females) or 90 days after the last dose of study medication (partners of male participants). 
Serious adverse events, including those spontaneously reported to the investigator, must be 
reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. Anticipated events will be 
recorded and reported as described in 
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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 
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 unblended. 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).
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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

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.

For convenience the investigator may choose to hospitalize the subject at times during the 
treatment period.
The cause of death of a subject in a study, whether or not the event is expected or associated with 
the study drug, is considered a serious adverse event.
12.3.3.
Pregnancy
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered serious adverse events and must be reported using 
the Serious Adverse Event Form. Any subject who becomes pregnant during the study must be 
promptly withdrawn from the study and discontinue further study treatment.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
subjects included in the study will be reported by the study-site personnel within 24 hours of 
their knowledge of the event using the appropriate pregnancy notification form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
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12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may 
have an impact on the safety and efficacy of the product. Timely, accurate, and complete 
reporting and analysis of PQC information from studies are crucial for the protection of subjects, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to 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 hydrochloride
(16.14% weight/volume [w/v]; equivalent to 14% w/v of esketamine base) in a nasal spray 
pump. The solution will consist of 161.4 mg/mL esketamine hydrochloride (equivalent to 
140 mg of esketamine base) formulated in 0.12 mg/mL ethylenediaminetetraacetic acid (EDTA) 
and 1.5 mg/mL citric acid at a pH of 4.5 in water for injection. It is provided in a nasal spray 
pump, which delivers 16.14 mg esketamine hydrochloride (14 mg esketamine base) per 100 L
spray. Each individual nasal spray pump (device) contains a total of 28 mg (ie, 2 sprays). 
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The placebo solution will be supplied as a clear, colorless intranasal solution of water for 
injection, with a bittering agent (denatonium benzoate [Bitrex®] at a final concentration of 
0.001mg/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
Oral Antidepressant Medications
Duloxetine
Duloxetine 30 mg will be obtained from commercial stock and provided under the responsibility of 
the sponsor. Please refer to the package insert/SmPC for the physical description and a list of 
excipients.22,23
Escitalopram
Escitalopram 10 mg will be obtained from commercial stock and provided under the 
responsibility of the sponsor. Please refer to the package insert/SmPC for the physical description 
and a list of excipients.27,28
Sertraline
Sertraline 50 mg and 25 mg (as applicable) will be obtained from commercial stock and provided 
under the responsibility of the sponsor. Please refer to the package insert/SmPC for the physical 
description and a list of excipients. 79,80
Venlafaxine XR
Venlafaxine 75 mg and 37.5 mg (as applicable) will be obtained from commercial stock and 
provided under the responsibility of the sponsor. Please refer to the package insert/SmPC for the 
physical description and a list of excipients.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 200 µL. Each device delivers 16.14 mg 
esketamine hydrochloride (14 mg esketamine base) or 0.1 µg of denatonium benzoate per 100 µL
spray.
Each nasal spray device will be individually packaged in a blister tray and subsequently put into a 
carton box. Each carton box constitutes a non-child-resistant subject kit, labeled with a unique 
medication kit number.
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Device for Practicing Intranasal Study Drug Administration
The demonstration intranasal device will also be supplied by the sponsor and will contain placebo 
solution. Subjects will practice spraying into the air and will not spray intranasally.
Oral Antidepressant Medication
Oral antidepressant tablets or capsules will remain in their commercial packaging.
If blisters are supplied, each blister will be packaged into a child-resistant dose pack to constitute 
a subject kit, labeled with a unique medication kit number. These will be labeled according to 
applicable regulatory requirements.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
Study drug will be stored at the study site in a secure area with restricted access until dispensed to 
the subjects. 
All study drug must be stored at controlled temperatures as indicated on the product-specific 
labeling.
Please refer to the pharmacy manual/study site investigational product manual and instructions for 
use documents for additional guidance on study drug preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study.
The dispensing of study drug to the subject, and the return of study drug from the subject (if 
applicable), must be documented on the drug accountability form. Subjects must be instructed to 
return all original containers, whether empty or containing study drug.
The study drug administered to the subject must be documented on the drug accountability form. 
All study drug will be stored and disposed of according to the sponsor's instructions. Study-site 
personnel must not combine contents of the study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and must 
be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the investigational product destruction form. When the study site is an authorized 
destruction unit and study drug supplies are destroyed on-site, this must also be documented on the
investigational product destruction form.
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Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member of 
the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only to 
subjects participating in the study. Returned study drug must not be dispensed again, even to the 
same subject. 
Whenever a subject brings his or her study drug to the study site for pill count (ie, compliance 
check), this is not seen as a return of supplies. 
Study drug may not be relabeled or reassigned for use by other subjects. The investigator agrees 
neither to dispense the study drug from, nor store it at, any site other than the study sites agreed 
upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Practice intranasal devices 

Investigator's Brochure for esketamine

Local prescribing information for oral antidepressant options in double-blind induction 
phase

Investigational Product (IP) Binder, including the IP Procedures Manual

Laboratory manual and materials

Clinician-administered and subject-reported outcome assessments:

Paper versions, as applicable

Electronic devices and associated materials

IWRS Manual

ECG equipment and associated materials (eg, manual)

Instructions for Use documents (subject and healthcare provider versions) for intranasal 
study medication

Rater qualifications/requirements for select clinician-administered assessments

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
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
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.
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. Thus, the study cannot be completed in healthy 
subjects. 
Potential subjects will be fully informed of the risks and requirements of the study and, during 
the study, subjects will be given any new information that may affect their decision to continue 
participation.
For eligibility, subjects must have had non-response to at least 1 prior antidepressant treatment 
and be currently taking an antidepressant treatment at the start of the screening/prospective 
observational phase that will be continued as prospective treatment in the screening/prospective 
observational phase. Only subjects with non-response to their current antidepressant treatment 
after 4 weeks of prospectively observed treatment (for a total duration of antidepressant 
treatment of at least 6 weeks by the end of the screening/prospective observational phase), will 
be eligible to proceed to the double-blind 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 phase and at the end of this phase, those who are responders and 
willing to do so may participate in the maintenance study (ESKETINTRD3003). Subjects who 
are not responders or who otherwise choose not to enter the ESKETINTRD3003 study will enter
the 24 week follow-up phase
All subjects will be provided with an additional 4 week supply of the oral antidepressant 
medication 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.
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Justification for Using Placebo
Intranasal placebo is being used as a double-blind for intranasal esketamine to maintain study 
blinding. All subjects will also receive a newly initiated oral antidepressant during the 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.72 In a meta-analysis of drug studies 
conducted in MDD, it was reported that adult subjects did not have higher rates of suicide 
behaviors or attempts in the placebo group compared with those receiving an active 
antidepressant.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 to not participate in a placebo-controlled study due to the potential for 
increased distress and dysfunction from prolonged depression. 
Therefore, the use of an active-controlled study allows for assessment of efficacy of a new 
compound to allow for scientifically meaningful results. 
Moreover, the duration of the double-blind induction phase is relatively short (4 week duration). 
Subjects will visit the study site at least twice a week during the double-blind induction phase,
and their symptoms will be carefully monitored during each study visit. Safety evaluations will 
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 
ESKETINTRD3003 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. 
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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).
Only subjects who had non-response to their current oral antidepressant treatment, where a 
clinician would consider changing it in the future due to lack of response, will be enrolled.
Only qualified and trained investigators will participate in the study.
The total blood volume to be collected is considered to be within the normal range allowed for 
this subject population over this time frame. The approximate blood volume to be collected is 
123.5 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 (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of human 
subjects. Compliance with this standard provides public assurance that the rights, safety, and 
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
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
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
subjects, data or study conduct), the ICF, applicable recruiting materials, and subject compensation 
programs, and the sponsor has received a copy of this approval. This approval letter must be dated 
and must clearly identify the IEC/IRB and the documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s). 
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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-related 
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing 
IEC/IRB and be in a language that the subject can read and understand. The informed consent 
should be in accordance with principles that originated in the Declaration of Helsinki, current ICH 
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw consent 
to participate at any time. They will be informed that choosing to not participate will not affect the 
care the subject will receive for the treatment of his or her disease. Subjects will be told that 
alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow up if needed and that their records may 
be accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject is authorizing such access, and agrees to allow his or her study 
physician to re-contact the subject for the purpose of obtaining consent for additional safety 
evaluations, if needed.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. After 
this explanation and before entry into the study, consent should be appropriately recorded by 
means of the subject's personally dated signature. After having obtained the consent, a copy of the 
ICF must be given to the subject.
Where local regulations require, a separate ICF may be used for the required DNA component of 
the study.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be limited 
to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality and 
compliance with applicable data privacy protection laws and regulations. Appropriate technical 
and organizational measures to protect the personal data against unauthorized disclosures or 
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access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original medical 
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and 
regulatory inspection. This consent also addresses the transfer of the data to other entities and to 
other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps will 
be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory PK, 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 research samples
(Withdrawal from the Use of Samples in Future Research).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help 
ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
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when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be 
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involves only logistic or administrative aspects of the study, the IRB (and IEC where 
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
(see Contact Information page(s) provided separately). Except in emergency situations, this contact 
should be made before implementing any departure from the protocol. In all cases, contact with the 
sponsor must be made as soon as possible to discuss the situation and agree on an appropriate 
course of action. The data recorded in the eCRF and source documents will reflect any departure 
from the protocol, and the source documents will describe this departure and the circumstances 
requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities in 
each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)
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
Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all sub-investigators

Documentation of sub-investigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by the 
investigator in the study file. To ensure subject confidentiality, no copy will be made. All reports 
and communications relating to the study will identify subjects by subject identification and date of 
birth. In cases where the subject is not randomized into the study, the date seen and date of birth 
will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentations consistent in the type and level of detail with that 
commonly recorded at the study site as a basis for standard medical care must be available for the 
following: subject identification, eligibility, and study identification; study discussion and date of 
signed informed consent; dates of visits; results of safety and efficacy parameters as required by 
the protocol; record of all adverse events and follow-up of adverse events; concomitant 
medication; drug receipt/dispensing/return records; study drug administration information; and
date of study completion and reason for early discontinuation of study drug or withdrawal from the 
study, if applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).
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The minimum source documentation requirements for Section 4.1 (Inclusion Criteria) and 
Section 4.2 (Exclusion Criteria) that specify a need for documented medical history are as follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries

Antidepressant treatment in the current episode of depression
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. All CRF entries, corrections, 
and alterations must be made by the investigator or authorized study-site personnel. The 
investigator must verify that all data entries in the CRF are accurate and correct.
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an eCRF, and transmitted in a secure manner 
to the sponsor within the timeframe agreed upon between the sponsor and the study site. The 
electronic file will be considered to be the eCRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documents. All data relating to the study 
must be recorded in eCRFs prepared by the sponsor. Data must be entered into 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 
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study-site personnel before the study, periodic monitoring visits by the sponsor, and uploading data 
transfers from external service providers into the sponsor's data base. Written instructions will be 
provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review eCRFs for accuracy and completeness during on-site monitoring visits and 
after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period if 
required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
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 eCRFs with the hospital or clinic records (source 
documents); a sample will be reviewed. The nature and location of all source documents will be 
identified to ensure that all sources of original data required to complete the eCRF are known to 
the sponsor and study-site personnel and are accessible for verification by the sponsor study-site 
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contact. If electronic records are maintained at the study site, the method of verification must be 
discussed with the study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be provided 
for review of study-related documents. The monitor will meet with the investigator on a regular 
basis during the study to provide feedback on the study conduct.
In addition to on-site monitoring visits, the 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 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 
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with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the eCRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible for 
being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding esketamine or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomic or exploratory biomarker research 
data, generated as a result of this study, are considered confidential and remain the sole property of 
the sponsor. The investigator agrees to maintain this information in confidence and use this 
information only to accomplish this study, and will not use it for other purposes without the 
sponsor's prior written consent.
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 
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for abstracts, poster presentations, or other materials. If requested by the sponsor in writing, the 
investigator will withhold such publication for up to an additional 60 days to allow for filing of a 
patent application. In the event that issues arise regarding scientific integrity or regulatory 
compliance, the sponsor will review these issues with the investigator. The sponsor will not 
mandate modifications to scientific content and does not have the right to suppress information. 
For multicenter study designs and sub-study approaches, secondary results generally should not be 
published before the primary endpoints of a study have been published. Similarly, investigators 
will recognize the integrity of a multicenter study by not submitting for publication data derived 
from the individual study site until the combined results from the completed study have been 
submitted for publication, within 12 months of the availability of the final data (tables, listings, 
graphs), or the sponsor confirms there will be no multicenter study publication. Authorship of 
publications resulting from this study will be based on the guidelines on authorship, such as those 
described in the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, which 
state that the named authors must have made a significant contribution to the design of the study or 
analysis and interpretation of the data, provided critical review of the paper, and given final 
approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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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), it must
be continued
unchanged until the end of Week 4 of
the 
screening/prospective observational phase, therefore this requirement is not applicable. In such cases the 
investigator may choose to taper the relevant medication during the up to 3-week taper period based on 
their clinical judgment.
Note in the following table: N, Prohibited; Y, Permitted, with restrictions (please refer to the column
labeled “Comments” for additional guidance).
Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for 
Prohibition
Amantadine
N
N
PD interaction
Anorexiants 
(eg, phentermine, 
phendimetrazine)
N
N
Safety
Anticholinesterase 
inhibitors
N
N
Subject 
population is 
excluded
Anticonvulsants
N
N
Subjects with seizures are excluded.
Use as adjunctive treatment for major 
depressive disorder (MDD) is 
prohibited. 
-Note: Anticonvulsants used for 
indications other than seizures may be 
allowed (eg valproate for migraine; 
pregabalin)
Safety and PD 
interaction
Antidepressants 
(other than the specific 
antidepressant started in 
the 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 other indications (eg, 
trazodone for sleep), the use of any 
medication listed on the ATRQ is not 
permitted during the treatment phase.
Safety and PD 
interaction
Antipsychotics
N
N
PD interaction
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Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for 
Prohibition
Benzodiazepines (at 
dosages equal to or less 
than the equivalent of 
6 mg/day lorazepam) and 
non-benzodiazepine 
sleeping medication 
(including: zolpidem, 
zaleplon, eszopiclone, and 
ramelteon)
Y
Y
Prohibited within 12 hours prior to the 
start of each intranasal treatment session 
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
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
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Drug Class
Episodic 
Use (as 
needed)
Continuous 
Use
Comments
Reason for 
Prohibition
Non-vitamin K antagonist 
oral anticoagulation agents 
(eg, dabigatran, 
rivaroxaban, apixaban
N
N
Safety
Opioids
N
N
PD interaction
Psychostimulants 
(eg, amphetamines, 
methylphenidate, and 
modafanil, armodafinl)
N
Y
Prescribed psychostimulants taken for 
indications other than MDD can be 
continued but must not be taken within 
12 hours prior to the intranasal 
treatment session or for 2 hours after the 
intranasal treatment session.
Cardiovascular 
safety
ADHD medications (e.g., 
atomoxetine, guanfacine)
N
Y
Can be continued but must not be taken 
within 12 hours prior to the intranasal 
treatment session or for 2 hours after the 
intranasal treatment session..
Safety
Reserpine
N
N
PD interaction
Scopolamine
N
N
PD interaction
St. John’s Wort
N
N
PD interaction 
and PK
Thyroid hormone 
supplement for treatment 
of thyroid condition only 
(not for depression)
N
Y
Safety
Thyroxine/ 
triiodothyronine (T3), 
thyroid hormone 
prescribed for depression
N
N
PD interaction
Warfarin
N
N
Primary 
condition 
where used is 
excluded
Abbreviations: N, Prohibited; PD, pharmacodynamics; PK, pharmacokinetics; Y, Permitted, with restrictions (please 
refer to the column labeled “Comments” for additional guidance).
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Attachment 2: New York Heart Association Classification of Cardiac Disease
New York Heart Association Classification of Cardiac Disease
Category
Description
Functional Capacity
Class I
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
Class II
Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
Class III
Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable 
at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any 
physical activity is undertaken, discomfort is increased.
Objective Assessment
A
No objective evidence of cardiovascular disease.
B
Objective evidence of minimal cardiovascular disease.
C
Objective evidence of moderately severe cardiovascular disease.
D
Objective evidence of severe cardiovascular disease.
Source: Criteria Committee of the New York Heart Association. Functional capacity and objective assessment. In: 
Dolgin M, ed. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels, 9th ed. Boston, 
MA: Little, Brown & Co; 1994, 253-255.
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Attachment 3: 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. 
Adjustments to the titration schedule may be required in other countries in order to conform to local 
prescribing information.
Global titration schedule:
Oral Antidepressant 
(Active Comparator)
Titration Schedule
Week 1
(Starting Day 1)
Week 2
(Starting Day 8)
Week 3
(Starting Day 15)
Week 4
(Starting Day 22)
Duloxetine
60 mga
60 mg
60 mg
60 mg
Escitalopram
10 mg
20 mg
20 mg
20 mg
Sertraline
50 mg
100 mg
150 mg
200 mg
Venlafaxine XR
75 mg
150 mg
225 mg
225 mg
aSubjects should be initiated with 60 mg/day. Subjects that have in the past shown increased sensitivity towards 
serotonin reuptake inhibitors (SSRI) /norepinephrine reuptake inhibitors (SNRI) can, at the discretion of the treating 
physician, be started on a 30 mg dose and up-titrated into the therapeutic range of 60 mg by the start of Week 2.
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Attachment 4: Anticipated Events
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. 22,23,27,28,42,79,80,87 ,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
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
Sertraline

Most common treatment-emergent AEs associated with sertraline (incidence of at least 5% for 
sertraline or at least twice the incidence in placebo subjects) were ejaculation failure, dry mouth, 
increased sweating, somnolence, tremor, dizziness, fatigue, pain, malaise, abdominal pain, 
anorexia, constipation, diarrhea/loose stools, dyspepsia, nausea, agitation, insomnia, and 
decreased libido, and serotonin syndrome. 

Increased the risk compared to placebo of suicidal thinking and behavior, activation/mania; 
bleeding events related to SSRI use (have ranged from ecchymosis, hematomas, epistaxis, and 
petechiae to life-threatening hemorrhages), hyponatremia (appears to be the result of the 
syndrome of inappropriate antidiuretic hormone secretion [SIADH]); serotonin syndrome
Reporting of Anticipated Events
These events will be captured on the eCRF 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
NCT02417064