Conditions: Depressive Disorder, Major
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 212
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy of Seltorexant compared with placebo as adjunctive therapy to an antidepressant in improving depressive symptoms in participants with major depressive disorder with insomnia symptoms (MDDIS) who have had an inadequate response to current antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

Detailed description:
Major depressive disorder (MDD) is a common, serious, recurrent disorder. Seltorexant (JNJ-42847922) is a potent and selective antagonist of the human orexin-2 receptor (OX2R) that is being developed for the adjunctive treatment of MDDIS. The hypothesis for this study is that adjunctive treatment with seltorexant is superior to placebo in treating depressive symptoms, as measured by change in Montgomery Asberg Depression Rating Scale (MADRS) total score from baseline to Day 43 in adult and elderly participants with MDDIS who have had an inadequate response to treatment with a SSRI/SNRI. The study will be conducted in 3 phases: a screening phase (up to 30 days), a double-blind (DB) treatment phase (43 days), and a post treatment follow-up phase (7 to 14 days after DB treatment phase). Total duration of study is up to 12 weeks. Efficacy, safety, pharmacokinetics, and biomarkers will be assessed at specified time points during this study.

Arms:
arm 1: Participants will receive Seltorexant orally once daily from Day 1 to Day 42 (until the end of Week 6). arm 2: Participants will receive matching placebo tablets orally once daily from Day 1 to Day 42 (until the end of Week 6).

Interventions: intervention 1: Seltorexant intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive Seltorexant tablets. intervention 2: Participants will receive matching placebo tablets.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 25 June 2021
Janssen Research & Development *
Clinical Protocol
A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Study to 
Evaluate the Efficacy and Safety of Seltorexant 20 mg as Adjunctive Therapy to 
Antidepressants in Adult and Elderly Patients with Major Depressive Disorder with 
Insomnia Symptoms Who Have Responded Inadequately to Antidepressant Therapy
Protocol 42847922MDD3002; Phase 3
AMENDMENT 2
JNJ-42847922  (seltorexant)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration 
Investigational New Drug (IND) regulations (21 CFR Part 312).
EudraCT NUMBER: 2020-000338-16
Status:
Approved
Date:
25 June 2021
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-170246974, 4.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04532749


JNJ-42847922 (seltorexant)
Clinical Protocol 42847922MDD3002 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 25 June 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
25 June 2021
Amendment 1
29 October 2020
Original Protocol
10 April 2020
Amendment 2 (25 June 2021)
Overall Rationale for the Amendment: The overall reason for the amendment is to clarify and modify 
eligibility criteria based on early enrolment experiences. To make the following changes at screening: lower 
the initial screening assessment of the Hamilton Depression Rating Scale (HDRS), 17 items total score 
from 22 to 20 and ≥18 at end of screening; increase the maximum duration of stable antidepressant therapy 
from 12 months to 18 months; increase the length of the current depressive episode to ≤24 months
(≤18 months); revise the upper limit of body mass index (BMI) eligibility range to 40 kg/m2 (from 37 
kg/m2); extend the screening period for up to 2 weeks if approved by the medical monitor. This amendment 
also includes changes to laboratory tests to remove evaluation of prothrombin time (PT) and clarify follicle 
stimulating hormone (FSH) testing; added text to specify that locally approved (including under emergency 
use authorization COVID-19 vaccination may be used during the trial with the recommendation that 
vaccination occurs at least 5 days prior to the start of dosing, or once randomized, at least 5 days prior to 
the next scheduled visit.
Section Number
and Name
Description of Change
Brief Rationale
1.1 Synopsis; 
2 Introduction; 
2.2.2.3 Safety and 
Tolerability
Removed the text stating development of 
seltorexant for treatment of insomnia disorders.
Sponsor has discontinued the 
development of seltorexant for 
insomnia disorder due to business 
considerations.
1.1 Synopsis, Overall 
Design; 4.1 Overall 
Design; 5.1 Inclusion 
Criteria (#3 and #4); 6.1 
Study Interventions 
Administered  
Increased the maximum duration of stable 
antidepressant therapy with a selective 
serotonin reuptake inhibitor (SSRI)/ serotonin-
norepinephrine reuptake inhibitor (SNRI) for 
inclusion into the study from 12 months to 
18 months.
To update and clarify eligibility 
criteria based on early enrollment 
experiences and to provide 
improved clarity in the inclusion 
and exclusion criteria and ensure 
alignment throughout different 
sections.
4.1 Overall Design
Added text to elaborate eligibility based on 
current SSRI/SNRI treatment.
1.3 Schedule of Activities 
(footnote ‘y’); 
5.1 Inclusion criteria (#2)
Updated footnote ‘y’ to clarify that major 
depressive disorder (MDD) symptoms item 4 
for insomnia needs to be positive prior to 
randomization 
Modified inclusion criterion 2 to increase the 
length of current depressive episode to ≤24 
months and specified that the item 4 (insomnia 
symptoms) of the Structured Clinical Interview 
for DSM-5 Axis I Disorders– Clinical Trials 
Version (SCID-CT) should be positive for IS 
prior to randomization.
1.3 Schedule of Activities 
(footnote ‘x’)
Clarified that both patient and clinical ISI are 
required for randomization.
5.2 Exclusion criteria (#1)
Cutoff level of hemoglobin A1c for controlled 
diabetes was increased to ≤8.5%.


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Section Number
and Name
Description of Change
Brief Rationale
1.2 Schema; 1.3 Schedule 
of Activities (footnote 
‘cc’); 6.5 Concomitant 
Therapy
Added footnote to allow an extension of up to 
2 weeks to the screening period if approved by 
the medical monitor.
To allow flexibility in screening 
phase.
1.3 Schedule of Activities 
(footnote ‘w’)
Clarified that the Screening visit 1 can occur 
over more than 1 day, if needed.
1.2 Schema
In Figure 1, the duration of screening was 
changed from 4 weeks to 30 days to align with 
the Schedule of Activities.
1.3 Schedule of Activities 
(footnote ‘o’)
Clarified the timing of first and second 
screening, central rating interviews in relation 
to the baseline visit.
1.3 Schedule of Activities
Increased the Study Window for screening 
visit 2 from +1 to -2 to +1
1.3 Schedule of Activities 
(heading and footnote ‘p’)
In footnote ‘p’, clarified that patient insomnia 
severity index (ISI) should be completed prior 
to randomization.
4.1 Overall Design
Text was deleted as mentioned below (deleted 
text is in strikethrough):
After providing signed informed consent and 
within 30 days prior to the DB treatment 
phase, participants experiencing a major 
depressive episode will be screened to evaluate 
their eligibility for study participation.
1.3 Schedule of Activities
(footnote ‘e’); 
10.2 Appendix 2 Clinical 
Laboratory Tests
Revised text to remove evaluation of PT at 
screening visits.
To remove PT testing as 
seltorexant has no known effects 
on clotting or hepatic functioning
1.3 Schedule of Activities 
(footnote ‘n’); 5.1 
Inclusion Criteria (#13); 
10.5 Appendix 5
Contraceptive and Barrier 
Guidance and Collection 
of Pregnancy Information
Added the following text:
In women who are <40 years old and have 
amenorrhea, FSH should be performed to 
determine post-menopausal status, based on 
the reference range of central laboratory. In 
women who are ≥40 years old and have 
amenorrhea for less than 12 months, FSH test 
may be performed at investigator judgment to 
assist in determining their post-menopausal 
status. In women who are ≥40 years old and 
have amenorrhea for ≥12 months, FSH is not 
required. 
In Inclusion criterion #13 and Appendix 5, it 
was specified that in woman who are 
permanently sterile, FSH testing is not 
required.
To clarify FSH testing 
requirements in women aged ≥40 
years and <40 years.
1.3 Schedule of Activities 
(footnote ‘r’); 8.1.3. 
Subjective Sleep 
Parameters (CSD)
Clarified that Consensus Sleep Diary (CSD) 
completion is encouraged but not required 
before randomization and the collection of 
CSD is made flexible
To provide flexibility for CSD 
completion.
1.3 Schedule of Activities 
(footnote 'r'); 4.1 Overall 
Design
Clarified that completion of CSD is 
encouraged to be completed for 7 mornings 
prior to the scheduled assessment (deleted 
“consecutive”).


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Section Number
and Name
Description of Change
Brief Rationale
4.1 Overall Design; 5.1 
Inclusion criteria (#5)
It was clarified that the HDRS-17 total score 
must be ≥20 at the first screening interview
with >20% improvement in HDRS-17 score 
from first to second screening and ≥18 at end 
of screening.
To facilitate recruitment of 
patients with moderate-severe 
symptoms of MDD.
1.1 Synopsis, Overall 
Design; 4.1 Overall 
Design; 5.1 Inclusion 
criteria (#3)
Defined the inadequate response as <50% 
reduction but with some improvement [ie, 
improvement >0%] in depressive symptom 
severity with residual symptoms present other 
than insomnia, and overall good tolerability.
5.1 Inclusion criteria (#7)
BMI eligibility range revised to be between 18 
and 40 kg/m2, inclusive.
To facilitate recruitment of 
patients with higher weight.
5.2 Exclusion criteria 
(#19); 5.4 Screen 
Failures; 
8.2.3 Electrocardiogram 
(ECG)
Clarified that triplicate recording of 
electrocardiograms (ECGs) will be performed 
if the corrected QT interval by Fridericia 
(QTcF) is prolonged on the initial ECG at each 
time point the ECG is done per the Schedule of 
Activities (SoA).
To ensure safety of the 
participants
6.5. Concomitant Therapy
If the investigator determines that more time is 
needed to stop the sedative hypnotic safely, the 
investigator may request an extension of 
screening by up to 2 weeks so that the last dose 
of disallowed medication is at least 7 days 
prior to baseline.
In #3, added buspirone to medications that are 
not allowed at least 7 days prior to Day 1 until 
the end of first follow-up visit. 
Added use of up to two doses of a hypnotic 
between day -7 and day -2 for sleep as needed 
as long as it is not the night before an 
assessment
Clarified in #5 that muscle relaxants (eg, 
cyclobenzaprine, carisoprodol, baclofen) may 
be used for up to 7 days during the study but 
may not be used for 7 days prior to 
baseline/Day 1.
Clarified in item #6 that IV and IM steroids as 
well as oral steroids are prohibited from Day -7 
until the end of the DB treatment.
To allow some use of hypnotics 
prior to randomization after 
standing hypnotics and 
benzodiazepines are stopped by 
Day -7 since the patient 
population includes patients with
at least moderate symptoms of 
insomnia.
To prohibit buspirone from 
Day -7 until the first follow-up 
visit and to clarify the allowed use 
of muscle relaxants.
To disallow IV and IM 
administration of systemic 
steroids.
1.1 Synopsis; Overall 
Design; 6.5 Concomitant 
therapy; 8.3 Adverse 
Events and Serious 
Adverse Events; 
10.9. Appendix 9
Changes in Study-Related 
Procedures as a Result of 
the COVID-19 Pandemic
To clarify that for participants who receive an 
approved or authorized vaccine, it is 
recommended that this occurs at least 5 days 
prior to the start of dosing, or once randomized 
at least 5 days prior to the next scheduled visit 
(Synopsis and Appendix 9). Any vaccine 
administered and adverse events following 
vaccination should be recorded in the source 
and eCRF.
To allow administration of 
COVID-19 vaccine during study 
participation.
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted


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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT FIGURES ........................................................................................................................ 8
1.
PROTOCOL SUMMARY ..................................................................................................................... 9
1.1.
Synopsis........................................................................................................................................... 9
1.2.
Schema .......................................................................................................................................... 18
1.3.
Schedule of Activities (SoA)........................................................................................................... 19
2.
INTRODUCTION................................................................................................................................ 24
2.1.
Study Rationale.............................................................................................................................. 24
2.2.
Background .................................................................................................................................... 25
Nonclinical Studies ..................................................................................................................... 25
Clinical Studies ........................................................................................................................... 28
2.2.2.1.
Human Pharmacokinetics........................................................................................................ 28
2.2.2.2.
Efficacy .................................................................................................................................... 30
2.2.2.3.
Safety and Tolerability............................................................................................................. 32
2.3.
Benefit/Risk Assessment ............................................................................................................... 33
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 35
3.1.
Hypothesis ..................................................................................................................................... 37
4.
STUDY DESIGN ................................................................................................................................ 37
4.1.
Overall Design................................................................................................................................ 37
4.2.
Scientific Rationale for Study Design............................................................................................. 40
Study Population......................................................................................................................... 40
Blinding, Control, and Intervention Groups................................................................................. 42
DNA and Biomarker Collection................................................................................................... 43
Efficacy Measures ...................................................................................................................... 43
Pharmacokinetic Assessments................................................................................................... 45
Safety Evaluations...................................................................................................................... 46
Study-Specific Ethical Design Considerations ........................................................................... 46
4.3.
Justification for Dose...................................................................................................................... 47
4.4.
End of Study and End of Treatment Definitions............................................................................. 47
5.
STUDY POPULATION ...................................................................................................................... 48
5.1.
Inclusion Criteria ............................................................................................................................ 48
5.2.
Exclusion Criteria ........................................................................................................................... 51
5.3.
Lifestyle Considerations................................................................................................................. 55
5.4.
Screen Failures .............................................................................................................................. 56
6.
STUDY INTERVENTION................................................................................................................... 56
6.1.
Study Interventions Administered .................................................................................................. 56
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 57
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 58
6.4.
Study Intervention Compliance ...................................................................................................... 59
6.5.
Concomitant Therapy..................................................................................................................... 59
6.6.
Intervention After the End of the Study.......................................................................................... 62
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 63
7.1.
Discontinuation of Study Intervention ............................................................................................ 63
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 64
Withdrawal From the Use of Genetic Research Samples.......................................................... 64
7.3.
Lost to Follow-up............................................................................................................................ 65


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8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 65
8.1.
Efficacy Assessments .................................................................................................................... 66
Montgomery-Åsberg Depression Rating Scale (MADRS).......................................................... 67
Insomnia Severity Index (ISI) ..................................................................................................... 67
Subjective Sleep Parameters (CSD) .......................................................................................... 67
Patient Reported Outcomes Measurement Information System-Sleep Disturbance 
(PROMIS-SD) Short Forms ........................................................................................................ 68
Patient Global Impression of Severity (PGI-S) ........................................................................... 68
Patient Global Impression of Change (PGI-C): .......................................................................... 68
Patient Health Questionnaire, 9-Item (PHQ-9)........................................................................... 68
Clinical Global Impression-Severity (CGI-S) .............................................................................. 68
Sheehan Disability Scale (SDS) ................................................................................................. 69
Ruminative Response Scale (RRS) ........................................................................................... 69
European Quality of Life, 5-Dimension, 5-Level (EQ-5D-5L) Questionnaire.............................. 69
Hamilton Depression Rating Scale (HDRS-17) – Screening Only ............................................. 69
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(MGH-ATRQ) – Screening Only ................................................................................................. 69
Structured Clinical Interview for DSM-5 Axis I Disorders– Clinical Trials Version (SCID-
CT) – Screening Only ................................................................................................................. 70
Site Independent Qualification Assessment - Screening Only................................................... 70
8.2.
Safety Assessments....................................................................................................................... 70
Physical Examination.................................................................................................................. 70
Vital Signs................................................................................................................................... 71
Electrocardiogram (ECG) ........................................................................................................... 71
Clinical Safety Laboratory Assessments .................................................................................... 71
Physician Withdrawal Checklist (PWC)...................................................................................... 71
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................... 72
Arizona Sexual Experiences Scale (ASEX)................................................................................ 72
Mini Mental State Examination (MMSE) – Screening Only........................................................ 72
8.3.
Adverse Events and Serious Adverse Events ............................................................................... 72
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 73
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 73
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 74
Pregnancy................................................................................................................................... 74
Adverse Events of Special Interest............................................................................................. 75
8.4.
Treatment of Overdose .................................................................................................................. 75
8.5.
Pharmacokinetics........................................................................................................................... 76
Evaluations ................................................................................................................................. 76
Analytical Procedures................................................................................................................. 76
Pharmacokinetic Parameters and Evaluations........................................................................... 76
8.6.
Biomarkers ..................................................................................................................................... 77
8.7.
Pharmacogenomics ....................................................................................................................... 77
8.8.
Medical Resource Utilization and Health Economics .................................................................... 77
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 77
9.1.
Statistical Hypotheses.................................................................................................................... 77
9.2.
Sample Size Determination ........................................................................................................... 78
9.3.
Populations for Analyses................................................................................................................ 78
9.4.
Statistical Analyses ........................................................................................................................ 78
Efficacy Analyses........................................................................................................................ 78
Safety Analyses .......................................................................................................................... 81
Other Analyses ........................................................................................................................... 82
9.5.
Interim Analysis.............................................................................................................................. 83
9.6.
Independent Data Monitoring Committee ...................................................................................... 83
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 84
10.1.
Appendix 1: Abbreviations ............................................................................................................. 84


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10.2.
Appendix 2: Clinical Laboratory Tests ........................................................................................... 86
10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 88
Regulatory And Ethical Considerations...................................................................................... 88
Financial Disclosure.................................................................................................................... 91
Informed Consent Process ......................................................................................................... 91
Data Protection ........................................................................................................................... 92
Long-Term Retention of Samples for Additional Future Research ............................................ 93
Committee Structure................................................................................................................... 93
Publication Policy/Dissemination of Clinical Study Data ............................................................ 93
Data Quality Assurance.............................................................................................................. 94
Case Report Form Completion................................................................................................... 95
Source Documents ..................................................................................................................... 95
Monitoring ................................................................................................................................... 96
On-Site Audits............................................................................................................................. 97
Record Retention........................................................................................................................ 97
Study And Site Start And Closure .............................................................................................. 98
10.4.
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................................................... 99
Adverse Event Definitions And Classifications........................................................................... 99
Attribution Definitions................................................................................................................ 100
Severity Criteria ........................................................................................................................ 100
Special Reporting Situations .................................................................................................... 100
Procedures ............................................................................................................................... 101
Contacting Sponsor Regarding Safety ..................................................................................... 102
Product Quality Complaint Handling......................................................................................... 102
Contacting Sponsor Regarding Product Quality....................................................................... 103
10.5.
Appendix 5: Contraceptive and Barrier Guidance and Collection of Pregnancy Information...... 104
10.6.
Appendix 6: Examples of Concomitant Drugs to be Avoided (Strong Inhibitors and 
Moderate/Strong Inducers of CYP3A4 or CYP2C9 or Dual Inhibitors/Inducers of CYP3A4 
and CYP2C9. In Addition, Moderate CYP3A4 or CYP2C9 Inhibitors for Participants with 
Creatinine Clearance <60 mL/min or Clinically Significant Hepatic Disease). ............................ 107
10.7.
Appendix 7: Administration of a PRO at Scheduled Visits........................................................... 109
10.8.
Appendix 8: Benzodiazepine Equivalence Table (30 mg diazepam or 3 mg lorazepam) ........... 110
10.9.
Appendix 9: Changes in Study-Related Procedures as a Result of the COVID-19 
Pandemic ..................................................................................................................................... 111
10.10.
Appendix 10: Protocol Amendment History ................................................................................. 115
11.
REFERENCES................................................................................................................................. 119
INVESTIGATOR AGREEMENT ............................................................................................................... 122


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LIST OF IN-TEXT FIGURES 
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 18


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Study to Evaluate the 
Efficacy and Safety of Seltorexant 20 mg as Adjunctive Therapy to Antidepressants in Adult and Elderly 
Patients with Major Depressive Disorder with Insomnia Symptoms Who Have Responded Inadequately to 
Antidepressant Therapy
Seltorexant (JNJ-42847922) is a potent and selective antagonist of the human orexin-2 receptor (OX2R) 
that is being developed for the adjunctive treatment of major depressive disorder (MDD) with insomnia 
symptoms (MDDIS). Preclinical evidence supports a role for the orexin system in modulating the stress
component of hypothalamic-pituitary-adrenal (HPA) axis function and other aspects of stress-
responsiveness and arousal, which are critical components of the pathophysiology of depression. In 
addition, data support the importance of attenuating insomnia symptoms (IS) to attain and sustain remission 
in MDD, and further suggest that the sleep enhancing effects of OX2R antagonists may be of benefit to 
patients with MDD.
Multiple studies showed the benefit of seltorexant on depressive symptoms and improving sleep in 
participants with MDD and reducing elevated morning cortisol in depressed participants with IS. In the 
42847922MDD2001 study, seltorexant at 20 mg dose showed a statistically significant reduction of 
depressive symptoms (Montgomery-Asberg Depression Rating Scale [MADRS]) compared with placebo. 
The depressive symptom reduction was greater in participants with a clinician Insomnia Severity Index 
(ISI) ≥15 for the 20 mg dose. The improvements in depressive symptoms observed with seltorexant 20 mg 
were maintained over the 6-month study period in the 42847922MDD2002 study. 
Seltorexant overall has been well tolerated with adverse event (AE) rates similar to those observed on 
placebo and with low discontinuation rates. Three adverse drug reactions (ADRs [somnolence, abnormal 
dreams, and sleep paralysis]) have been identified with seltorexant and are consistent with its mechanism 
of action.
The present study is being conducted to investigate the antidepressant effects of 20 mg seltorexant (versus 
placebo), as adjunctive treatment to a selective serotonin reuptake inhibitor [SSRI] or 
serotonin-norepinephrine reuptake inhibitor [SNRI]) in adults (18 to 64 years, inclusive) and elderly (65 to 
74 years, inclusive) with MDDIS, who have had an inadequate response to treatment with a SSRI/SNRI. 
The change in the MADRS; the structured interview guide for the MADRS (SIGMA) total score from 
baseline to Day 43 in participants with MDDIS will be utilized for primary assessment of efficacy.
OBJECTIVES AND ENDPOINTS
For the following objectives and endpoints, MDDIS is defined as MDD with IS as a) moderate to severe IS 
by a patient version ISI total score of ≥15 at the end of screening and b) a positive response for IS (MDD 
symptoms Item 4) on the Structured Clinical Interview for DSM-5 Axis I Disorders Clinical Trials Version
(SCID-CT). In addition, the clinician version ISI total score ≥15 is also required since this version was used 
in the Phase 2 program.
Objectives
Endpoints
Efficacy
Primary

To assess the efficacy of seltorexant 20 mg 
compared with placebo as adjunctive therapy 
to an antidepressant in improving depressive 
symptoms in participants with MDDIS who 

Change from baseline to Day 43 in the 
MADRS total score.


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Objectives
Endpoints
have had an inadequate response to current 
antidepressant therapy with an SSRI or SNRI
Key Secondary
To assess the efficacy of seltorexant compared with placebo as an adjunctive therapy to an antidepressant 
in participants with MDDIS on the following:

MDD 
symptoms 
other 
than 
insomnia 
symptoms

Change from baseline to Day 43 in the 
MADRS without sleep item (MADRS-WOSI) 
total score.

Patient-reported 
assessment 
of 
sleep 
outcomes

Change from baseline to Day 43 in sleep 
disturbance using the Patient Reported 
Outcome Measurement Information System-
Sleep Disturbance (PROMIS-SD) Short Form 
(8a) T-score.
Secondary
To assess the efficacy of seltorexant compared with placebo as adjunctive therapy to an antidepressant 
in participants with MDDIS on the following:

Core symptoms of depression.

Change from baseline to Day 43 in the 
MADRS-6 total score.

Response of depressive symptoms

Proportion of responders on depressive 
symptoms scale, defined as a ≥50% 
improvement in MADRS total score, from 
baseline to Day 43.

Patient-reported symptoms of depression

Change from baseline to Day 43 in Patient 
Health Questionnaire, 9-Item (PHQ-9) total 
score. 
Exploratory
To assess the efficacy of seltorexant compared with placebo as adjunctive therapy to an antidepressant 
on the following: 

Patient-reported sleep diary

Change from baseline to Day 43 in subjective 
sleep parameters as measured by the 
Consensus Sleep Diary (CSD).

Remission of depressive symptoms

Proportion of participants with remission of 
depressive symptoms, defined as a MADRS 
total score ≤12 at Day 43.

Patient-reported health-related quality of life

Change from baseline to Day 43 in health-
related quality of life and health status, as 
assessed by the European Quality of Life, 
5 Dimension, 
5-Level 
(EQ-5D-5L) 
questionnaire.

Patient-reported 
global 
functioning 
(work/school, social and family life)

Change from baseline to Day 43 in the 
Sheehan Disability Scale (SDS) total score.


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Status: Approved,  Date: 25 June 2021
Objectives
Endpoints

Patient-reported insomnia symptoms

Change from baseline to Day 43 in the 
patient-reported Insomnia Severity Index 
(ISI) total score.

Patient-reported assessment of sleep outcomes

Change from baseline over time in sleep 
symptoms 
using 
the 
Patient 
Global 
Impression of Severity (PGI-S).

Patient-reported assessment of change in 
depressive symptoms

Change from baseline over time in depressive 
symptoms 
using 
the 
Patient 
Global 
Impression of Change (PGI-C).

Clinical symptom severity

Change from baseline over time in the 
Clinical Global Impression-Severity (CGI-S) 
score.

Patient-reported rumination symptoms

Change from baseline to Day 43 in the 
ruminative response scale (RRS) total score.
Safety

To assess the safety and tolerability of 
seltorexant as adjunctive therapy to an 
antidepressant in participants with MDDIS in 
the short-term compared with placebo

Adverse events (AEs) including AEs of 
special interest (AESI)

Vital signs 

Weight/ Body mass index (BMI)

Suicidality assessment using the Columbia 
Suicide Severity Rating Scale (C-SSRS) 

Withdrawal symptoms assessment using the 
Physician Withdrawal Checklist, 20-items
(PWC-20) 

Laboratory values and electrocardiogram 
(ECG)

Patient-reported sexual functioning using 
Arizona Sexual Experiences Scale (ASEX)
Additional exploratory objectives:

To identify diagnostic biomarkers and to investigate changes in MDD-related biomarkers (eg, HPA 
axis, metabolic function and, biomarkers of immune system activation) in relation to clinical response 
on depression symptoms and IS upon adjunctive treatment with seltorexant.

To identify genetic (eg, CYP genes) and other factors that may influence the pharmacokinetic (PK), 
safety, or tolerability of seltorexant.

To assess the plasma exposure of seltorexant and its M12 metabolite along with alpha-1-acid 
glycoprotein levels in participants with MDDIS when used as adjunctive treatment. 
Hypothesis
The hypothesis for this study is that adjunctive treatment with seltorexant is superior to placebo in treating 
depressive symptoms, as measured by change in MADRS total score from baseline to Day 43 in adult and 
elderly participants with MDDIS who have had an inadequate response to treatment with a SSRI/SNRI.


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Status: Approved,  Date: 25 June 2021
OVERALL DESIGN
This is a multicenter, double-blind (DB), randomized, parallel-group, placebo-controlled, 6-week, study 
with seltorexant 20 mg study to assess the efficacy and safety of seltorexant as an adjunctive therapy in 
adults (18 to 64 years, inclusive) and elderly (65 to 74 years, inclusive) participants with MDDIS, who have 
had an inadequate response to current antidepressant therapy with a SSRI/SNRI. 
The study will consist of 3 phases: a screening phase (up to 30 days), a DB treatment phase (43 days), and 
a posttreatment follow-up phase (7 to 14 days after DB treatment phase). Approximately 386 participants 
with MDDIS will be enrolled in this study. The study population will include participants who meet 
Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5) diagnostic criteria for MDD 
(SCID-CT) with MDDIS at screening, and who have had an inadequate response (defined as <50% 
reduction but with some improvement [ie, improvement >0%] in depressive symptom severity with residual 
symptoms present other than insomnia, and overall good tolerability, as assessed by Massachusetts General 
Hospital-Antidepressant Treatment Response Questionnaire [MGH-ATRQ]) to current antidepressant 
therapy with a SSRI/SNRI (administered at or above a stable therapeutic dose for at least 6 weeks [and not 
more than 18 months] in the current episode). A Site-Independent Qualification Assessment will assess the 
validity of the participants’ diagnosis for inclusion in the study. In the DB treatment phase, participants will 
be randomly assigned to receive placebo or seltorexant 20 mg in a 1:1 ratio for 6 weeks. 
Participants should take their assigned study drug at home, once daily at bedtime during DB treatment 
phase. Participants will continue to take their baseline SSRI/SNRI antidepressant (at the same dose, without 
change, and at approximately the same time of the day as prior to entering the study) during the study 
starting at screening, and through the DB treatment phase and the follow-up phase.
After the last dose of treatment, all participants should have the End-of-Phase visit, preferably the day after 
the last dose. After completion of this visit, the participant enters the follow-up phase where participants 
who receive at least 1 dose of the study drug and do not withdraw consent will have further assessments 
during the follow-up per the Schedule of Activities (SoA). For the follow-up phase, there will be a phone 
call the day after the End-of-Phase visit to assess for any clinical change since stopping the study medication 
and a visit 7-14 days after the End-of-Phase visit. All participants who discontinue study drug in the DB 
treatment phase, will have an Early Withdrawal visit (Visit 8 in the SoA) and a Follow-up visit (Visit 10 in 
the SoA). Participants who discontinue study drug prior to Day 35 may continue after the Follow-up visit 
(Visit 10 in the SoA) with additional follow-up visits every 2 weeks per the SoA until Day 50-57.
The worldwide COVID-19 pandemic may impact the conduct of clinical studies due to the challenges from 
quarantines, site closures, travel limitations, and other considerations if site personnel or study participants 
become potentially exposed to or infected with COVID-19. To assure the safety of study participants, 
maintain compliance with Good Clinical Practice (GCP), and minimize risks to study integrity, if necessary, 
in consultation with the sponsor, the method of assessments may be changed (eg, paper assessments 
replaced by electronic assessments). In addition, site visits may be replaced with telephone, internet-based 
video conferencing applications, or home visits by qualified health care professionals (HCP). Normal 
procedures, as detailed in this protocol, will be resumed as soon as possible thereafter. For participants who 
receive an approved or authorized vaccine, it is recommended that this occurs at least 5 days prior to the 
start of dosing, or once randomized at least 5 days prior to the next scheduled visit.
NUMBER OF PARTICIPANTS
This study will enroll approximately 386 participants, to target approximately 374 participants in the full 
analysis set 1 (FAS1) in this study.


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INTERVENTION GROUPS AND DURATION
The assigned study drug (seltorexant or placebo) will be self-administered by the participant at home once 
daily at bedtime from Day 1 to Day 42. The duration of participation in the study for an individual 
participant (including screening, DB treatment, and follow-up phases) will be approximately 12 weeks. 
DESCRIPTION OF INTERVENTIONS
Seltorexant, 20 mg tablets will be provided for oral administration. Placebo will be supplied as matching 
tablets. Participants will be instructed to take their assigned dose of study drug orally once daily at bedtime. 
The study drug must be swallowed whole with water and not chewed, divided, dissolved, or crushed.
EFFICACY EVALUATIONS
The efficacy of study drug will be evaluated using the MADRS (SIGMA version), MADRS-WOSI, 
PROMIS-SD (Short Form 8a), PGI-S (insomnia), MADRS-6, ISI (patient version), PHQ-9, CGI-S
(depression), PGI-C (depression), SDS, RRS, CSD, and EQ-5D-5L.
PHARMACOKINETIC EVALUATIONS
Sparse blood samples will be collected for measurement of plasma concentrations of seltorexant and its 
M12 metabolite.
In addition, blood samples will be collected for determination of plasma concentrations of seltorexant, its 
M12 metabolite, and alpha-1-acid glycoprotein in participants who discontinue study drug for an AE, have
an AESI, or have a serious adverse event (SAE), if the sample can be obtained within 15 hours of the last 
study drug administration.
Blood samples will also be collected to determine alpha-1-acid glycoprotein levels at each PK collection 
day (as indicated in the SoA) to calculate the unbound concentrations. 
BIOMARKER EVALUATIONS 
Blood samples for the assessment of biomarkers related to the immune system activity, growth factors, 
metabolic, and HPA axis activation will be collected during the DB treatment phase under fasting 
conditions. 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.
PHARMACOGENOMIC (DNA/RNA) EVALUATIONS
Blood samples for genetic research will be collected from participants who consent separately to this 
component of the study (where local regulations permit) to allow for the potential identification of genetic, 
epigenetic and/or transcription factors that may influence the PK, efficacy, safety, or tolerability of 
seltorexant and to identify genetic and/or epigenetic factors associated with MDDIS. Participation in 
genetic research is optional.
SAFETY EVALUATIONS
Safety evaluations will include collection of AEs and concomitant medications, as well as assessment with 
physical examination including a brief neurological examination, body weight, BMI, vital signs, 12-lead 
ECG, urine drug screening, alcohol breath test, and clinical laboratory tests (hematology, serum chemistry 
panel, lipid panel, insulin, hemoglobin A1c [HbA1c], thyroid-stimulating hormone [TSH], free thyroxine 
[FT4], and urinalysis). Serum or urine pregnancy tests will be performed for women of childbearing 
potential. Additional serum and urine pregnancy tests and drug and alcohol tests may be conducted as 
needed per the investigator’s judgment.


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Status: Approved,  Date: 25 June 2021
Menstrual cycles will be tracked during the study in premenopausal women who are still having their 
menses, using a participant diary and participant’s verbal report.
In addition, emergence of suicidal ideation will be assessed using the C-SSRS, potential withdrawal effects 
will be assessed by the clinician using the PWC-20, and sexual functioning will be assessed using the 
ASEX.  
STATISTICAL METHODS 
Sample Size Calculation
Approximately 386 participants (randomized in 1:1 ratio to placebo and seltorexant 20 mg) are planned to 
be enrolled in the DB treatment phase. The enrollment is targeted to achieve approximately 374 participants 
eligible to be included in FAS1. Assuming a treatment difference of 4.4 points in change from baseline in 
MADRS total score between seltorexant and placebo, a standard deviation of 12, and a 1-sided significance 
level of 0.025 (equivalently 2-sided 0.05), this sample size will provide approximately 90% power in a 
comparison between seltorexant and placebo in the primary efficacy analysis, accounting for a drop-out 
rate of approximately 15%. The assumed treatment difference and standard deviation used in this 
calculation are based on Phase 2 (42847922MDD2001) study results, as well as on clinical judgment.
Interim Analysis
One interim analysis (IA) will be conducted to evaluate futility for Studies 42847922MDD3001 (another 
seltorexant Phase 3 study) and 42847922MDD3002 (with 2 sets of data evaluated at the same time
combined and for each study separately). Both the pooled analyses of data from 2 studies and the analyses 
of individual study data will be used in evaluating futility. An Independent Data Monitoring Committee 
(IDMC) will meet once to evaluate the unblinded efficacy data at the IA and make recommendation on 
whether to declare futility. The details of the IA will be included in the IDMC Charter and the IA Statistical 
Analysis Plan (SAP). For including this IA for futility, there will be no adjustment to overall type I error 
level for Studies 42847922MDD3001 and 42847922MDD3002.
IDMC will also periodically review safety data.
Efficacy Analyses
Two full analysis sets (FAS) will be defined as follows:

FAS1: defined as all participants who were randomly assigned to study drug and received at least 
1 dose of study drug and met pre-specified stratification criteria (included in a separate document).
FAS1 will be used for primary efficacy analysis for all submissions, with the exception of the 
European Union (EU) dossier.

FAS2: defined as all participants who were randomly assigned to study drug and received at least 
1 dose of study drug. FAS2 will be used for primary efficacy analysis for the EU dossier.
The analyses of primary and key secondary endpoints (and other efficacy analyses) will be based on FAS 
(FAS1 for the non-EU dossier, and FAS2 for the EU dossier). For the EU dossier, the primary analysis will 
be based on FAS2, and the FAS1 will be used for supplementary analyses; for the non-EU dossier, the 
primary analysis will be based on FAS1, and the FAS2 will be used for supplementary analyses.
The primary efficacy endpoint is the change in MADRS total score from baseline to Day 43.
The first key secondary endpoint is the change in MADRS-WOSI from baseline to Day 43. The second key 
secondary endpoint is the change in PROMIS-SD T-score from baseline to Day 43.


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Status: Approved,  Date: 25 June 2021
There are two primary estimands defined for the primary efficacy endpoint:
Estimand 1:
Population: participants with MDDIS and an inadequate response to current antidepressant therapy with a 
SSRI/SNRI, as reflected by the inclusion/exclusion criteria (participants need to meet pre-specified 
stratification criteria [included in a separate document] for this estimand).
Endpoint: change in MADRS total score from baseline to Day 43.
Intercurrent events and corresponding strategies: 

Treatment discontinuation of add-on study drug only (Hypothetical strategy: as if the intercurrent event 
had not occurred)

Treatment discontinuation of both underlying antidepressant and add-on study drug (Hypothetical
strategy: see above)

Switch of add-on treatment and/or underlying antidepressant (Hypothetical strategy: see above)
Summary measure: difference in treatment means.
Estimand 2:
Population: participants with MDDIS and an inadequate response to current antidepressant therapy with a 
SSRI/SNRI, as reflected by the inclusion/exclusion criteria.
Endpoint: change in MADRS total score from baseline to Day 43.
Intercurrent events and corresponding strategies: 

Treatment discontinuation of add-on study drug only (Treatment policy strategy: all observed values 
of the endpoint are used regardless of whether or not the participant had experienced this intercurrent 
event)

Treatment discontinuation of both underlying antidepressant and add-on study drug (Hypothetical 
strategy: as if the intercurrent event had not occurred). 

Switch of add-on treatment and/or underlying antidepressant (Hypothetical strategy: as if participants 
had discontinued treatment instead of switching)
A supplementary estimand will be defined with the same components as Estimand 2, with the hypothetical 
strategy being replaced by a treatment policy strategy for the intercurrent event of treatment discontinuation 
of both underlying antidepressant and add-on study drug.
With the exception of the EU dossier, the primary estimand is Estimand 1, and the supplementary estimand 
is Estimand 2. For the EU dossier, the primary estimand is Estimand 2, and the supplementary estimand is 
Estimand 1.
Under Estimand 2, MADRS will need to be collected after study drug discontinuation for participants who 
did not withdraw consent and included in the analyses when the treatment policy strategy is applied.
Main Analysis Under Estimand 1
The comparison between seltorexant and placebo will be performed using the appropriate contrasts in a 
mixed model for repeated measures (MMRM), with main comparison on Day 43. The MMRM will include 
country, age group (adults [<65 years] and elderly [≥65 years]), baseline rumination level (RRS total score 


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<54, ≥54), time, treatment (placebo and seltorexant), and treatment by time interaction as factors, and 
baseline MADRS total score as a covariate. 
Sensitivity Analysis Under Estimand 1:
For Estimand 1, delta adjustment with a tipping point will be conducted as a sensitivity analysis.
Main Analysis Under Estimand 2
The copy reference (CR) multiple imputation (MI) method will be performed. A mixed model (which will 
include country, age group [adults {<65 years} and elderly {≥65 years}], baseline rumination level [RRS 
total score <54, ≥54], time, treatment [placebo and seltorexant], and treatment by time interaction as factors, 
and baseline MADRS total score as a covariate) will be applied to each imputed dataset (with the CR MI 
method), and the Rubin’s rule will be used to combine results from each imputed dataset.
Sensitivity Analysis Under Estimand 2:
For Estimand 2, the Copy Increment from Reference (CIR) multiple imputation method will be performed 
as a sensitivity analysis.
Key Secondary Efficacy Endpoints
The same estimands (except the endpoint) and corresponding analyses as for the primary endpoint will be 
used for the key secondary endpoints.
Testing Procedure for Primary and Key Secondary Endpoints
The fixed sequence testing procedure will be applied to control the familywise error rate (FWER) at 
two-sided 0.05 level accounting for multiplicity due to the primary (MADRS total score) and key secondary 
efficacy endpoints (MADRS-WOSI and PROMIS-SD). The fixed sequence testing procedure will first test 
the primary endpoint at two-sided 0.05 level. If the hypothesis corresponding to the primary endpoint is 
rejected, then the first key secondary endpoint (MADRS-WOSI) will be tested at the two-sided 0.05 level; 
if the hypothesis corresponding to the primary endpoint is not rejected, then, the testing procedure will stop.
If the hypothesis corresponding to MADRS-WOSI is rejected, then the second key secondary endpoint 
(PROMIS-SD) will be tested at two-sided 0.05 level; if the hypothesis corresponding to MADRS-WOSI is 
not rejected, then the testing procedure will stop.
Pharmacokinetic Analysis
Plasma concentration-time data will be displayed by visit date, and time for seltorexant and its M12 
metabolite.
In addition, plasma concentrations of seltorexant, its M12 metabolite, and alpha-1-acid glycoprotein in 
participants who discontinue study drug for an AE, have an AESI, or have an SAE if the sample can be 
obtained within 15 hours of the last dose will be tabulated.
The alpha-1-acid glycoprotein levels will be tabulated for each participant by visit date and time and will 
be used to calculate the unbound concentrations.
Biomarker Analysis
The exploratory biomarkers will be tabulated by treatment and summary statistics will be calculated. 
Posttreatment changes in exploratory biomarkers will be summarized by treatment group. Associations 
between baseline biomarker levels and clinical endpoints may be explored. Results may be presented in a 
separate biomarker report.


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Pharmacogenomic Analysis
A composite genotype may be derived from the raw genotyping data for the analyzed genes, as appropriate.
The relationship between genetic subgroups and seltorexant PK endpoints may be examined through 
descriptive statistics or graphically.
Safety Analyses  
Safety analyses will be based on the safety analysis set, which consists of all participants who were 
randomly assigned to study drug and received at least 1 dose of study drug. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). All 
reported AEs with onset during the DB treatment phase and AEs that have worsened since baseline (ie, 
treatment-emergent adverse events [TEAEs]), will be included in the analysis. Serious adverse events will 
be summarized separately.
Laboratory data will be summarized by type of laboratory test and treatment. Descriptive statistics will be 
calculated for each laboratory analyte at baseline and for observed values and changes from baseline at each 
scheduled time point.
Descriptive statistics of pulse, sitting blood pressure (systolic and diastolic), temperature for observed 
values will be provided and changes from baseline, will be summarized at each scheduled time point by 
treatment. Changes in body weight and BMI will be summarized descriptively.
Participants with abnormal findings in physical examination and ECG will be listed. Results from the 
ASEX, PWC-20, and C-SSRS will be tabulated by treatment.


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1.2.
Schema
Figure 1:
Schematic Overview of the Study 
All participants will continue their baseline antidepressant during the entire study
* An extension of up to 2 weeks of the screening phase may be allowed (eg, if needed to confirm eligibility criteria 
or for scheduling difficulties) with permission from the medical monitor. If there is an extension, screening 
visit 2 should still occur within 1-7 days prior to Day 1/baseline.
An interim analysis will be performed to evaluate futility.
All participants who discontinue early from treatment in the double-blind treatment phase will have an Early 
Withdrawal visit (Visit 8 in the SoA) and Follow-up visit (Visit 10 in the SoA). Participants who discontinue 
study drug prior to Day 35 may continue after the Follow-up visit (Visit 10 in the SoA) with additional 
Follow-up visits, every 2 weeks per the SoA until Day 50-57.
Abbreviations: EW=Early withdrawal; FU=Follow-up; MDD=Major depressive disorder; 
SNRI=Serotonin-norepinephrine reuptake inhibitor; SoA=Schedule of Activities; SSRI=Selective serotonin 
reuptake inhibitor






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Status: Approved,  Date: 25 June 2021
Phase
Screeningcc
DB Phase
Posttreatment 
Follow-upa
Baseline
Telephone 
contact
Telephone 
contact
End-of- DB 
Treatment/ 
Early 
Withdrawala
Telephone 
Contactb
Follow-up 
Visitb
Additional 
FU visit for 
EW of study 
druga
Study Day
-30 
to -9
w
-5 
to -2
p
1
2
8
15
29
43
1 day 
after 
Visit 8
7-14 
days 
after 
Visit 8
Every two 
weeks up 
to Day 
50-57
Study Week
-4 to 
-2
-1
1
1
2
3
5
7
Visit
1w
2
3
4
5
6
7
8
9
10
Visit window
-2/+1
+1
±2
± 2
± 3
± 3
Concomitant medications
Continuous
Adverse events
Continuous
Abbreviations:  
AE=adverse event, AESI=adverse event of special interest, ASEX=Arizona Sexual Experiences Scale, CGI-
S=Clinical Global Impression-Severity, CSD=Consensus Sleep Diary, C-SSRS=Columbia Suicide Severity Rating 
Scale, DB=double-blind, DNA=deoxyribonucleic acid, ECG=electrocardiogram, eCRF=electronic case report form, 
EOP=End-of-Phase, EQ-5D-5L=European Quality of Life, 5-Dimension, 5-Level questionnaire, EW=early 
withdrawal, FSH=follicle stimulating hormone, FT4= free thyroxine, FU=follow-up, HbA1c=hemoglobin A1c, 
HDRS-17=Hamilton Depression Rating Scale 17-item, ICF=Informed Consent Form, ISI=Insomnia Severity Index, 
MADRS=Montgomery-Asberg Depression Rating Scale, MGH-ATRQ=Massachusetts General Hospital-
Antidepressant Treatment Response Questionnaire, MMSE=Mini Mental State Examination, PGI-C=Patient Global 
Impression of Change, PGI-S=Patient Global Impression of Severity, PHQ-9=Patient Health Questionnaire 9-item, 
PK=pharmacokinetic, PROMIS-SD=Patient Reported Outcome Measurement Information System-Sleep 
Disturbance, PWC-20=Physician Withdrawal Checklist, 20-items, RNA=Ribonucleic Acid, RRS=Ruminative 
Response Scale, SAE=serious adverse event, SCID-CT=Structured Clinical Interview for DSM-5 Axis I Disorders–
Clinical Trials Version, SDS=Sheehan Disability Scale, SIGMA=structured interview guide for the Montgomery-
Asberg Depression Rating Scale, SNRI=serotonin-norepinephrine reuptake inhibitor, SSRI=selective serotonin 
reuptake inhibitor, TSH=thyroid-stimulating hormone.
Footnotes:  
a.
All participants who discontinue study drug in the DB treatment phase, will have an Early Withdrawal visit (Visit 8 in the 
SoA) and a Follow-up visit (Visit 10 in the SoA). Participants who discontinue study drug prior to Day 35 may continue 
after the Follow-up visit (Visit 10 in the SoA) with additional follow-up visits every 2 weeks per the SoA until Day 50-57.
b.
If a participant enters the open-label treatment phase of another seltorexant study after completion of the DB phase, the 
telephone contact (1 day after Visit 8) and the follow-up visit (7-14 days after Visit 8) will not be conducted.
c.
For all participants, 1 PK sample will be collected in the morning on Day 15 between approximately 8 and 14 hours after 
dosing at night on Day 14 and 1 PK sample will be collected in the morning on Day 43, between approximately 8 and 14 
hours after dosing at night on Day 42. Study drug dosing time on the day before each PK sample collection will be 
accurately recorded by exact dosing date and time by the participant in the participant diary. In addition, blood samples will 
be collected for determination of plasma concentrations of seltorexant, its M12 metabolite, and alpha-1-acid glycoprotein in 
participants who discontinue study drug for an AE, have an AESI, or have an SAE if the sample can be obtained within 15 
hours of the last study drug administration.
d.
The ICF must be signed before first study-related activity. Consent to DNA and RNA collection is optional as detailed in a 
separate ICF. Participants who are rescreened will be assigned a new participant number, undergo the informed consent 
process, and then restart a new screening phase. Study sites may be asked by the sponsor to obtain informed consent using a 
validated electronic system instead of a paper-based process.
e.
The clinical laboratory assessments (including TSH, hematology, serum chemistry, HbA1c, insulin, lipid panel), and 
urinalysis should be performed under fasting conditions (with the possible exception of screening laboratory tests).
f.
Free thyroxine (FT4) analysis will be performed for participants with known hypothyroidism, who have been on stable 
treatment for at least 3 months prior to screening, and for any participant with an abnormal thyroid stimulating hormone 
(TSH). For participants with abnormal TSH or taking thyroid medication, FT4 should be performed whenever the TSH is
performed. 


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g.
A urine and/or blood sample will be collected and sent to the central laboratory to assess compliance with background 
antidepressant medications. If urine and/or blood test is negative, one retest may be performed at the discretion of the 
investigator. With a negative test, other means of assessing adherence, including confirming prescription records and 
performing pill counts and prior good compliance with antidepressant medication may be sufficient to demonstrate 
compliance per investigator’s judgment.
h.
Participants will administer the assigned study drug once daily at bedtime from Day 1 to Day 42. A participant diary will be 
provided to the participants. Participants are required to record the administration of study drug or any missed doses in 
patient diaries, which will be checked at visits. Pill counts of study drug will be performed at postbaseline visits until end of 
the DB treatment phase. 
i.
As this is a blinded study, blood samples for PK will be collected from all participants, including placebo-treated
participants, but samples from placebo-treated participants will not be analyzed for PK. These samples will be stored and 
may be analyzed if needed (eg, suspicion of an incorrect treatment assignment).
j.
Pharmacogenomic and epigenetic blood samples will be collected only from participants who have consented to provide 
optional DNA and RNA samples for research. The predose sample may be collected anytime during screening up through 
Day 1 assessments.  
k.
To avoid interference caused by lipid content in morning blood specimens collected for biomarker evaluation, biomarker 
samples will be collected under fasting conditions. 
l.
Start date (first day) of last menstrual period and length of menstrual cycle (days) will be collected from premenopausal 
women who are still having their menses.
m.
If blood sampling or vital sign measurement is scheduled for the same time point as ECG recording, the procedures are 
recommended to be performed in the following order: ECG, vital signs, blood draw.
n.
Serum or urine pregnancy tests are performed in women of childbearing potential only. Women of childbearing potential 
must have a negative serum pregnancy test at screening and a negative urine pregnancy test before treatment starts. 
Additional serum and urine pregnancy tests may be performed as determined necessary by the investigator, to establish the 
absence of pregnancy at any time during the participant’s participation in the study. In women who are <40 years old and 
have amenorrhea, FSH should be performed to determine post-menopausal status, based on the reference range of central 
laboratory. In women who are ≥40 years old and have amenorrhea for less than 12 months, FSH test may be performed at 
investigator judgment to assist in determining their post-menopausal status. In women who are ≥40 years old and have 
amenorrhea for ≥12 months, FSH is not required. Serum testing will be used at screening and urine testing thereafter for 
women of childbearing potential only.
o.
HDRS-17 and clinician version of ISI will be performed by independent central raters for these visits only. The first remote 
interview should occur within the 1st week of the screening phase. The 2nd interview should occur at least 1 week after the 
first interview and within 1-7 days prior to the Day 1/baseline visit, preferably between Day-5 and Day -2.
p.
The assessment at Day -5 to Day -2 may be done at the site or remotely in a quiet place, based on investigator judgment.
Minor variations in the sequence and timing of assessments on the second screening visit  may be allowed as long as all 
assessments (including patient ISI) are completed and scored prior to randomization.
q.
For Day 2 and Day 8 telephone contacts, the site will ask about adherence to study drug, but formal drug accountability (pill 
counts) will not be done.
r.
The CSD should be completed by the participants at home after waking up for the day and preferably within an hour of 
waking for the day. The CSD is encouraged to be completed for 7 mornings leading up to and including the targeted Study 
Day for Day 1, Day 43, and Follow-Up Visits. Completion of the CSD is not required for randomization. The screening 
CSD should be started only after the last disallowed concomitant medication has been stopped. The diary will be provided to 
participants at Screening to collect sleep data prior to and including Day 1, on Day 29 to collect sleep data between Day 29 
and Day 43, and at Day 43 to collect data during Follow-up period. 
s.
PROs completed at a visit are recommended to be completed in the order stated in the SoA.
t.
It is recommended that the raters for the efficacy assessments (MADRS and CGI-S) not be involved in study drug dosing, 
AE assessments, or other safety evaluations.
u.
To be performed only in participants of age ≥65 years.
v.
Alpha 1-acid glycoprotein sample should be collected at the same time as each PK sample.
w.
Screening visit 1 can occur over more than 1 day, if needed.
x.
The patient rated ISI is recommended to be performed before the clinician rated ISI. Both the patient and clinician ISI at the 
2nd screening visit are required for randomization. Generally, the patient rated ISI is recommended to be performed before 
the clinician rated ISI, however if it is was not done earlier, the 2nd patient ISI may be completed on Day 1 prior to 
randomization.
y.
At baseline, the SCID-CT completed at screening should be reviewed for any changes in symptoms or diagnoses, including 
MDD symptoms item 4 for insomnia which needs to be positive prior to randomization. A new SCID-CT does not need to 
be completed at baseline.
z.
Sites should specify the date of C-SSRS suicidal ideation with intent or plan history within the past 6 months and/or suicidal 
behavior with in the past 1 year prior to screening in the eCRF. Participants are excluded if they have serious suicidal 
ideation (corresponding to a positive response to C-SSRS item 4 or 5) within 3 months or suicidal behavior within 6 months 
of study entry. 
aa.
A physical examination should include a brief neurological examination. 
bb. Two different versions of the MGH-ATRQ scale will be used based on age (for participants <65 years old and for 
participants ≥65 years old) at the beginning of screening. 


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cc.
An extension of up to 2 weeks of the screening phase may be allowed (eg, if needed to confirm eligibility criteria or for 
scheduling difficulties) with permission from the medical monitor. If there is an extension, screening visit 2 should still 
occur within 1-7 days prior to Day 1/baseline.


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2.
INTRODUCTION
Seltorexant (JNJ-42847922) is a potent and selective antagonist of the human orexin-2 receptor 
(OX2R) that is being developed for adjunctive treatment of major depressive disorder (MDD) with 
insomnia symptoms (MDDIS).
Preclinical evidence supports a role for the orexin system in modulating the stressed component 
of hypothalamic-pituitary-adrenal (HPA) axis function and other aspects of stress-responsiveness.
Clinical data from multiple Phase 1 and 2 studies also support a role for orexin antagonism in 
depression. In depressed patients, average cerebrospinal fluid (CSF) orexin levels have not been 
demonstrated to be different from controls, nor to correlate with the severity of depressive illness; 
however, the diurnal variation of CSF orexin levels has been shown to be blunted in patients with 
depression, with a trend toward elevated orexin levels in CSF across the entire diurnal period. The 
most striking elevation has been noted at the physiologic nighttime nadir. A pathologically 
elevated limbic drive from the amygdala in depressed patients may explain this finding, and it is 
possible that normalizing cortisol during that particularly exaggerated cortisol elevation (ie, during 
sleep) may significantly reduce depressive symptoms. 
Across the Phase 1 and 2 placebo-controlled studies, seltorexant, particularly the 20 mg dose, has 
been shown to be more efficacious than placebo in reducing MDD symptoms, especially in patients 
with insomnia symptoms (IS). Overall, seltorexant has been safe and well tolerated in patients with 
MDD and/or insomnia disorder, and Obstructive Sleep Apnea (OSA) as well as healthy 
participants. 
The term “study intervention” throughout the protocol, refers to study drug (seltorexant or 
placebo).
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.
2.1.
Study Rationale
Major depressive disorder is a common, serious, recurrent disorder, with worldwide lifetime 
prevalence estimates ranging from 10% to 15% in most countries. Its negative impact on role 
functioning in various settings (eg, school performance, marriage, parenting, and the workplace), 
quality of life, physical health, and life expectancy has been well-documented. Loss of work 
production and absenteeism due to major depressive episodes or MDD has been estimated to 
account for approximately 30 to 50 billion dollars in annual human capital.21 As of October 2015, 
with an estimated 350 million sufferers, depression has been ranked by the World Health 
Organization as the leading cause of disability worldwide, and the prevalence is rising.51
Inadequate response to first-line pharmacologic treatment for MDD is common and represents an 
important unmet medical need. In the National Institute of Mental Health (NIMH)-sponsored 
Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study only 28% of 
participants achieved remission (defined as a score of ≤7 on the HAM-D17) during first-line 
treatment with a selective serotonin reuptake inhibitor (SSRI).41 All currently approved drugs 
indicated for adjunctive therapy in patients with MDD (including quetiapine, aripiprazole, and 


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brexpiprazole) belong to the atypical antipsychotic family, and have tolerability issues that, in 
some cases, may lead to non-adherence, or early discontinuation. Aside from serious risks, such 
as neuroleptic malignant syndrome (NMS) and tardive dyskinesia, these agents are well-known to 
be more commonly associated with risks such as hyperglycemia/diabetes mellitus, dyslipidemia, 
weight gain, and next day drowsiness. As such, it is postulated that seltorexant may have 
tolerability advantages with respect to metabolic changes or weight gain over the atypical 
antipsychotic medications currently available for adjunctive treatment resulting in improved 
compliance and ultimately better efficaciousness by providing a new adjunctive treatment with 
unique mechanism of action. 
In 
addition 
to 
a 
hypothesized 
role 
in 
modulating 
autonomic 
arousal 
and 
hypothalamic-pituitary-adrenal (HPA) axis hyper-activity, (ie, the chronic activation of the stress 
system associated with MDD), the sleep-enhancing effects of a selective OX2R antagonist, such 
as seltorexant, are expected to confer benefit in MDD. At present, about two-thirds of depressed 
patients take sleep medications in addition to their antidepressant regimen for sleep disturbance 
(SD).22 Some of the most common side effects of these hypnotics include cognitive impairment, 
risk of dependence and abuse, risk of respiratory depression, next-day sedation, and weight 
gain.14,35
Moreover, sleep disturbances (both insomnia and hypersomnia) have been associated with a 
suboptimal response to antidepressant
therapy, an increased risk for relapse (in 
antidepressant-responsive patients), and prodromal depression.3,23 Untreated insomnia hinders 
recovery from depression in patients >60 years old36 and longer-lasting insomnia increases the risk 
of new depressive episode.5,36 Further, hyper-arousal characterizes a major subgroup of patients 
with MDD and is a core feature of this disorder that negatively affects sleep.
The proposed study, 42847922MDD3002, is a 6-week, double-blind (DB), placebo-controlled 
study intended to confirm the efficacy and safety of 20 mg seltorexant versus placebo as an 
adjunctive treatment in adults (18 to 64 years, inclusive) and elderly (65 to 74 years, inclusive) 
participants with MDDIS, who have had an inadequate response to current antidepressant therapy 
with an SSRI/ serotonin-norepinephrine reuptake inhibitor (SNRI).
2.2.
Background
Nonclinical Studies
 
 
 
 
 
 
CCI


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CCI




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evening dose of seltorexant oral tablet formulation after a high fat high-calorie meal resulted in 
31% higher mean AUC∞and 11% lower mean Cmax. The tmax was delayed by approximately 
2 hours for both doses after high fat high calorie meal (Study 42847922MDD1011, preliminary 
data).
Effect of Age
In elderly non-Asian adult healthy participants, Cmax and AUC∞of seltorexant, and metabolites 
M12 and M16 were comparable with values in young non-Asian adult healthy participants after a 
single dose of seltorexant 20 mg or 40 mg (Study 42847922EDI1014). 
In Study 42847922ISM2005, (participants with insomnia disorder; seltorexant 5, 10 or 20 mg) no 
clear difference was observed for the PK of seltorexant, M12, and M16 between non-elderly 
participants and elderly participants.
Effect of Race
 
 
 
 
 
 
 
Human Absorption, Distribution, Metabolism and Excretion (ADME) Study
In human ADME Study 42847922EDI1008 (seltorexant 40 mg oral solution, evening dosing 
3 hours after last meal), based on the mean ratios of the AUCs, seltorexant, M12, and M16 
represented approximately 20%, 15% and 6%, respectively, of the total radioactivity exposure in 
plasma. In total, 56.3% of the administered radioactivity was recovered in urine and 43.8% was 
recovered in feces.
Drug-Drug Interaction
 
 
 
 
 
 
 
Multiple oral doses of seltorexant 40 mg did not affect the steady-state PK of a combination oral 
contraceptive containing ethinyl estradiol and levonorgestrel in healthy female adult participants 
CCI
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(Study 42847922MDD1003). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2.2.2.
Efficacy
Depression
 
 
 
 
 
 
 
 
 
 
 
CCI
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The effects of seltorexant on mechanistic factors related to depression and sleep were explored in 
a monotherapy study (42847922MDD1009) where the 20 mg more than 40 mg dose showed 
benefit compared with placebo in improving MDD symptoms with particular benefit in 
participants with a patient ISI >15.
Another Phase 2 study (42847922MDD2002) explored the potential differentiating factors of 
seltorexant (20 to 40 mg) compared with quetiapine, both dosed flexibly, as adjunctive treatment 
to current antidepressant therapy over a 6-month treatment duration to assess time to all-cause 
discontinuation, response and change in depressive symptoms, as well as longer term tolerability. 
Though for the primary endpoint of all cause discontinuations the outcome was similar for both 
compounds, seltorexant showed a lower rate of discontinuations for potentially treatment-related 
reasons (all discontinuations except for social reasons [eg, moving to another state, change in work 
schedule] or needing to stop the underlying SSRI/SNRI). Examining depression symptoms change 
on the MADRS by mode dose, the 20 mg seltorexant mode dose group showed more improvement 
than the 40 mg mode dose group and this improvement was greater in the subpopulation with a
clinician ISI ≥15, supporting similar results seen in Studies 42847922MDD2001 and 
42847922MDD1009. Further, the 20 mg seltorexant mode dose group showed a larger MADRS 
change from baseline than quetiapine extended-release (XR) and more participants with response 
(≥50% improvement of baseline MADRS total score) at Week 24. Tolerability favored seltorexant 
compared with quetiapine XR based on overall rate of adverse events (AEs) and discontinuations 
and efficacy of seltorexant 20 mg mode dose group appears to maintain or improve over the 
24-week study duration.
Insomnia disorder
The effect of seltorexant on improvement in insomnia disorder was shown in one Phase 1 study 
(42847922EDI1002) and 2 Phase 2 studies (42847922ISM2002 and 42847922ISM2005).
In particular, the dose ranging, randomized, 2-week study (42847922ISM2005) comparing 3 doses 
of seltorexant (5, 10, and 20 mg) with both placebo and zolpidem in participants with insomnia 
disorder without significant psychiatric co-morbidity showed a significant improvement with 
seltorexant 10 mg and 20 mg compared with placebo that started on the first night of treatment and 
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the end of the 2-week treatment based on the latency to persistent sleep (LPS) and the Wake After 
Sleep Onset over first 6 hours (WASO-6) measured by the polysomnography (PSG). The 
seltorexant 20 mg dose showed greater improvement than zolpidem (5-10 mg) on latency to 
persistent sleep (LPS) on Nights 1 and 13 and on WASO-6 at Night 13.
2.2.2.3.
Safety and Tolerability 
Seltorexant has been administered in single-dose studies at dose levels of up to 120 mg in healthy 
participants and up to 40 mg in participants with MDD and comorbid insomnia disorder. In 
multiple-dose studies, seltorexant has been administered at doses of up to 60 mg once daily in 
healthy participants, 20 mg once daily in participants with MDD, and 40 mg once daily in 
participants with insomnia disorder. Safety and tolerability of seltorexant has also been assessed 
in combination with itraconazole, rabeprazole, rifampin, midazolam, warfarin, and an oral 
contraceptive; one study involved comparison with zolpidem.
Overall, seltorexant was generally well tolerated when administered alone or in combination with 
other studied medications. The most common treatment-emergent adverse event (TEAE) reported 
overall was somnolence. Other frequently-reported TEAEs were headache and dizziness; however, 
the incidence of these TEAEs were generally similar between seltorexant- and placebo-treated 
participants. 
There was 1 death reported in a participant treated with seltorexant in the completed Phase 2 Study 
42847922MDD2002. A 
-year-old female participant with history of
 (substance 
use disorder was ruled out) experienced a fatal serious adverse event (SAE) of subarachnoid 
hemorrhage and subdural hematoma as a result of head trauma after falling while 
 
 the SAE occurred 51 days after starting study drug and 3 days after 
the last recorded intake. The death occurred  days later on study Day 
 This event was 
considered by the investigator as not related to study drug.
There was one SAE that was reported as possibly related to seltorexant in Phase 2 study 
(Study 42847922ISM2005). A 
-year-old female participant in the seltorexant 20 mg group 
reported an SAE of cortical hemorrhage with no reported history of trauma or fall (onset 6 days 
after the first study drug intake) which was deemed as mild in severity and possibly related. The 
hemorrhage resolved within 4 weeks without sequelae.
Three adverse drug reactions (ADRs) have been identified for seltorexant to date, which may be 
related to the mechanism of action: sleep paralysis, abnormal dreams, and somnolence.
There were no clinically significant, consistent, treatment-related effects in clinical laboratory 
parameters (hematology, biochemistry, and urinalysis); neurological and physical examinations; 
vital signs; or electrocardiogram (ECG) measurements. In a thorough QT study 
(42847922MDD1007), there was no evidence of QT/ corrected QT (QTc) interval prolongation of 
clinical or regulatory concern at a therapeutic (40 mg) or a supratherapeutic (100 mg) dose 
compared with placebo, based on QTc interval by Fredericia (QTcF), QTc interval by Bazett
(QTcB), and QTc prolongation (QTcP) intervals. In addition, there were no consistent or clinically 
P
P
PPD
P
P
PP
D
P
P
PPD
PPD


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relevant changes over time for other ECG parameters (heart rate, RR interval, PR interval, or QRS 
width). 
Across studies, there was no apparent dose-related or meaningful trend in effect with seltorexant 
compared with placebo for 1) sleepiness, alertness, or next day sleepiness, 2) worsening of 
suicidality, or 3) reduction of cognition. In a recently completed placebo-controlled crossover 
study (42847922MDD1010) in adult participants with OSA treated with seltorexant or placebo, 
there were no clinically significant mean differences between the treatment groups for safety 
assessments measured by the Bond-Lader Visual Analog Scales (B-L VAS) score, and on next-
morning residual effects, including cognitive function, measured by Karolinska Sleepiness Scale 
(KSS) scores. In terms of OSA symptoms. there was no clinically meaningful difference on the 
Apnea-hypopnea Index (AHI) on Day 4 between seltorexant 40 mg and placebo, but after a single 
dose, the Apnea-hypopnea Index (AHI) was higher in the seltorexant group than placebo. There 
was no meaningful difference on SpO2 between treatment groups on Day 1 or Day 4.
Refer to the latest version of the Investigator's Brochure17 for additional details on the AEs seen in 
studies with seltorexant conducted thus far.
2.3.
Benefit/Risk Assessment
As further described in Section 2 and the rationale for this study (Section 2.1), MDD is a common, 
serious, recurrent mental disorder. MDD is the leading cause of disability, and its prevalence is 
rising.51
Current therapies commonly used as first-line antidepressant treatment in patients with MDD (eg, 
SSRIs and SNRIs), are sub-optimally effective in some patients who require adjunctive treatment, 
or who are otherwise poorly compliant because of their associated AEs, such as weight gain and 
sexual side effects. Currently approved adjunctive treatments are limited to the atypical 
antipsychotic drug class, which also present considerable tolerability concerns (eg, metabolic 
syndrome, akathisia, and extrapyramidal symptoms). The orexin receptor antagonist class offers a 
novel mechanism of action that may prove to be a valuable alternative in the adjunctive treatment 
of MDD, but without the side effects observed with other medications commonly used in this 
setting such as weight gain, sexual side effects, akathisia, or extrapyramidal symptoms. The 
preliminary data regarding effects on cortisol and stress-response suggest that seltorexant may 
have clear advantages over the standard of care in patients with certain co-morbid medical 
conditions typically associated with dysregulation of the HPA axis. 
The currently available data (see Section 2.2.2, Clinical Studies, and the seltorexant Investigator’s 
Brochure17) support this clinical study that investigates the efficacy and safety of seltorexant in 
adult participants with MDDIS who have responded inadequately to commonly used 
antidepressant treatments with consistent benefits for the 20 mg dose in MDD patients. In addition, 
seltorexant 10, 20 and 40 mg doses have been shown to improve the sleep, both induction and 
maintenance of sleep, in patients with insomnia disorder while maintaining normalized sleep 
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The benefits of seltorexant for MDD extend beyond the benefit on sleep. In the clinical studies, 
changes in the core symptoms of depression (HDRS-6 or MADRS-6) as well as the full scales 
without the sleep item were similar to that seen with the entire scale. Further, seltorexant 20 mg 
has consistently shown a greater benefit in patients with at least moderate IS and only a minimal 
benefit for patients with fewer sleep problems (typically ISI<15). Since the likelihood of benefit 
is higher in patients with sleep problems, only participants with an ISI≥15 will be enrolled in this 
study.
Additionally, the safety and tolerability data so far accumulated for seltorexant in both healthy 
participants and participants with MDD and/or insomnia disorder were generally acceptable based 
on a thorough review of the safety information from completed clinical studies related to study 
drug. The most commonly reported TEAEs in the seltorexant group which were higher in 
incidence than the placebo group were somnolence and vivid dreams with most TEAEs being mild 
or moderate in intensity. Adverse drug reactions attributed to seltorexant are sleep paralysis,
somnolence, and abnormal dreams. Few participants reported these events at doses planned for 
this study and all were self-limited and mild or moderate in intensity. There is no evidence for 
changes in clinical laboratories, ECGs, or vital signs in both short- and long-term studies. Overall 
TEAE rates of seltorexant tend to be similar to that of placebo. Interaction between seltorexant 
and alcohol has not been evaluated in humans. Preclinical data suggest that seltorexant does not 
exacerbate alcohol-induced motor incoordination. Based on the short t1/2 of seltorexant, no 
accumulation of study drug is expected. Refer to Section 2.2.2, Clinical Studies, and the seltorexant 
Investigator’s Brochure17 for additional details. 
To ensure safe use of the study drug, besides routine safety monitoring and participant
management, this protocol also includes specific risk mitigation strategies, including: restrictions 
on driving, operating machinery, or engaging in hazardous activity when participants have had 
insufficient sleep or are feeling sedated the next day (Section 5.3, Lifestyle Considerations); 
frequent visits to the site (every 2 weeks); and reducing suicidality risk inherent in the underlying 
depression by excluding high risk participants (Section 5.2, Exclusion Criteria) and performing 
Columbia Suicide Severity Rating Scale (C-SSRS) at visits (see Section 8.2.6 for details). 
The information obtained to date regarding seltorexant suggests that the potential benefits to 
patients with MDDIS in fulfilling an unmet medical need outweigh the identified risks (eg, ADRs) 
and potential risks at the doses selected for further investigation.
More detailed information about the known and expected benefits and risks of seltorexant may be 
found in the Investigator’s Brochure.17
In the event of a national emergency, mitigation strategies are described in Section 10.9
Appendix 9: Changes in Study-Related Procedures as a Result of the COVID-19 Pandemic. 


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3.
OBJECTIVES AND ENDPOINTS
For the following objectives and endpoints, MDDIS is defined as MDD with IS as a) moderate to 
severe IS by a patient version ISI total score of ≥15 at the end of screening and b) a positive 
response for IS (MDD symptoms Item 4) on the Structured Clinical Interview for DSM-5 Axis I 
Disorders Clinical Trials Version (SCID-CT). In addition, the clinician version ISI total score ≥15 
is also required since it was used in the Phase 2 program.
Objectives
Endpoints
Efficacy
Primary

To assess the efficacy of seltorexant 20 mg 
compared with placebo as adjunctive 
therapy to an antidepressant in improving 
depressive symptoms in participants with 
MDDIS who have had an inadequate 
response to current antidepressant therapy 
with a SSRI or SNRI

Change from baseline to Day 43 in the 
MADRS total score.
Key Secondary
To assess the efficacy of seltorexant compared with placebo as an adjunctive therapy to an 
antidepressant in participants with MDDIS on the following:

MDD symptoms other than insomnia 
symptoms

Change from baseline to Day 43 in the 
MADRS 
without 
sleep 
item 
(MADRS-WOSI) total score.

Patient-reported 
assessment 
of 
sleep 
outcomes

Change from baseline to Day 43 in sleep 
disturbance using the Patient Reported 
Outcome 
Measurement 
Information 
System-Sleep Disturbance (PROMIS-SD)
Short Form (8a) T-score.
Secondary
To assess the efficacy of seltorexant compared with placebo as adjunctive therapy to an 
antidepressant in participants with MDDIS on the following:

Core symptoms of depression.

Change from baseline to Day 43 in the 
MADRS-6 total score.

Response of depressive symptoms

Proportion of responders on depressive 
symptoms scale, defined as a ≥50% 
improvement in MADRS total score, from 
baseline to Day 43.

Patient-reported symptoms of depression

Change from baseline to Day 43 in Patient 
Health Questionnaire, 9-Item (PHQ-9) 
total score. 
Exploratory


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To assess the efficacy of seltorexant compared with placebo as adjunctive therapy to an 
antidepressant on the following: 

Patient-reported sleep diary

Change from baseline to Day 43 in 
subjective sleep parameters as measured 
by the Consensus Sleep Diary (CSD).

Remission of depressive symptoms

Proportion of participants with remission 
of depressive symptoms, defined as a 
MADRS total score ≤12 at Day 43.

Patient-reported health-related quality of 
life

Change from baseline to Day 43 in health-
related quality of life and health status, as 
assessed by the European Quality of Life, 
5 Dimension, 
5-Level 
(EQ-5D-5L) 
questionnaire.

Patient-reported 
global 
functioning 
(work/school, social and family life)

Change from baseline to Day 43 in the 
Sheehan Disability Scale (SDS) total 
score.

Patient-reported insomnia symptoms

Change from baseline to Day 43 in the 
patient-reported ISI total score.

Patient-reported 
assessment 
of 
sleep 
outcomes

Change from baseline over time in sleep 
symptoms
using the Patient Global 
Impression of Severity (PGI-S).

Patient-reported assessment of change in 
depressive symptoms

Change from baseline over time in 
depressive symptoms using the Patient 
Global Impression of Change (PGI-C).

Clinical symptom severity

Change from baseline over time in the 
Clinical 
Global 
Impression-Severity 
(CGI-S) score.

Patient-reported rumination symptoms

Change from baseline to Day 43 in the 
RRS total score.
Safety

To assess the safety and tolerability of 
seltorexant as adjunctive therapy to an 
antidepressant in participants with MDDIS 
in the short-term compared with placebo

Adverse events (AEs) including AEs of 
special interest (AESI)

Vital signs 

Suicidality assessment using the Columbia 
Suicide Severity Rating Scale (C-SSRS) 

Withdrawal symptoms assessment using 
the Physician Withdrawal Checklist, 
20-items (PWC-20) 

Laboratory values and electrocardiogram 
(ECG)


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
Patient-reported sexual functioning using 
Arizona 
Sexual 
Experiences 
Scale 
(ASEX)
Additional exploratory objectives:

To identify diagnostic biomarkers and to investigate changes in MDD-related biomarkers (eg, 
HPA axis, metabolic function and, biomarkers of immune system activation) in relation to 
clinical response on depression symptoms and IS upon adjunctive treatment with seltorexant.

To identify genetic (eg, CYP genes) and other factors that may influence the PK, safety, or 
tolerability of seltorexant.

To assess the plasma exposure of seltorexant and its M12 metabolite along with alpha-1-acid 
glycoprotein levels in participants with MDDIS when used as adjunctive treatment. 
3.1.
Hypothesis
The hypothesis for this study is that adjunctive treatment with seltorexant is superior to placebo in 
treating depressive symptoms, as measured by change in MADRS total score from baseline to 
Day 43 in adult and elderly participants with MDDIS who have had an inadequate response to 
treatment with a SSRI/SNRI.
4.
STUDY DESIGN
4.1.
Overall Design
This is a multicenter, DB, randomized, parallel-group, placebo-controlled 6-week study with 
seltorexant 20 mg to assess the efficacy and safety of seltorexant as an adjunctive therapy in adult 
and elderly participants with MDDIS (18 to 74 years of age, inclusive), who have had an 
inadequate response to current antidepressant therapy with a SSRI/SNRI. In addition, PK, 
pharmacogenomics, and biomarkers will also be evaluated. 
Approximately 386 participants with MDDIS will be enrolled in this study. The planned study 
dose of seltorexant is 20 mg.
The study will consist of 3 phases: a screening phase (up to 30 days), a DB treatment phase 
(43 days), and a posttreatment follow-up phase (7 to 14 days after the DB treatment phase). 
Participants will continue to take their baseline SSRI/SNRI antidepressant (at the same dose, 
without change, and at approximately the same time of the day as prior to entering the study) 
throughout the study during screening through the follow-up phase.
Screening Phase 
After providing signed informed consent, participants experiencing a major depressive episode 
will be screened to evaluate their eligibility for study participation. Participants must meet 
Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5) diagnostic criteria for 
MDD, without psychotic features, based upon clinical assessment and confirmed by the Structured 


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Clinical Interview for DSM-5 Axis I Disorders– Clinical Trials Version (SCID-CT) and have 
MDDIS (see Section 4.2.1, Study Population). Both clinician and patient versions of the ISI along 
with the SCID-CT will be performed during screening to determine IS.
Eligible participants must have a HDRS-17 total score ≥20 at the first screening interview with no 
greater than 20% improvement from the first to second screening interview and ≥18 at end of 
screening. The HDRS-17 and ISI (clinician version) will be administered by independent central
raters (further details are provided in Section 5.1 Inclusion Criteria #5 and #6). Participants must 
have had an inadequate response to at least 1, but no more than 2 antidepressants (SSRI or SNRI), 
administered at an adequate dose and duration in the current depressive episode (Section 5.1,
Inclusion Criteria #3 and #4). An inadequate response is defined as <50% reduction but with some 
improvement (ie, improvement >0%) in depressive symptom severity with residual symptoms 
present other than insomnia, and overall good tolerability, as assessed by Massachusetts General 
Hospital-Antidepressant Treatment Response Questionnaire (MGH-ATRQ). A participant will not 
be eligible for study participation if they had an adequate response to the current antidepressant, 
ie, if there was an initial response of ≥50% for more than 4 weeks (or a remission) but a subsequent 
reduction in response to <50% (ie, antidepressant tachyphylaxis (ADT) [also known as 
antidepressant tolerance, antidepressant “poop-out,” or “breakthrough” depression] to the current 
SSRI/SNRI) and the SSRI/SNRI dose remained unchanged. A reduction of response to <50% after 
responding for at least 4 weeks would indicate a relapse and start of a new episode. If the 
SSRI/SNRI was changed or the dose was increased in the new episode this would count as a new 
antidepressant trial. Multiple doses of the same SSRI/SNRI in the same episode count as only 1 
antidepressant treatment. An adequate trial is defined as an antidepressant treatment for at least 6 
weeks on a stable but not more than 18 months in the current episode at or above the stable 
therapeutic dose specified in the MGH-ATRQ. The inadequate response must include the 
participant’s current SSRI/SNRI treatment. Augmenting agents or second antidepressants 
including other non-SSRI/SNRI antidepressant(s) may be present at the beginning of screening as 
these medications can be stopped during screening after consultation with the primary treating 
physician. Residual symptoms need to include symptoms other than insomnia. Medical records, 
pharmacy records, records of conversation with the treating physician, or other equivalent 
documents can be used to verify the inadequate treatment status.
Medical history of insomnia disorder according to the DSM-5 will be reported at screening based 
on the SCID-CT. To characterize baseline sleep status, the participants are asked to complete the 
CSD for 7 days prior to the baseline visit.
Prohibited medications will be tapered and discontinued prior to the start of the DB treatment 
phase. Participants must be free of any prohibited medications for a period of at least 1 to 4 weeks, 
based on drug’s half-lives, or potential drug-drug interactions, prior to the start of the DB treatment 
phase (see Section 6.5, Concomitant Therapy, for details). 
Safety evaluations (eg, physical examination including a brief neurological examination, vital 
signs, ECG, C-SSRS, urine drug screen, alcohol breath test, and clinical laboratory tests) will be 
performed to assess eligibility. Menstrual cycle evaluation will be also be performed. Adverse 


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events will be collected from the time a signed and dated informed consent form (ICF) is obtained 
until the completion of the last study procedure on the final follow-up visit. 
Section 5.4, Screen Failures, describes options for re-testing.
Double-Blind Treatment Phase 
Participants who meet all inclusion criteria and none of the exclusion criteria will be randomly 
assigned to receive placebo and seltorexant 20 mg in a 1:1 ratio for 6 weeks. 
Participants should take their assigned study drug at home, once daily at bedtime, from Day 1 to 
Day 42. Participants for whom tolerability at the assigned dose is unacceptable should be 
withdrawn from the study drug, and the AE should be recorded as a reason for discontinuation. 
Throughout the study, participants will need to continue their baseline SSRI/SNRI antidepressant 
(at the same dose and taken around the same time of the day as prior to entering the study) on 
which they have had inadequate response at the time of screening. All participants who discontinue 
study drug in the DB treatment phase, will have an Early Withdrawal visit (Visit 8 in the Schedule 
of Activities [SoA]) and a Follow-up visit (Visit 10 in the SoA). Participants who discontinue 
study drug prior to Day 35 may continue after the Follow-up visit (Visit 10 in the SoA) with 
additional follow-up visits every 2 weeks per the SoA until Day 50-57.
Efficacy and safety assessments, sparse PK sampling, biomarkers sampling, and other study 
procedures will be performed at each visit per the SoA. If a participant withdraws from the study 
drug, the End-of-Phase/Early Withdrawal visit assessments (including MADRS) will be 
performed per the SoA, preferably on the day after the last dose or as soon as the participant is 
available for the assessment. 
Entry to the follow-up phase should not be conducted in participants who withdraw consent for 
further study assessments; however, they should complete DB End-of-Phase visit if they are 
willing to do so.
Follow-Up/End of Study Visit
Telephone Contact
One day after completion of the End-of-Phase/Early Withdrawal visit per the SoA, a telephone 
contact will be made for follow-up safety assessments. During this call, the PWC-20 will be 
administered, and information on AEs and concomitant medications will be collected. However, 
for completers of the DB phase who may continue the treatment with seltorexant after the study 
completion in another study/access program, the follow-up phase will not be mandatory.
Follow-up Visit
Participants who received at least 1 dose of study drug, except those who withdrew consent for the 
study or who are lost to follow-up, will return to the study center for a follow-up visit within 7 to 
14 days after the last dose of study drug. At the follow-up visit, safety and efficacy 
assessments/procedures, will be completed per the SoA. 


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For participants who have completed the study (at the end of DB treatment phase), this follow-up 
visit is the last visit. All participants who discontinue study drug in the DB treatment phase, will 
have an Early Withdrawal visit (Visit 8 in the SoA) and a Follow-up visit (Visit 10 in the SoA). 
Participants who discontinue study drug prior to Day 35 may continue after the Follow-up visit 
(Visit 10 in the SoA) with additional Follow-up visits, every 2 weeks per the SoA until Day 50-57.
At the start of the follow-up phase, further clinical/standard of care for the treatment of depression 
should be arranged by the study investigator and/or the participant’s treating physician. The 
decision to continue and/or change the antidepressant in this phase will be at the discretion of the 
investigator and/or participant’s treating physician. 
The duration of participation in the study for an individual participant (including screening, DB
treatment, and follow-up phases) will be up to 12 weeks. 
Changes in Study-Related Procedures as a Result of the COVID-19 Pandemic
The worldwide COVID-19 pandemic may impact the conduct of clinical studies due to the 
challenges from quarantines, site closures, travel limitations, and other considerations if site 
personnel or study participants become potentially exposed to or infected with COVID-19. To 
assure the safety of study participants, maintain compliance with Good Clinical Practice (GCP),
and minimize risks to study integrity, if necessary, in consultation with the sponsor, the method of 
assessments may be changed (eg, paper assessments replaced by electronic assessments). In 
addition, site visits may be replaced with telephone, internet-based video conferencing 
applications, or home visits by qualified health professionals (see Section 10.9, Appendix 9: 
Changes in Study-Related Procedures as a Result of the COVID-19 Pandemic for further details). 
Normal procedures, as detailed in this protocol, will be resumed as soon as possible thereafter.
A diagram of the study design is provided in Section 1.2, Schema (Figure 1).
4.2.
Scientific Rationale for Study Design
Study Population
In the context of mood disorders, IS have been associated with a suboptimal response to 
antidepressant drug therapy, an increased risk for relapse (in antidepressant-responsive patients), 
and prodromal depression.3,4,19,20,49 While the orexin system promotes wakefulness, increasingly 
it is also associated with hyperarousal2 and motivational behaviors.43 Hyperarousal characterizes 
a major subgroup of patients with MDD.13 OX2R antagonists may have utility to normalize 
hyperarousal in patients with MDD and thereby have an antidepressant effect beyond their utility 
as hypnotics. It is proposed that in many patients a cycle exists that involves rumination/dysphoric 
arousal leading to sleep problems, thereby perpetuating/exacerbating a depressive episode.32
Therefore, OX2R antagonists, such as seltorexant may have clinical efficacy in the treatment of 
MDD, in particular with symptoms of insomnia and rumination, and especially as an adjunctive 
therapy to conventional antidepressant drug therapy. It has been well established that IS predicts
the future onset of depressive symptoms as well as precedes relapse in depressive symptoms in 
MDD patients who have previously remitted.30 Further, this seems to be particularly true of 
ruminative thinking that impairs the ability to sleep. In addition, sleep disturbance is a well-


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recognized symptom of MDD (one of the diagnostic 9 symptoms in DSM-5) and a common 
symptom seen in patients with MDD (60%-70%) that often requires additional medications (such 
as hypnotics), over the counter medication, and/or substance use. It was further shown that 
depression has not only qualitative but also quantitative effects on the sleep; severely depressed 
participants manifest a more severely disturbed sleep pattern than those with mild-to-moderate 
depression.5
Seltorexant has been found to be an effective sleep medication in 2 Phase 2 studies, improving 
both sleep onset and sleep maintenance with a balanced increase in REM and NREM sleep. 
Moreover, the results of the 42847922MDD2001 study showed seltorexant 20 mg has been 
efficacious in improving depression symptoms in participants with MDD and was even more 
effective in participants with IS. In addition, the analysis of MADRS scale without sleep item and 
MADRS-6 suggest that the greater improvement observed in the MDD subgroup with ISI total 
score ≥15 signifies a greater improvement in overall depression symptoms and not only in IS.
The study population will include adult and elderly men and women who meet DSM-5 diagnostic 
criteria for MDD (confirmed by the SCID-CT),11 who have MDDIS and who have had an 
inadequate response to at least 1 but no more than 2 antidepressant therapies with a SSRI or SNRI, 
administered at an adequate stable dose and duration in the current episode, indicating that the 
participant required additional treatment but does not have TRD. 
MDDIS is defined as:
a.
moderate to severe IS by a patient version ISI total score of ≥15 at the end of screening and
b. a positive response for IS on the SCID-CT (MDD symptoms Item 4). 
In addition, the clinician version ISI total score ≥15 is also required since this version was used in 
the Phase 2 program.
The patient version of the ISI is being used as the primary determinant of the IS since it has shown 
good sensitivity and specificity in the determinant of insomnia29 while the clinician version of the 
ISI is used to link to the Phase 2 program where the clinician ISI was used to determine the high 
ISI population. The two versions show good correlation and are based on the same questions with 
15 being the minimum score for moderate symptoms of insomnia.1 The sleep item of the MDD 
symptoms (specifically the major depressive episode criteria) needs to be positive for insomnia 
symptoms to demonstrate the presence of sleep problems as one of the symptoms of the 
participant’s MDD diagnosis.
A Site-Independent Qualification Assessment will assess the validity of the participants’ diagnosis 
for inclusion in the study. The Site Independent Qualification Assessment is a tool to facilitate 
participant selection for MDD clinical studies, with a goal to ensure enrollment of participants 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 the placebo response.


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In the Phase 3 aMDD studies, elderly patients up to 74 years of age will be included for those with 
onset of first depressive episode before age 60 years. Seltorexant has been shown to have similar 
PK in healthy elderly participants up to age 85 as in adult healthy volunteers. Efficacy for sleep 
was similar to non-elderly adults in the insomnia study, 42847922ISM2005, in patients up to age 
85, and efficacy for depression in patients up to age 70 was similar in aMDD study 
(Study 42847922MDD2002) though a limited number of elderly were included. Adverse event 
rates and tolerability have been similar in adults and the elderly (Refer to the Investigator's 
Brochure17 for details). The age limit of 74 years in this study and the requirement for first episode 
of MDD prior to age 60 have been determined based on the evidence in the literature that late life 
onset MDD appears to be associated with different pathophysiology compared to earlier onset 
MDD, ie, more related to age related changes in the brain and less to genetic predisposition.18,48
Further, antidepressants tend to be less effective in older patients.44 In the recent esketamine nasal 
spray trials in elderly with treatment-resistant depression, esketamine was more effective in the 
younger elderly (<75 years) and those with earlier onset.33 Based on this information, the elderly 
population up to 74 years will be included in this study. In addition, since symptoms of dementia 
can be difficult to distinguish from MDD, patients 65 years and older need to have a normal range 
score on the Mini Mental State Examination (MMSE), based on level of education.
Unlike many other mental disorders, the age of onset of depression has a wide range, with a median 
onset of early to mid-20s, although significant proportions of patients may experience onset 
between late adolescence to late adulthood. Hence, the age of the study population in this protocol 
is intentionally broad. Women have a two-fold increased risk of depression over men, and 
separation and divorce are additional risk factors across the sexes.21
The inclusion of women of childbearing potential is supported by fertility studies in rats showing 
that initially observed effects on fertility are fully reversible after withdrawal of seltorexant.
Blinding, Control, and Intervention Groups
A placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of seltorexant treatment. Randomization will be used to 
minimize bias in the assignment of participants to treatment groups, to increase the likelihood that 
known and unknown participant attributes (eg, demographic and baseline characteristics) are 
evenly balanced across treatment groups, and to enhance the validity of statistical comparisons 
across treatment groups. A 1:1 (placebo: seltorexant 20 mg) randomization scheme will be used.42
Blinded treatment will be used to reduce potential bias during data collection and evaluation of 
clinical endpoints.
Randomization will be stratified by country, age group (adults [<65 years] versus elderly 
[≥65 years]), baseline rumination level (RRS total score <54, ≥54) and by baseline MADRS 
groups (dichotomized at a pre-specified cutoff [included in a separate document]). The cutoff of 
54 for dichotomizing RRS groups was selected based on analysis results in a Phase 2 aMDD study 
as well as literature data.


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DNA and Biomarker Collection
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in drug distribution and response and can also serve as a marker for disease 
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to a drug. The goal of the pharmacogenomic component is to collect deoxyribonucleic 
acid (DNA) to allow the identification of genetic, epigenetic, and/or transcription factors that may 
influence the PK, efficacy, safety, or tolerability of seltorexant and to identify genetic and/or 
epigenetic factors associated with MDD. Specifically, genetic and epigenetic or transcription
changes in genes known to be in pathways relevant to depression (HPA axis, inflammation, growth 
factors, monoamine transporters, ion channels, circadian rhythm) will be evaluated. The DNA and 
ribonucleic acid (RNA) collections are optional procedures as detailed in a separate ICF.
Increasingly, it is recognized that psychiatric disorders may be associated with altered 
immune/metabolic activation patterns. Blood samples will be collected to explore biomarkers 
related to immune system activity, HPA axis activation, and neurotropic factors (including but not 
limited to growth factors, inflammation, or endocrine markers). Many of these factors may be 
influenced by stage of menstrual cycle in women; therefore, the menstrual cycle will be tracked in 
premenopausal women who are still having their menses during the study, by the participant diary 
and participant’s verbal report. Biomarker samples may help to explain interindividual variability 
in clinical outcomes and/or identify population subgroups that respond differently to seltorexant.
The DNA, RNA, and protein biomarker samples may be used to help address emerging issues and 
to enable the development of safer, more effective, and ultimately individualized therapies.
Efficacy Measures
Primary Efficacy Measure 
MADRS: The 10-item MADRS is a clinician-administered scale designed to measure depression 
severity and detects changes due to antidepressant treatment.28 The MADRS scale is a validated, 
reliable scale and acceptable to regulatory health authorities as a primary scale to determine 
efficacy in major depression. 
Key Secondary Efficacy Measures
MADRS-WOSI: The MADRS-WOSI is defined as the full MADRS without the sleep item. It is 
a subset of 9 out of 10 items of MADRS.
PROMIS-SD (Short Form 8a): The Patient Reported Outcomes Measurement Information 
System captures self-reported, qualitative health aspects in the domains of physical, mental, and 
social health.52 This measure has been developed using state of the art psychometric techniques, 
such as Item Response Theory Models, and have been shown to adequately represent sleep 
disturbance. This measure provides high total test information with high validity and 
reliability.37,52 A short form version (consisting of 8 items) of the PROMIS-SD will be used in this 
study.


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Secondary/Exploratory Efficacy Measures
MADRS-6: The 6-item MADRS measures the core symptoms of depression severity and detects 
changes due to antidepressant treatment.28 It is a subset of MADRS (6 out of 10 items). The 
MADRS scale is a validated, reliable scale and acceptable to regulatory health authorities as a 
primary scale to determine efficacy in major depression.
PHQ-9: The PHQ-9 is a 9-item, patient-reported outcome measure to assess depressive 
symptoms.47
CGI-S: The CGI-S provides an overall clinician-determined summary measure of the severity of 
the participant’s illness that takes into account all available information, including knowledge of 
the participant’s history, psychosocial circumstances, symptoms, behavior, and the impact of the 
symptoms on the participant’s ability to function.15
RRS: The RRS assesses rumination as the process of “compulsively focused attention on the 
symptoms of one’s distress, and on its possible causes and consequences, as opposed to its 
solutions” as established by Nolen-Hoeksema in 1998.32 The 22 items of the RRS measure aspects 
of rumination, brooding and reflective pondering. 
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).9,10
SDS: The 5-item SDS, a patient-reported outcome measure, has been widely used and accepted 
for assessment of functional impairment and associated disability.25,45
ISI: The ISI is a validated 7-item questionnaire assessing the nature, severity, and impact of 
insomnia. The main purpose of the ISI in this study is to measure the severity of sleep problems to 
determine if a participant meets the study specific criteria for IS. The primary determinant for 
efficacy will be the patient self-administered version of the ISI which will be assessed at both 
screening visits and subsequent visits as indicated in the SoA. The clinician version will be used 
at both screening visits by the independent central raters who will not have access to the patient 
version. When administered at the same visit, the patient version should be completed prior to the 
clinician version. The clinician version was used in the Phase 2 studies and is being included as a 
link to the previous studies. The patient version has more extensive testing and is able to provide 
the participant’s assessment of their own symptoms.1,29 Evaluation of sleep in this study is 
important as insomnia and other sleep problems are common in MDD and may contribute to the 
persistence of a depressive episode or may be a residual symptom of a current depressive episode, 
despite other symptoms of depression having responded to treatment.24,30,31,35
PGI-S for Sleep Symptoms: The PGI-S for sleep symptoms consists of 2 patient-reported items
to capture the participant’s perceived severity of difficulty falling and staying asleep as well as the 
problem of not feeling rested the next day. Both items have the recall period of the past 7 days.


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PGI-C for Depression Symptoms: The PGI-C for depression is a single item patient-reported 
outcome (PRO) that will capture the participant’s perceptions of improvement or deterioration in 
depression symptoms compared with when the participant started the study drug. The PGI-C is the 
patient-reported counterpart to the CGI.
CSD-CORE- Subjective Sleep Parameters (Consensus Sleep Diary - Core Administration):
Participants will be asked to provide answers to questions to determine their subjective experience
of sleep by recording their answers in a CSD. The CSD is the only sleep diary developed with 
rigorous methodology for patient-reported outcome development, including employing user/focus 
group feedback and expert feedback to establish construct validity. It has undergone psychometric 
testing and its content validity has been confirmed by patient focus groups. The Core version of 
the CSD will be used.6
HDRS-17 (Screening only): The HDRS-17 is among most widely used and validated clinician 
administered depression assessment scale.16 It contains 17 items pertaining to symptoms of 
depression experienced over the past week. This assessment is used only during screening to 
validate an inclusion criterion.
MGH-ATRQ (Screening Only): The MGH-ATRQ is used to determine treatment response and 
resistance in MDD. The MGH-ATRQ evaluates the adequacy of duration and dose of all 
antidepressant medications used for the current major depressive episode. The MGH-ATRQ will 
be completed by the clinician in collaboration with the participant. Two different versions of the 
scale will be used: for participants <65 years old and for participants ≥ 65 years old.   
SCID-CT (Screening Only): The Structured Clinical Interview for DSM-5 (SCID-5) is a 
semi-structured interview guide for making the major DSM-5 diagnoses. It is administered by a 
clinician or trained mental health professional who is familiar with the DSM-5 classification and 
diagnostic criteria as well as clinical diagnostics.
Site Independent Qualification Assessment (Screening Only):
The Site Independent 
Qualification is used to confirm the diagnosis of depression and eligibility for the study. It is 
administered by independent clinicians who are familiar with the DSM-5 classification and 
diagnostic criteria as well as clinical diagnostics.
For additional details on efficacy measures, see Section 8.1, Efficacy Assessments.
Pharmacokinetic Assessments
A population PK analysis using sparse PK data from this study will be performed at the completion 
of the study. The purpose of the planned population PK analysis will be to assess and confirm the 
PK of seltorexant and its M12 metabolite in the target patient population, and the potential impact 
of covariates. The results of the population PK analysis will be reported separately.
In addition, blood samples will be collected for determination of plasma concentrations of 
seltorexant, its M12 metabolite, and alpha-1-acid glycoprotein in participants who discontinue 


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study drug for an AE, have an AESI, or have an SAE if the sample can be obtained within 15 hours 
of the last study drug administration.
Blood samples will also be collected to determine alpha-1-acid glycoprotein levels at each PK 
collection day (as indicated in the SoA) to calculate the unbound concentrations.
Safety Evaluations
Standard safety evaluations including collection of AEs and concomitant medications, physical 
examination (including a brief neurological examination), body weight, BMI, vital signs, 12-lead 
ECG, urine drug screening, alcohol breath test, and clinical laboratory tests will be performed to 
monitor participant safety throughout the study. A serum or urine pregnancy test will be performed 
only for women of childbearing potential (WOCBP) according to the SoA. Additional serum and 
urine pregnancy tests and drug and alcohol tests may be conducted as needed per the investigator’s 
judgment. 
Menstrual cycles will be tracked during the study in premenopausal women who are still having 
their menses, using a participant diary and participant’s verbal report.
C-SSRS: Emergence of suicidal ideation will be assessed using the C-SSRS. The C-SSRS has 
been used frequently in clinical studies and it is a standard measure for suicidal ideation 
assessment; its use is in accordance with Food and Drug Administration (FDA) guidance.50
ASEX: The ASEX is a patient-reported 5-item rating scale that quantifies sex drive, arousal, 
vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Possible 
total scores range from 5 to 30, with the higher scores indicating more sexual dysfunction. The 
scale has shown satisfactory reliability and validity.27
PWC-20: Potential withdrawal effects will be assessed by the clinician using the PWC-20. The 
PWC-20 is a reliable and sensitive instrument for the assessment of discontinuation symptoms.40
MMSE (Screening only): The MMSE test is a 30-point questionnaire that is used extensively in 
clinical and research settings to measure cognitive impairment. It is commonly used in medicine 
and allied health to screen for dementia. The test is divided into two sections: the first section 
requires vocal responses and covers orientation, memory, and attention. The second part tests 
ability to name, follow verbal and written commands, write a sentence spontaneously, and copy a 
complex polygon similar to a Bender-Gestalt Figure. The score ranges from 0 (minimum score) to 
30 (maximum score) and it is calculated by the sum of the sub-items scored 0 (incorrect answer) 
or 1 (correct answer).8,12 The MMSE will be done only in participants of age ≥65 years.
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during 
the study, participants will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may 
be withdrawn at any time with no reason given and without penalty or loss of benefits to which 


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they would otherwise be entitled. Only participants who are fully able to understand the risks, 
benefits, and potential AEs of the study, and provide their consent voluntarily will be enrolled.
4.3.
Justification for Dose
The 20 mg seltorexant dose selected for this study was shown to be well-tolerated in the Phase 1 
and Phase 2 studies in both healthy volunteers and patients with MDD and/or insomnia disorder. 
The proposed dose for this study (20 mg) was selected based on anticipated efficacious dose level, 
plasma concentrations in relation to the NOAEL in Good Laboratory Practice toxicology studies, 
the clinical safety and tolerability profile, and anticipated plasma concentrations for the selected 
dose level. 
The final dose selection for this study was based on the results of the 42847922MDD2001, 
42847922MDD2002, and 42847922MDD1009 studies.
In Study 42847922MDD2001, an adjunctive fixed dose study, comparing seltorexant 10 mg, 
20 mg and 40 mg versus placebo, a clinically meaningful reduction of depressive symptoms was 
observed for seltorexant 20 mg over placebo. The seltorexant 40 mg dose showed numerical trends 
for efficacy but did not separate statistically from placebo. No improvement in depressive 
symptoms were seen with the 10 mg dose versus placebo.
The lack of effects on cortisol and a reduced impact on polysomnography (PSG) parameters, 
indicates that 10 mg is unlikely to be a consistently effective dose for MDD. Similarly, in other 
efficacy studies (Study 42847922MDD1009, and Study 42847922MDD2002), the 20 mg dose has 
shown greater improvement in the MADRS than the 40 mg dose. Hence, 20 mg may be the 
minimally effective dose for MDD and with greater efficacy than the 40 mg dose and will be the 
only seltorexant dose used in this study.
Overall, seltorexant has been well tolerated in doses from 10 to 120 mg in single-dose studies in 
healthy participants, 10 to 40 mg used in multi-dose studies in patient population, and up to 60 mg 
in multidose studies in healthy participants. There has been no clear dose response in terms of AEs. 
Sedation has been seen somewhat more often than placebo across studies. In addition, reduced 
REM latency observed to be dose-related and therefore seen at doses of 40 mg and higher with 
some increased AEs such as abnormal dreams.  
Hence, this study will only include the 20 mg dose of seltorexant.
4.4.
End of Study and End of Treatment Definitions
A participant will be considered to have completed the DB treatment phase if he or she has 
completed the Day 43 visit of the DB treatment phase and has not discontinued study drug early 
during DB phase. 
A participant will be considered to have completed the follow-up phase if he or she has completed 
assessments at all follow-up visits.


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Participants who discontinue study drug for any reason before completion of DB treatment phase 
will not be considered to have completed the study.
The end of study is considered as the last study assessment shown in the SoA, completed for the 
last participant in the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final participant assessment at that study site, in the time frame 
specified in the Clinical Trial Agreement.
5.
STUDY POPULATION
Screening for eligible participants will be performed within 30 days before administration of the 
study drug. Refer to Section 5.4, Screen Failures for conditions under which the repeat of any 
screening procedures is allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described in the 
following 2 subsections. If there is a question about these criteria, the investigator must consult 
with the appropriate sponsor representative and resolve any issues before enrolling a participant in 
the study. Waivers are not allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2, 
Sample Size Determination.
5.1.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1.
Male or female, aged 18 to 74 years (inclusive). 
Note: Participants should be at least 18 years of age or older as per the legal age of consent 
in the jurisdiction in which the study is taking place.
2.
Criterion modified per Amendment 2
2.1 Meet DSM-5 diagnostic criteria for MDD, without psychotic features (DSM-5 
296.22, 296.23, 296.32, or 296.33), based upon clinical assessment and confirmed by the 
SCID-CT diagnosed with first depressive episode prior to age 60. The duration of the 
current depressive episode must be ≤24 months. The sleep item of the MDD symptoms 
(Item 4 [insomnia symptoms] of the SCID-CT) should be positive for IS prior to 
randomization.
3.
Criterion modified per Amendment 2
3.1 Have had an inadequate response to at least 1 but no more than 2 antidepressants (see 
the inclusion criterion 4 below), administered at an adequate dose and duration in the 
current episode of depression. The current antidepressant cannot be the first 
antidepressant treatment for the first lifetime episode of depression. An inadequate 
response is defined as <50% reduction but with some improvement (ie, improvement 
>0%) in depressive symptom severity with residual symptoms other than insomnia 
present, and overall good tolerability, as assessed by the MGH-ATRQ (see Section 4.1). 
An adequate trial is defined as an antidepressant treatment for at least 6 weeks on a stable 
dose (and no greater than 18 months in the current episode) at or above the minimum


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therapeutic dose specified in the MGH-ATRQ, must include the participant’s current 
antidepressant treatment. Note: Participants with no improvement on the current 
SSRI/SNRI should not be enrolled in the study. If a participant has received 2 SSRI/SNRI 
treatments of sufficient dose and duration in the current episode, and has shown <25% 
improvement to both, then the participant would not qualify based on exclusion 
criterion 9.
4.
Criterion modified per Amendment 1
4.1. Criterion modified per Amendment 2
4.2 Is receiving and tolerating well any one of the following SSRI or SNRI for depressive 
symptoms at screening, in any formulation and available in the participating country: 
citalopram, 
duloxetine, 
escitalopram, 
fluvoxamine, 
fluoxetine, 
milnacipran, 
levomilnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, or 
vortioxetine at a stable dose (at therapeutic dose level) for at least 6 weeks, and for no 
greater than 18 months in the current episode.
Note: The above SSRI/SNRI needs to be approved for the treatment of MDD according 
to the local label of the country where the clinical site is located.
Note: Dose and duration of treatment should be documented in the source documents by 
the investigator based on available evidence such as using the medical or pharmacy 
records. The investigator will use this information to complete the MGH-ATRQ.
Note: Participants using fluvoxamine as baseline SSRI and have normal renal and hepatic 
function may enter the study. See renal and hepatic impairment restrictions in Section 6.5
(Concomitant Therapy).
5.
Criterion modified per Amendment 1
5.1. Criterion modified per Amendment 2 
5.2 Have a HDRS-17 total score ≥20 at the first screening interview, must not demonstrate 
a clinically significant improvement (ie, an improvement of >20% on their HDRS-17 total 
score) from the first to the second independent HDRS-17 rating, and must have a 
HDRS-17 total score ≥18 at the second screening interview.
6.
Have a patient version of the ISI total score ≥15 as well as a clinician version of the ISI 
total score ≥15 at the second screening visit.
7.
Criterion modified per Amendment 2
7.1 Body mass index (BMI) between 18 and 40 kg/m2, inclusive (BMI=weight/height2).
8.
Must be an outpatient at screening.
9.
Criterion modified per Amendment 1
9.1. Participant must be medically stable on the basis of the following: physical 
examination (including a brief neurological examination), vital signs (including blood 
pressure), and 12-lead ECG performed at screening and baseline. If there are any 
abnormalities that are not specified in the inclusion and exclusion criteria, their clinical 
significance must be determined by the investigator and recorded in the participant's 
source documents and initialed by the investigator.


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10.
Participant must be medically stable on the basis of clinical laboratory tests performed at 
screening. If the results of the serum chemistry panel, hematology, or urinalysis are 
outside the normal reference ranges, the participant may be included only if the 
investigator judges the abnormalities or deviations from normal to be not clinically 
significant or to be appropriate and reasonable for the population under study. This 
determination must be recorded in the participant's source documents and initialed by the 
investigator.
11.
Must sign an ICF indicating that he or she understands the purpose of and procedures 
required for the study and be willing to participate in the study.
12.
A woman of childbearing potential must have a negative highly sensitive serum (β human 
chorionic gonadotropin [β-hCG]) pregnancy test at screening and a negative urine 
pregnancy test predose on Day 1 of the DB phase prior to randomization.
13.
Criterion modified per Amendment 2
13.1 Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for participants in clinical studies.
a.
Before entering the study, a woman must be either:

Postmenopausal
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In women who are <40 years old and have 
amenorrhea, FSH should be performed to determine post-menopausal status,
based on the reference range of central laboratory. In women who are ≥40 years 
old and have amenorrhea for less than 12 months, FSH test may be performed at 
investigator judgment to assist in determining their post-menopausal status. In 
women who are ≥40 years old and have amenorrhea for ≥12 months, FSH is not 
required.

Permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, 
bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy. No 
FSH testing is required.
b. Of childbearing potential and

Practicing a highly effective method of contraception (failure rate of <1% per year 
when used consistently and correctly) (see Section 10.5, Appendix 5, 
Contraceptive and Barrier Guidance and Collection of Pregnancy Information). 
The investigator should evaluate the potential for contraceptive method failure 
(eg, noncompliance, recently initiated) in relationship to the first dose of study 
intervention.
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 


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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 
participant.)
−
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 participants in clinical studies

Agrees to remain on a highly effective method throughout the study and for at 
least 1 month after the last dose of study drug.
Note: If the childbearing potential status changes after start of the study or the risk of 
pregnancy changes (eg, a woman who is not heterosexually active becomes active) a 
female participant or female partner of a male participant must begin a highly effective 
method of contraception, as described throughout the inclusion criteria. If reproductive 
status is questionable, additional evaluation should be considered.
14.
A woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the 
purposes of assisted reproduction during the study and for a period of at least 1 month 
after receiving the last dose of study drug.
15.
During the study and for a minimum of 1 spermatogenesis cycle (defined as 
approximately 3 months) after receiving the last dose of study drug, a man

who is sexually active with a woman of childbearing potential must agree to use 
a 
barrier 
method 
of 
contraception 
(eg, 
condom 
with 
spermicidal 
foam/gel/film/cream/suppository) and his female partner must use a highly 
effective method of contraception.

who is sexually active with a woman who is pregnant must use a condom.

must agree not to donate sperm.
16.
Criterion deleted per Amendment 1.
5.2.
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study:
1.
Criterion modified per Amendment 1
1.1. Criterion modified per Amendment 2
1.2. Has a recent (last 3 months) history of, or current signs and symptoms of, 

severe renal insufficiency (creatinine clearance [CrCl] <30 mL/min); 


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
clinically significant or unstable cardiovascular, respiratory, gastrointestinal, 
neurologic, hematologic, rheumatologic, immunologic or endocrine disorders. 

uncontrolled Type 1 or Type 2 diabetes mellitus. Note: Participants with Type 1 
or Type 2 diabetes mellitus who are controlled (hemoglobin A1C ≤8.5% and 
glucose ≤150 mg/dL at screening) may be eligible to participate if otherwise 
medically healthy, and if on a stable regimen of glucose-lowering medications 
for at least 2 months prior to screening.
2.
Has a history of narcolepsy or seizures (except childhood seizures)
3.
Has clinically significant hepatic disease as defined by:

≥2x Upper Limit of Normal (ULN) increase of aspartate aminotransferase (AST) 
or alanine aminotransferase (ALT) at screening (one retest is permitted) 

significant liver disease including cirrhosis, ascites, active hepatitis etc (fatty 
liver disease and Gilbert’s syndrome will be allowed as long as it does not meet 
above criteria).
4.
Has taken a strong inhibitor of CYP3A4 or CYP2C9 or moderate/strong inducer of 
CYP3A4 or CYP2C9 or a dual inhibitor/inducer of CYP3A4 and CYP2C9 within 14 days 
before the first study drug administration on Day 1 or will require treatment during the 
study. See Section 10.6, Appendix 6, for examples of strong inhibitors or moderate/strong 
inducers of CYP3A4 or CYP2C9 or dual inhibitors/inducers of CYP3A4 and CYP2C9.
5.
Has taken a moderate inhibitor of CYP3A4 or CYP2C9 within 14 days before the first 
study drug administration on Day 1 or will require treatment during the study and has:
limited renal (CrCl <60 mL/min) or
hepatic disease (AST/ALT >1.5X ULN and bilirubin >1.5X ULN).
See Section 10.6, Appendix 6, for examples of moderate CYP3A4 or CYP2C9 inhibitors.
6.
Has current signs/symptoms of hypothyroidism or hyperthyroidism. For participants with 
a history of thyroid disease and for participants who, regardless of thyroid history have 
the thyroid stimulating hormone (TSH) value out of range, a free thyroxine (FT4) test will 
be conducted. If the FT4 value is abnormal and considered to be clinically significant 
(after discussion with the sponsor’s study responsible physician/scientist or designee) the 
participant is not eligible.
Participants with a pre-existing history of thyroid disease/disorder who are treated with 
thyroid hormones need to be on a stable dosage for 3 months prior to the start of the 
screening phase.
Participants taking thyroid supplementation for antidepressant purposes are not allowed 
in the study.
7.
Has Cushing’s Disease, Addison’s Disease, primary amenorrhea, or other evidence of 
significant medical disorders of the HPA axis.
8.
Criterion modified per Amendment 1
8.1. Has a current or recent history of homicidal ideation or serious suicidal ideation 
within the past 3 months, corresponding to a positive response on item 4 (active suicidal 
ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation 


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with specific plan and intent) for ideation on the C-SSRS, or a history of suicidal behavior 
within the past 6 months, as validated by the C-SSRS at screening or Day 1. Participants 
with prior suicidal behavior in the past year, or prior serious suicidal ideation/plan within 
the past 6 months, should be carefully screened. For current suicidal ideation, only 
participants with non-serious items (1-3 of the suicidal ideation section of the C-SSRS) 
may be included at the discretion of the investigator.
9.
Has a history of treatment-resistant MDD, defined as a lack of response to 2 or more 
adequate antidepressant treatments in the current episode, as indicated by no or minimal 
(<25% improvement in symptoms) when treated with an antidepressant of adequate dose 
(per MGH-ATRQ) and duration (at least 6 weeks).
10.
Has a history or evidence of clinically meaningful noncompliance with current 
antidepressant therapy.
11.
Has a primary DSM-5 diagnosis of panic disorder, generalized anxiety disorder, social 
anxiety disorder, or specific phobia which has been the primary focus of psychiatric 
treatment within the past 2 years. These are allowed as secondary diagnoses if MDD is 
the primary focus of treatment according to the investigator.
12.
Criterion modified per Amendment 1
12.1. Current active DSM-5 diagnosis of obsessive-compulsive disorder, posttraumatic 
stress disorder, anorexia nervosa, bulimia nervosa or fibromyalgia. These disorders need 
to be in remission for at least 1 year for the participant to be enrolled.
13.
Criterion modified per Amendment 1
13.1. Has history or current diagnosis of a psychotic disorder, bipolar disorder, 
intellectual disability, autism spectrum disorder, borderline personality disorder, or 
somatoform disorders.
14.
Has any significant primary sleep disorder, including but not limited to obstructive sleep 
apnea, restless leg syndrome, or parasomnias. Patients with insomnia disorder are 
allowed.
15.
Criterion modified per Amendment 1
15.1. Has a history of moderate to severe substance use disorder including alcohol use 
disorder according to DSM-5 criteria within 6 months before screening or positive test 
result(s) for alcohol and/or drugs of abuse (eg, opiates [including methadone], cocaine, 
amphetamines, methamphetamines, cannabinoids, cannabidiol [CBD], barbiturates, 
3,4-Methylenedioxymethamphetamine [MDMA]) at screening or at baseline.
Note: One retest during screening is allowed at investigator’s judgment. Tobacco and 
caffeine use are not exclusionary.
16.
Taking, at screening, benzodiazepines at high dosages greater than the equivalent of 
30 mg diazepam or 3 mg of lorazepam at long duration which might result in 
benzodiazepine withdrawal syndrome. Participants must have a negative benzodiazepine 
test at baseline and be free of signs of the benzodiazepine abstinence syndrome. (see 
Section 10.8, Appendix 8: Benzodiazepine Equivalence Table).
17.
Had a clinically significant acute illness per investigator judgment within 7 days before 
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18.
Has a known malignancy or history of malignancy within 5 years before screening 
(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 study responsible physician/scientist or designee, is considered cured with 
minimal risk of recurrence).
19.
Criterion modified per Amendment 2
19.1. Has clinically significant ECG abnormalities at screening or Day 1 prior to 
randomization that may jeopardize the participants’ safety or the integrity of the study, 
in the Investigator’s judgment, defined as:

During screening and/or Day 1, a QT interval corrected according to 
Fridericia’s formula (QTcF): ≥450 msec (males); ≥470 msec (females). Note: 
If the QTcF is prolonged on the initial ECG at a given time point, the average 
QTcF of 3 ECGs, recorded 4 minutes apart, must not be ≥450 msec for males 
and ≥470 msec for females.

Evidence of 2nd and 3rd degree atrioventricular block.

Features of new ischemia

Other clinically important arrhythmia or cardiac abnormalities
20.
Criterion Modified per Amendment 1:
20.1. Has within the last 5 years received any prior antidepressant treatment with 
ketamine/esketamine, electroconvulsive therapy, vagal nerve stimulation, or a deep brain 
stimulation device.
Note: Participants who previously had taken up to 2 doses of ketamine/esketamine and 
did not continue (eg, did not benefit from the treatment or experienced tolerability issues) 
can be considered for enrollment.
21.
Ongoing psychological treatments (eg, Cognitive Behavior Therapy, Interpersonal 
Psychotherapy, Psychodynamic Psychotherapy etc.), initiated within 6 weeks prior to 
start of screening. Note: a participant who has been receiving ongoing psychological 
treatment for a period of greater than 6 weeks is eligible, if the investigator deems the 
psychological treatment to be of stable duration and frequency.
22.
Has received experimental therapies (psychological, pharmacologic or noninvasive 
device) within 30 days before screening or if greater than 2 experimental therapies in the 
past year prior to screening.
23.
Has known allergies, hypersensitivity, intolerance or any contraindication to seltorexant
or its excipients (refer to Investigator's Brochure17 for seltorexant).
24.
Has had a >7 days exposure or poor tolerability to seltorexant in previous studies (per 
patient report or other information).
25.
Donation of 1 or more units (approximately 450 mL) of blood or acute loss of an 
equivalent amount of blood within 30 days before the first dose of study drug.
26.
Has cognitive impairment per investigator judgment that would render the informed 
consent invalid or limit the ability of the participant to comply with the study 
requirements. Participant has neurodegenerative disorder (eg, Alzheimer’s disease, 


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vascular dementia, Parkinson’s disease with clinical evidence of cognitive impairment) 
or evidence of mild cognitive impairment (MCI). Participants of age ≥65 years: has a 
MMSE <25 or <23 for those participants with less than high school equivalent education.
27.
Has any condition for which, in the opinion of the investigator, participation would not 
be in the best interest of the participant (eg, compromise the well-being) or that could 
prevent, limit, or confound the protocol-specified assessments.
28.
Has taken any disallowed therapies as noted in Section 6.5, Concomitant Therapy.
29.
Is pregnant, or breastfeeding, or planning to become pregnant while enrolled in this study 
or within 1 month after the last dose of study drug.
30.
Plans to father a child while enrolled in this study or within 3 months after the last dose 
of study drug.
31.
Has had major surgery, (eg, requiring general anesthesia) within 2 weeks before 
screening, or will not have fully recovered from surgery, or has surgery planned during 
the time the participant is expected to participate in the study.
Note: Participants with planned surgical procedures to be conducted under local 
anesthesia may participate.
32.
Employee of the investigator or study site, with direct involvement in the proposed study 
or other studies under the direction of that investigator or study site, as well as family 
members of the employees or the investigator.
Note: Investigators should ensure that all study enrollment criteria have been met. If a participant's 
clinical status changes (including any available laboratory results or receipt of additional medical 
records) after screening but before the first dose of study drug is given such that he or she no longer
meets all eligibility criteria, then the participant should be excluded from participation in the study. 
Section 5.4, Screen Failures, describes options for re-testing. The required source documentation 
to support meeting the enrollment criteria are noted in Section 10.3, Appendix 3: Regulatory, 
Ethical, and Study Oversight Considerations.
The sponsor or designee will evaluate and approve or reject requests to rescreen an individual 
participant on a case-by-case basis. Refer to Section 5.4, Screen Failures for further details on 
rescreening participants.
5.3.
Lifestyle Considerations
Potential participants are recommended to follow the following lifestyle restrictions during the 
study to be eligible for participation:
1.
The use of limited amounts of alcohol, 

Males: up to 2 drinks daily on average over a week (2 glasses wine [12%, 5 fluid 
ounces {148 mL} each], 2 regular beers [5%, 12 fluid ounces {355 mL} each], or 
2 shots liquor [40%, 1.5 ounces {44 mL} each]), will be allowed during the study. 

Female and elderly: up to 1 drink daily on average over a week (1 glass wine [12%, 
5 fluid ounces {148 mL} each], 1 regular beer [5%, 12 fluid ounces {355 mL} 


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each], or 1 shot liquor [40%, 1.5 ounces {44 mL} each]), will be allowed during 
the study.

Alcohol should not be consumed on the day of a study visit prior to assessments.
2.
Participants will be advised not to donate blood during the study.
3.
Participants should be cautioned not to drive a car or operate machinery or engage in 
any potentially hazardous activities if they have had insufficient sleep following 
administration of the study drug or at any time during the study if the participant feels 
that his or her baseline competency is impaired, such as feeling sedated.
Note: At any point during the study, if participants manifest significant next-day sleepiness, they 
are advised to inform the investigator. These participants should be advised not to drive or operate 
machinery and if next-day sleepiness is persistent, these participants may be discontinued.
5.4.
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant 
identification and age at initial informed consent. In cases where the participant is not randomized 
into the study, limited one-time re-testing of abnormal screening values, including laboratory 
values, urine toxicology tests, vital signs, and ECGs that potentially lead to exclusion are allowed 
at an unscheduled visit during the screening phase to reassess eligibility. If the QTcF is prolonged 
on the initial ECG at a given time point, the average QTcF of 3 ECGs, recorded 4 minutes apart, 
must not be ≥450 msec for males and ≥470 msec for females. If a participant does not meet all 
inclusion and exclusion criteria at initial screening visit (eg, a screen failure), but in the future is 
expected to meet the eligibility criteria, the participant may be rescreened on one occasion only. 
This should be discussed with and approved by the sponsor’s study responsible physician/scientist 
or designee prior to re-screening. Participants who are rescreened will be assigned a new 
participant number, undergo the informed consent process, and then restart a new screening phase. 
Participants who failed screening on DSM-5 criteria for MDD, HDRS-17 total score, or on ISI 
total score cannot be rescreened.
6.
STUDY INTERVENTION
6.1.
Study Interventions Administered
This study is planned to investigate a seltorexant dose of 20 mg as an adjunctive treatment for 
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Seltorexant will be supplied as tablets of 20 mg. Placebo will be supplied as matching tablets.
Study drug will be manufactured and provided under the responsibility of the sponsor. Refer to the 
latest version of the Investigator's Brochure17 for a list of excipients. Study drug will be provided 
in blister kits (otherwise described as “container” throughout the document) identified by a study 
number. Study drug labels will contain information to meet the applicable regulatory requirements.
All participants should take their assigned study drug once daily at bedtime, with water, with or 
without a meal, from Day 1 to Day 42.
The tablets must be swallowed whole with water and not chewed, divided, dissolved or crushed. 
Participants are required to record the administration of study drug or any missed doses in 
participant diaries, which will be checked at each scheduled visit. Pill counts of study drug will be 
performed at postbaseline visits during the treatment phase of the study. 
If a scheduled (ie, at bedtime) dose is missed, participants are advised not to take the dose in the 
morning and not to administer 2 doses at a time the next evening. The dose will be skipped. 
Information about the missing dose should be recorded in participant diaries which will be checked 
at each scheduled visit. 
Study-site personnel will instruct participants on how to store study drug for at-home use.
SSRI/SNRI Antidepressant Administration
The baseline SSRI/SNRI antidepressant dose needs to be stable for at least 6 weeks (and no more 
than 18 months in the current episode) prior to screening. Participants will continue to take their 
baseline SSRI/SNRI antidepressant (see Section 5.1 for a list of antidepressants) preferably at the 
same dose, without change, every day, at approximately the same time of the day as prior to 
entering the study throughout the study, starting at screening and including the follow-up phase. 
Lack of adherence to the SSRI/SNRI may be a cause for screen failure or study drug 
discontinuation.
The baseline antidepressant will not be provided by the sponsor. Participants or their insurance 
will be responsible for the cost of the SSRI/SNRI; the sponsor will not be responsible for the cost
unless otherwise specified by local regulations. If during the study, the participant can no longer 
provide for the SSRI/SNRI, this issue needs to be discussed with the sponsor’s study responsible 
physician/scientist or designee.
6.2.
Preparation/Handling/Storage/Accountability
All study drug must be stored at the site at controlled temperatures and conditions as indicated on 
the product-specific labeling.
Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study drug preparation, handling, and storage.
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 participant, and the return 


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of study drug from the participant (if applicable), must be documented on the study drug 
accountability form. Participants must be instructed to return all original containers, whether empty 
or containing study drug.
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 participant, must be 
available for verification by the sponsor's study site monitor during monitoring visits. The return to 
the sponsor of unused study drug, or used returned study drug for destruction, will be documented 
on the study drug return form. When the study site is an authorized destruction unit and study drug 
supplies are destroyed on-site, this must also be documented on the study drug return form.
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 
participants participating in the study. Returned study drug must not be dispensed again, even to the 
same participant. Whenever a participant brings his or her study drug to the study site for pill count, 
this is not seen as a return of supplies. Study drug may not be relabeled or reassigned for use by other 
participants. 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.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Central randomization will be implemented in conducting this study for entry to the DB phase. 
Participants will be assigned to 1 of 2 treatment groups (placebo and seltorexant) based on an 
algorithm implemented in the interactive web response system (IWRS) before the study. The 
randomization will be balanced by using randomly permuted blocks and will be stratified by 
country, age group (adults [18 to 64 years, inclusive] versus elderly [65 to 74 years, inclusive]),
baseline rumination level (RRS total score <54 and ≥54), and baseline MADRS group 
(dichotomized at a pre-specified cutoff [included in a separate document]). Based on the algorithm, 
the IWRS will assign a unique treatment code, which will dictate the study drug assignment and 
matching study drug kit for the participant.
To maintain the study blind during the DB treatment phase, the study drug container will have a 
label containing the study name, study number, blinded study drug name, unique container ID, and 
reference number. The label will not identify the study drug in the container. The study drugs will 
be identical in appearance and will be packaged in identical containers. 
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual participant.
Data that may potentially unblind the treatment assignment (ie, study drug concentrations, study 
drug preparation/accountability data, treatment allocation, and biomarker or other specific 
laboratory data) will be handled with special care to ensure that the integrity of the blind is 
maintained and the potential for bias is minimized. This can include making special provisions, 


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such as segregating the data in question from view by the investigators, clinical team, or others as 
appropriate until the time of database lock and unblinding. 
Under normal circumstances, the blind should not be broken until all participants have completed 
the study and the database is finalized. The investigator may in an emergency determine the 
identity of the study drug by contacting the IWRS. While the responsibility to break the study drug 
code in emergency situations resides solely with the investigator, it is recommended that the 
investigator contact the sponsor or its designee, if possible, to discuss the situation, before breaking 
the blind. Telephone contact with the sponsor or its designee will be available 24 hours per day, 
7 days per week. In the event the blind is broken, the sponsor must be informed as soon as possible. 
The date, time, and reason for the unblinding must be documented by the IWRS, in the appropriate 
section of 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 participant's source 
documents in a secure manner.
Participants who have had their study drug assignment unblinded during the DB treatment phase 
are required to return for the end-of-treatment/follow-up visit. 
6.4.
Study Intervention Compliance
The study drug will be self-administered by the participant at home from Day 1 to Day 42 of the 
DB treatment phase. 
The number of study drug tablets dispensed for self-administration by participants at home will be 
recorded and compared with the number returned during postbaseline visits. Participants are
required to record the administration of study drug or any missed doses in participant diaries, which 
will be checked at postbaseline visits.
Participants with repetitive noncompliance to the study drug in the DB treatment phase will be 
withdrawn from the study treatment. See Section 7.1 for reasons for withdrawal.
If appropriate, additional details may be provided in a site investigational product manual that is 
provided separately and noted in Section 8, Study Assessments and Procedures, Study-Specific 
Materials.
6.5.
Concomitant Therapy
Pre-study therapies administered up to 6 weeks before the first screening visit and any ongoing 
therapies must be recorded starting at screening except the ongoing oral antidepressant for which 
start date will be reported. 
Concomitant therapies must be recorded throughout the study beginning with signing of the 
informed consent (ie, screening) until the follow-up visit. Concomitant therapies should also be 
recorded beyond this time only in conjunction with new or worsening AEs or SAEs. For 
participants who fail screening, concomitant therapies do not need to be recorded unless there is 
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When possible, all sleep medication should be stopped within 21 days after signing the ICF 
(including sedative-hypnotics from the benzodiazepine, non-benzodiazepine and antihistamine 
classes as well as prazosin, if it is being used for the treatment of sleep problems). Rebound effects 
of stopping prestudy sleep medication and/or benzodiazepine may be remediated by tapering the 
medication. The investigator should consider if 21 days after screening (sedative hypnotics should
be stopped 7 days prior to first dose) is sufficient for the discontinuation of the hypnotic/sedating 
medications as for chronic or high dose benzodiazepine use a prolonged taper may be more 
appropriate, for which participant should be referred to PCP for clinical management and excluded 
from participation in this study. If the investigator determines that more time is needed to stop the 
sedative hypnotic safely, the investigator may request an extension of screening by up to 2 weeks 
so that the last dose of disallowed medication is at least 7 days prior to baseline/Day 1.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as psychotherapies, transcranial magnetic 
stimulation, acupuncture, special diets, exercise regimens) different from the study drug must be 
recorded in the eCRF. Recorded information will include a description of the type of the drug, 
treatment period, dosing regimen, route of administration, and its indication. Modification of an 
effective pre-existing therapy should not be made for the explicit purpose of entering a participant 
into the study.
Participants should continue to take their baseline SSRI/SNRI antidepressant throughout the entire 
study as described in Section 6.1, Study Interventions Administered. Concurrent antidepressant 
treatment(s) will also be included on the appropriate version of the MGH-ATRQ.
For safety reasons, the use of hypnotic drugs or some food supplements (see the following list of 
prohibited medication or food supplements) is prohibited from screening until the last study visit 
except for limited use as described below. Seltorexant has hypnotic properties and potential 
pharmacodynamic interactions with other hypnotic drugs have not been investigated. 
As discussed in Section 6.6, disallowed medication may be used for participants who discontinue 
early from the DB phase, during the extended follow-up period (after the first follow-up visit 
[Visit 10 in the SoA]). If clinically indicated, disallowed medications may be started after the 
End-of-Phase/Early Withdrawal visit to treat symptoms related to an AE or breakthrough MDD 
and/or insomnia symptoms prior to the first follow-up visit.
Participants must not use the following medications or food supplements prior to or during the 
study, as indicated, except to treat an AE or breakthrough symptoms as described above, preferably 
after the End-of-Phase/Early Withdrawal visit:
1.
Monoamine oxidase inhibitors within 4 weeks before screening until the first follow-up 
visit.
2.
Antipsychotic drugs from at least 14 days before Day 1 until the first follow-up visit
(Visit 10 in the SoA).
3.
Benzodiazepines, buspirone, non-benzodiazepine hypnotics (eg, zolpidem, zopiclone, 
zaleplon, eszopiclone, suvorexant and ramelteon), sedating antihistamines including 


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over-the-counter hypnotics (eg, diphenhydramine, doxylamine, and hydroxyzine), and 
melatonin from at least 7 days prior to Day 1 until the first follow-up visit (Visit 10 in the 
SoA). Sleep medication should be tapered off to prevent rebound insomnia.
Note: Zolpidem (up to 10 mg/d or similar GABAergic hypnotic) may be used only during 
screening, and up to 2 times between Day -7 and Day -2 as a rescue medication for 
insomnia. It should not be used on the day of or the day prior to the second screening 
central ratings assessments including the patient ISI or Baseline/Day 1. 
4.
Non-SSRI/SNRI antidepressants (eg, doxepin, trazodone, mirtazapine, bupropion, 
tricyclic antidepressants, agomelatine, and S-adenosyl methionine [SAMe]) from at least 
7 days prior to Day 1 until the first follow-up visit (Visit 10 in the SoA).
5.
Opiates and mood stabilizers (eg, lithium and anticonvulsants) from at least 7 days prior 
to Day 1 until the first follow-up visit (Visit 10 in the SoA). Muscle relaxants (eg,
cyclobenzaprine, carisoprodol, baclofen) may be used for up to 7 days during the study 
but may not be used for 7 days prior to baseline/Day1. 
6.
Stimulants (eg, dexamphetamine, methylphenidate, dexmethylphenidate), systemic (oral, 
IV, or IM) steroids, and appetite suppressants (ephedrine), and isoxsuprine from at least 
7 days before Day 1 until the end of the DB phase.
Limited use of decongestants (eg, phenylephrine, pseudoephedrine, and oxymetazoline) 
will be permitted, as needed, and must not exceed 7 consecutive days or be used within 
24 hours of a scheduled visit.
7.
A known strong inhibitor of CYP3A4 or CYP2C9 or moderate/strong inducer of CYP3A4 
or CYP2C9 or a dual inhibitor/inducer of CYP3A4 and CYP2C9 within 14 days before 
the first study drug administration on Day 1 and until the first follow-up visit (Visit 10 in 
the SoA). See Section 10.6, Appendix 6, for examples of strong inhibitors and 
moderate/strong inducers of CYP3A4 or CYP2C9 or dual inhibitors/inducers of CYP3A4 
and CYP2C9.
8.
For participants with limited renal (CrCl <60 mL/min) or hepatic disease (AST/ALT 
>1.5X ULN and bilirubin >1.5X ULN), see table below, moderate CYP3A4 inhibitors or 
CYP2C9 inhibitors are not allowed within 14 days before the first study drug 
administration on Day 1 and until the follow-up visit (Visit 10 in the SoA). See 
Section 10.6, Appendix 6, for examples of moderate CYP3A4 or CYP2C9 inhibitors.
For participants with limited recent renal or hepatic disease, use the following guidance 
for study participation and concomitant medication use:
Renal Function
(creatinine clearance [CrCl] in mL/min)
Impact on Study Participant
≥60
Eligible for study without restriction
30-59
Limitation on concurrent 
medications, see Appendix 6
<30
Exclude participant from study
Hepatic Function
Impact on Study Participant
Aspartate aminotransferase (AST)/ alanine 
aminotransferase (ALT) <1.5X Upper Limit of Normal 
(ULN) and/or
Bilirubin <1.5X ULN
Eligible for study without restriction


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AST/ALT >1.5X ULN and
Bilirubin >1.5X ULN 
Limitation on concurrent drugs, see 
Appendix 6
≥2X ULN) increase of AST or ALT at screening (one 
retest is permitted) 
Significant liver disease including cirrhosis, ascites, or 
active hepatitis (fatty liver disease and Gilbert’s 
syndrome will be allowed as long as the participant
does not meet first criteria).
Exclude participant from study
9.
Magnetic and electrical stimulation therapies: electroconvulsive therapy, vagal nerve 
stimulation, deep brain stimulations, transcranial magnetic stimulation (TMS) of any 
type, or direct current (DCS), or electrical stimulation, from screening to the End of Study 
visit. TMS or DCS or electrical stimulation use prior to screening is not exclusionary.
10.
Ketamine or esketamine within 5 years prior to and during the study (up to 2 doses are 
allowed in lifetime prior to screening).
11.
Other investigational drugs within 30 days prior to and during the study.
12.
St. John’s wort, ephedra, 5-hydroxytryptophan, ashwagandha, Chinese herbal 
medications known to affect CYP3A4 or CYP2C9, ginkgo, ginseng, or kava from at least 
7 days before Day 1 until the first follow-up visit (Visit 10 in the SoA).
When a prohibited medication is discontinued by the participant’s primary healthcare provider, the 
investigators should consult with the participant’s primary healthcare provider and consider the 
time needed to sufficiently eliminate a drug from body system, eg, 5 t1/2 of the drug. The sponsor 
must be notified as soon as possible of any instances in which prohibited therapies are 
administered. 
As described in the Exclusion Criteria, psychotherapy cannot be started during the DB treatment 
phase or during screening. Ongoing psychotherapy, if the investigator deems the treatment to be 
stable in duration and frequency may continue during the DB treatment phase as long as it was 
started more than 6 weeks prior to the beginning of the screening period. 
This study allows the use of locally approved (including emergency use-authorized [or country 
specific equivalent emergency use approved]) COVID-19 vaccines. If any vaccine (COVID-19 or 
other eg, Influenza vaccines) are administered, these should be recorded in the source documents 
and entered in the eCRF.
6.6.
Intervention After the End of the Study
Participants will be instructed that study drug will not be made available to them after they have 
completed the DB treatment phase and discontinued study drug treatment. Participants should 
return to their primary physician to determine standard of care. 
For participants who discontinue DB treatment early, MDD treatment may be modified (including 
use of disallowed medications) at the discretion of the investigator or treating clinician after the 
initial Follow-up visit (7 to 14 days after End of the DB phase [Visit 10 in the SoA]) during the 
extended follow-up phase. If needed during the follow-up period, a disallowed medication may be 


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started due to an AE or for breakthrough symptoms prior to the first follow-up visit. Concomitant 
medications and the indication for the use should be recorded at each Follow-up visit.
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
A participant's study drug must be discontinued if:

The participant withdraws consent to receive study drug.

The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the 
best interest of the participant to discontinue study drug.

Based upon the clinical judgment of the investigator and consideration of the recommended 
withdrawal criteria, a participant may be withdrawn for lack of efficacy. The recommended 
withdrawal criteria for worsening of depression would be an increase in MADRS total score 
of >25% from baseline and an increase in CGI-S of ≥1 point in 2 consecutive assessments.

The participant becomes pregnant. Refer to Section 10.5, Appendix 5: Contraceptive and 
Barrier Guidance and Collection of Pregnancy Information.

Noncompliance with study drug administration (ie, missing either 4 or more consecutive doses 
of study drug or a total of 8 or more doses during any 4-week period).

Investigator's impression of significant noncompliance with background antidepressant 
therapy, based in part on urinary antidepressant concentrations (citalopram, escitalopram, 
fluvoxamine, fluoxetine, paroxetine, sertraline, or venlafaxine) or, if concentration data are 
unavailable, prescription records and pill counts.

The participant persistently uses a disallowed medication as discussed with the sponsor’s 
study responsible physician/scientist or designee.

The participant shows signals of acute suicidal ideation with a clear plan or intent at any time 
during the study; the participant should be referred to appropriate medical/psychiatric care.

AST and/or ALT exceeds 5X ULN (confirmed by repeat testing).

AST and/or ALT exceeds 3X ULN and total bilirubin exceeds 1.5X ULN (confirmed by repeat 
testing).

Study drug blind is broken during the DB phase
If a participant discontinues study drug for any reason (except withdrawal of consent from study), 
end-of-treatment/early withdrawal assessments should be obtained as soon as possible. Follow-up 
assessments should be obtained according to the SoA. All participants who discontinue study drug 
in the DB treatment phase, will have an Early Withdrawal visit (Visit 8 in the SoA) and a 
Follow-up visit (Visit 10 in the SoA). Participants who discontinue study drug prior to Day 35
may continue after the Follow-up visit (Visit 10 in the SoA) with additional follow-up visits every 
2 weeks per the SoA until Day 50-57. If a participant discontinues study medication and enters the 
follow-up phase, other concomitant medications, including disallowed medication, may be started 
(see Section 6.5). If the reason for withdrawal from the study is withdrawal of consent, then no 


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additional assessments are allowed unless the participant agrees to take part in the End of 
Treatment visit.
7.2.
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent from study assessments

The investigator believes that for safety or tolerability reasons (eg, AE), worsening of 
symptoms, or if it is in the best interest of the participant to discontinue from the study. If 
possible, End of Treatment/Early Withdrawal visit should be completed. 

Death
When a participant withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn 
participant may not be assigned to another participant. If a participant discontinues study drug and 
withdraws from the study before the end of the DB treatment phase, end-of-treatment/early 
withdrawal assessment should be obtained preferably next day after the last dose of study drug 
intake or as soon as possible, and follow-up assessments should be obtained according to the SoA.
If the reason for withdrawal from the study is withdrawal of consent from study assessments, then 
no additional assessments are allowed.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of 
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent 
form apply as local regulations permit.
Withdrawal From the Use of Genetic Research Samples
A participant who withdraws their consent from the study will have the following options 
regarding the optional research sample:

The collected samples will be retained and used in accordance with the participant's original 
separate informed consent for optional research samples.

The participant may withdraw consent for optional research samples, in which case the 
samples will be destroyed, and no further testing will take place. To initiate the sample 
destruction process, the investigator must notify the sponsor study site contact of withdrawal 
of consent for the optional research samples and to request sample destruction. The sponsor 
study site contact will, in turn, contact the biomarker representative to execute sample 
destruction. If requested, the investigator will receive written confirmation from the sponsor 
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Withdrawal From the Optional Research Samples While Remaining in the Main Study
The participant may withdraw consent for optional research samples while remaining in the study. 
In such a case, the optional research samples will be destroyed. The sample destruction process 
will proceed as described above.
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term 
Retention of Samples for Additional Future Research in Section 10.3, Appendix 3: Regulatory, 
Ethical, and Study Oversight Considerations). In such a case, samples will be destroyed after they 
are no longer needed for the clinical study. Details of the sample retention for research are 
presented in the main ICF and in the separate ICF for optional research samples.
7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed 
lost to follow-up until all reasonable efforts made by the study-site personnel to contact the 
participant are deemed futile. The following actions must be taken if a participant fails to return 
for a required study visit:

The study-site personnel must attempt to contact the participant to reschedule the missed visit 
as soon as possible, to counsel the participant on the importance of maintaining the assigned 
visit schedule, to ascertain whether the participant wishes to or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must make every 
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, 
e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address, 
or local equivalent methods). These contact attempts should be documented in the
participant’s medical records.

Should the participant continue to be unreachable despite every reasonable effort to regain 
contact by the site, they will be considered to have withdrawn from the study.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The SoA summarizes the frequency and timing of PK, pharmacogenomic, biomarker, efficacy, 
and safety measurements applicable to this study.
The total blood volume to be collected from each participant will be approximately 150 mL but 
not to exceed 250 mL.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form.
Refer to the SoA for the timing and frequency of all sample collections.


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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.
Order of Assessments: 
Safety assessments, such as vital signs and ECG, are recommended to be performed before blood 
is drawn and food is provided. On days when fasting laboratory blood samples are taken, it is 
recommended that efficacy assessments including PRO assessments should be administered after 
food is provided and participants feel comfortable, without help or time pressure, and under quiet 
conditions. The PRO assessments will be completed by all participants where appropriate PROs 
and translations are available and approved. Participants should complete the PRO assessments in 
the order stated in the SoA in a language in which the participant is fluent and literate. Study 
personnel will instruct participants how to self-complete the PRO assessment (see Section 10.7,
Appendix 7: Administration of a PRO). Further details are provided in a separate manual provided 
to the site (see below in Study-Specific Materials).
Study-Specific Materials
The investigator will be provided with the following supplies:

Investigator's Brochure for seltorexant

Pharmacy manual/study site investigational product manual

Laboratory manual and materials

Guidance on the recommended order of study procedures and the MGH-ATRQ

A binder containing all patient- and investigator-administered questionnaires, outcome 
assessments scales, along with completion guidelines

Procedural documents for independent central rater interviews

Electronic data capture (eDC) manual

Sample ICF

IWRS Manual

Participant recruitment materials

Pre-printed labels for blood samples 

Participant diaries.
8.1.
Efficacy Assessments
The following efficacy assessments will be performed at the timepoints indicated in the SoA. 
Screening and prebaseline HDRS-17 and ISI (clinician version) will be administered by 
independent central raters. The MADRS (SIGMA), and CGI-S will be performed by appropriately
trained and certified investigators or designees. It is recommended that the raters for the efficacy 
assessments (MADRS and CGI-S) not be involved in study drug dosing, AE assessments, or other 


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safety evaluations. The CSD, ISI (patient version), PROMIS-SD (Short Form 8a), PHQ-9, PGI-S, 
PGI-C, EQ-5D-5L, SDS, and RRS will be completed by the participants.
Montgomery-Åsberg Depression Rating Scale (MADRS)
The MADRS is a clinician-administered scale designed to measure depression severity and detects 
changes due to antidepressant treatment.28 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, reduced sleep, reduced appetite, concentration 
difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. The test exhibits 
high inter-rater reliability. The typical recall period for the MADRS is 7 days.
MADRS-WOSI and MADRS-6: The MADRS without the sleep item (MADRS-WOSI) will also 
be assessed as a key secondary measure. It is a subset of 9 out of 10 items of MADRS. The 6-item 
MADRS (MADRS-6) is a clinician-administered scale designed to measure the core symptoms of 
depression severity and detects changes due to antidepressant treatment.28 It is a subset of MADRS 
(6 out of 10 items). The MADRS scale is a validated, reliable scale and acceptable to regulatory 
health authorities as a primary scale to determine efficacy in major depression.
Insomnia Severity Index (ISI)
The ISI is a 7-item questionnaire assessing the nature, severity, and impact of insomnia. The 
dimensions evaluated are: sleep onset, sleep maintenance, early morning awakening problems; 
sleep dissatisfaction; interference of sleep problem with daytime functioning; noticeability of sleep 
problems by others; and distress caused by the sleep difficulties. A 5-point Likert scale (0-4) is 
used to rate each item, yielding a total score ranging from 0 to 28. The total score is interpreted as 
follows: absence of insomnia (0-7); sub-threshold insomnia (8-14); moderate insomnia (15-21); 
and severe insomnia (22-28).
The patient self-administered version of the ISI will be used at both screening visits and subsequent 
visits as indicated in the SoA. The clinician version of the ISI will be administered at both 
screening visits by an independent central rater. When administered at the same visit, the patient 
version is recommended to be completed prior to the clinician version. The clinician should 
complete all ISI items based on a clinical interview with the participant; it is preferable not to ask 
the ISI questions verbatim to the participant to preserve some degree of independence between the 
patient and clinician versions of the ISI. The clinician performing the ISI should not have access 
to the score of the patient version of the ISI.
Subjective Sleep Parameters (CSD)
Participants will be asked to provide answers to questions to determine their subjective experience 
of sleep by recording their answers in a CSD. Prior to randomization, participants are asked to 
collect 7 days of data recording. Collection of the CSD during screening should be started only 
after the last sedating medication has been stopped. Completion of the CSD is not required for 
randomization. The CSD will be attempted to be collected for 7 days prior to the visits as indicated 
in the SoA. The Core version of the CSD will be used.6


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The parameters recorded include:

self-reported sleep onset latency (sSOL)

subjective total sleep time (sTST)

subjective wake after sleep onset (sWASO)

subjective number of nighttime awakenings (s-nNAW)

subjective quality of sleep (sQUAL)
Patient Reported Outcomes Measurement Information System-Sleep 
Disturbance (PROMIS-SD) Short Forms 
The PROMIS-SD (Short Form 8a) subscale consists of a static 8-item questionnaire. The 
PROMIS-SD instruments assess self-reported perceptions of sleep quality, sleep depth, and 
restoration associated with sleep. This includes perceived difficulties and concerns with getting to 
sleep or staying asleep, as well as perceptions of the adequacy of and satisfaction with sleep. Sleep 
Disturbance does not focus on symptoms of specific sleep disorders, nor does it provide subjective 
estimates of sleep quantities (total amount of sleep, time to fall asleep, amount of wakefulness 
during sleep). The Sleep Disturbance short form is universal rather than disease-specific. It 
assesses sleep disturbance over the past 7 days. 
Patient Global Impression of Severity (PGI-S)
The PGI-S for sleep symptoms consists of 2 patient-reported items to capture the participant’s 
perceived severity of difficulty falling and staying asleep as well as the problem of not feeling 
rested the next day. Both items have the recall period of the past 7 days.
Patient Global Impression of Change (PGI-C): 
The PGI-C for depression is a single item that will capture the participant’s perceptions of 
improvement or deterioration in depression symptoms compared with when the participant started 
the study drug.
Patient Health Questionnaire, 9-Item (PHQ-9)
The 9-item PHQ-9 scale scores each of the 9 symptom domains of the DSM-5 MDD criteria and 
it has been used both as a screening tool and a measure of response to treatment for depression. 
Each item is rated on a 4-point scale (0=not at all, 1=several days, 2=more than half the days, and 
3=nearly every day). The participant’s item responses are summed to provide a total score (range 
of 0 to 27), with higher scores indicating greater severity of depressive symptoms. The recall 
period is 2 weeks.
Clinical Global Impression-Severity (CGI-S)
The CGI-S provides an overall clinician-determined summary measure of the severity of the 
participant's illness that takes into account all available information, including knowledge of the 
participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the 
symptoms on the participant’s ability to function.15 The CGI-S evaluates the severity of 


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psychopathology on a scale of 1 to 7. Considering total clinical experience with the depression 
population, a participant is assessed on severity of illness at the time of rating according to: 
1=normal (not at all ill); 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 
6=severely ill; 7=among the most extremely ill patients. 
Sheehan Disability Scale (SDS)
The SDS, a patient-reported outcome measure, is a 5-item questionnaire which has been widely 
used and accepted for assessment of functional impairment and associated disability.25,45 The first 
3 items assess disruption of (1) work/school, (2) social life, and (3) family life/home 
responsibilities using a 0-10 rating scale. The scores for the first 3 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.
Ruminative Response Scale (RRS)
The RRS assesses rumination as the process of “compulsively focused attention on the symptoms 
of one’s distress, and on its possible causes and consequences, as opposed to its solutions” as 
established by Nolen-Hoeksema in 1998. The 22 items of the RRS measure aspects of rumination, 
brooding and reflective pondering.32 A 4-point Likert scale (1-4) is used to rate each item, yielding 
a total score ranging from 22 to 88.
European Quality of Life, 5-Dimension, 5-Level (EQ-5D-5L) 
Questionnaire
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily 
designed for self-completion by respondents. It is a descriptive system comprised of 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).9,10
Hamilton Depression Rating Scale (HDRS-17) – Screening Only
The HDRS-17 is among most widely used and validated clinician administered depression 
assessment scale.16 It contains 17 items pertaining to symptoms of depression experienced over 
the past week. The questions cover core symptoms of depression as well as appetite and sleep 
(3 items). Items are scored on a Likert scale of 0-4 or 0-2 depending on the item with a possible 
range of 0-54. 
Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire (MGH-ATRQ) – Screening Only
The MGH-ATRQ is used to determine treatment response and resistance in MDD. It evaluates the 
adequacy of duration and dose of all antidepressant medications used for the current major 
depressive episode. The MGH-ATRQ defines 6 weeks on an adequate dose of antidepressant 
medication as an adequate duration of treatment. It also provides specific operational criteria for 


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adequate dosage for each of the most commonly used antidepressants. In addition, the 
MGH-ATRQ assesses the degree of improvement on a scale from 0% (not improved at all) to 
100% (completely improved). The MGH-ATRQ will be completed by the clinician in 
collaboration with the participant. Two different versions of the scale will be used: for participants 
<65 years old and for participants ≥ 65 years old.   
Structured Clinical Interview for DSM-5 Axis I Disorders– Clinical
Trials Version (SCID-CT) – Screening Only
The Structured Clinical Interview for DSM-5 (SCID-5) is a semi-structured interview guide for 
making the major DSM-5 diagnoses. It is administered by a clinician or trained mental health 
professional who is familiar with the DSM-5 classification and diagnostic criteria as well as 
clinical diagnostics.
Site Independent Qualification Assessment - Screening Only
The Site Independent Qualification is used to confirm the diagnosis of depression and eligibility 
for the study. It is administered by independent clinicians who are familiar with the DSM-5 
classification and diagnostic criteria as well as clinical diagnostics. 
8.2.
Safety Assessments 
The collection of AEs and concomitant medications will start after the informed consent has been 
signed and will continue until the follow-up visit at the timepoints indicated in the SoA. 
The following safety assessments will be performed according to the SoA: physical examination, 
body weight, BMI, vital signs, 12-lead ECG, urine drug testing, alcohol breath test, pregnancy 
testing (serum pregnancy test at screening and urine pregnancy test thereafter for female 
participants of childbearing potential only), clinical laboratory tests (hematology, chemistry panel 
including fasting glucose, lipid panel, TSH, FT4, HbA1c, insulin, and urinalysis).
Additional blood and urine samples may be taken, or vital signs and ECGs recorded at the 
discretion of the investigators as needed.
Menstrual cycles will be tracked in premenopausal women who are still having their menses during 
the study, using a participant diary and participant’s verbal report.
Physical Examination
The study investigator, or other authorized and appropriately qualified designee, will perform the 
physical examinations that will include assessment of sensation, level of alertness, ataxia, tremor, 
and other routine components of a brief neurological examination. Height will be measured at 
screening only. Body weight will be measured at screening and throughout the study according to 
the SoA.
Body weight should be measured using a calibrated scale at each indicated visit. Participants 
should be weighed at approximately the same time of day on the same scale, wearing lightweight 
clothing without shoes; they will be instructed to empty their bladders before being weighed. 


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Vital Signs
Blood pressure and pulse/heart rate measurements will be assessed with the participant in a sitting 
position using a completely automated device. Manual techniques will be used only if an 
automated device is not available. Sitting 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).
In addition, oral or tympanic temperature will be measured. In the places where oral or tympanic 
temperature are not standard practice, axillary temperature can be used. The same temperature 
measure should be used throughout the study.
Electrocardiogram (ECG)
Twelve-lead ECGs, intended for safety monitoring, will be recorded in a supine position so that 
the different ECG intervals (RR, PR, QRS, QT) can be measured. The ECG will be recorded until 
4 regular consecutive complexes are available in good readable quality. If the QTcF is prolonged 
on the initial ECG at a given time point, the average QTcF of 3 ECGs, recorded 4 minutes apart, 
must not be ≥450 msec for males and ≥470 msec for females.
During the collection of ECGs, participants should be in a quiet setting without distractions 
(eg, television, cell phones). Participants should rest in a supine position for at least 5 minutes 
before ECG collection and should refrain from talking or moving arms or legs. If blood sampling 
or vital sign measurement is scheduled for the same time point as ECG recording, the procedures 
are recommended to be performed in the following order: ECG(s), vital signs, blood draw.
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will 
be collected as noted in Section 10.2, Appendix 2: Clinical Laboratory Tests. The investigator 
must review the laboratory results, document this review, and record any clinically relevant 
changes occurring during the study in the AE section of the eCRF. The laboratory reports must be 
filed with the source documents. Clinical laboratory assessments (including TSH, FT4, 
hematology, serum chemistry, HbA1c, lipid panel, and urinalysis) should be performed at 
approximately the same time under fasting conditions, except possibly at the screening visit. The 
clinical laboratory assessments, ECGs and vital signs should be done first and then food or coffee 
provided, before patient-reported outcomes and clinician rated observations are carried out.
Physician Withdrawal Checklist (PWC)
Potential withdrawal effects will be assessed by the PWC-20 according to the SoA.
The Physician Withdrawal Checklist (20 items; PWC-20) is a simple and accurate method used to 
assess potential withdrawal symptoms following cessation of treatment. The PWC-20 is a reliable 
and sensitive instrument for the assessment of discontinuation symptoms.40


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Columbia Suicide Severity Rating Scale (C-SSRS)
Emergence of potential suicidal ideation will be assessed using the C-SSRS at screening, and at 
all subsequent study visits. The C-SSRS is a low-burden measure of the spectrum of suicidal 
ideation and behavior that was developed to assess severity and track suicidal events through any 
treatment.38 It is a clinical interview providing a summary of both suicidal ideation and behavior 
that can be administered during any evaluation or risk assessment to identify the level and type of 
suicidality present. The C-SSRS has been used frequently in clinical studies, and is a validated, 
standard measure for suicidal ideation assessment.
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 at the 
screening visit. 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”). 
Sites should specify the date of C-SSRS suicidal ideation with intent or plan history within the 
past 6 months and/or suicidal behavior within the past 1 year prior to screening in the eCRF. 
Participants are excluded if they have serious suicidal ideation (corresponding to a positive 
response to C-SSRS item 4 or 5) within 3 months or suicidal behavior within 6 months of study 
entry. 
All subsequent C-SSRS assessments in this study will use the Since Last Visit version, which will 
assess suicidal ideation and behavior since the participant’s last visit.
Arizona Sexual Experiences Scale (ASEX)
The ASEX is a patient-reported 5-item rating scale that quantifies sex drive, arousal, vaginal 
lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Possible total 
scores range from 5 to 30, with the higher scores indicating more sexual dysfunction. The scale 
has shown satisfactory reliability and validity.27
Mini Mental State Examination (MMSE) – Screening Only
The MMSE test is a 30-point questionnaire that is used extensively in clinical and research settings 
to measure cognitive impairment. It is commonly used in medicine and allied health to screen for 
dementia. The test is divided into two sections: the first section requires vocal responses and covers 
orientation, memory, and attention. The second part tests ability to name, follow verbal and written 
commands, write a sentence spontaneously, and copy a complex polygon similar to a Bender-
Gestalt Figure. The score ranges from 0 (minimum score) to 30 (maximum score) and it is 
calculated by the sum of the sub-items scored 0 (incorrect answer) or 1 (correct answer).8,12 The 
MMSE will be done only in participants of age ≥65 years.
8.3.
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of participants, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 


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conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
Adverse events, including AESI, will be reported by the participant (or, when appropriate, by a 
caregiver, surrogate, or other informant) for the duration of the study.
For further details on AEs and SAEs (Definitions and Classifications; Attribution Definitions; 
Severity Criteria; Special Reporting Situations; Procedures) as well as product quality complaints, 
refer to Section 10.4, Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting.
This study allows the use of locally approved (including emergency use-authorized [or country 
specific equivalent emergency use approved]) COVID-19 vaccines. All adverse events, including 
those following vaccination, should be included in the source and entered in the eCRF.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
All AEs, including AESI, 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 participant's last 
study-related procedure, which may include contact for follow-up of safety. Serious adverse 
events, including those spontaneously reported to the investigator within 30 days after the last dose 
of study 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.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the 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 an SAE should be transmitted 
electronically or by facsimile (fax).
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in 
Section 10.4, Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
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Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where 
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or 
sponsor where required) must report SUSARs to the appropriate
Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise 
required and documented by the IEC/IRB. A SUSAR will be reported to regulatory authorities 
unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR summary, 
unless otherwise specified.
An anticipated event is an AE that commonly occurs in the study population independent of 
exposure to the drug under investigation. For the purposes of this study, if any of the following are 
reported as an SAE; these will be considered anticipated events:

Suicidal thinking, ideation/ behavior,

Sleep changes/difficulty sleeping, reduced sleep, abnormal sleep, tiredness, fatigue, reduced 
energy,

Difficulty in sexual desire, performance or satisfaction,

Reduced appetite, weight changes (loss or increase),

Irritability, anger, impulsive behavior, 

Agitation, feeling anxious/anxiety, tension, panic attacks, phobia.
These anticipated events will be periodically analyzed in aggregate by the sponsor during study 
conduct. The sponsor will prepare a safety report in narrative format if the aggregate analysis 
indicates that the anticipated event occurs more frequently in the treatment group than in the 
control group and the sponsor concludes there is a reasonable possibility that the drug under 
investigation caused the anticipated event.
The plan for monitoring and analyzing the anticipated events is specified in a separate Anticipated 
Events Safety Monitoring Plan. The assessment of causality will be made by the sponsor’s 
unblinded safety assessment committee.
The sponsor assumes responsibility for appropriate reporting of the listed anticipated events 
according to the requirements of the countries in which the studies are conducted.
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be 
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event 
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered SAEs and must be reported using the Serious Adverse Event Form. Any participant 
who becomes pregnant during the study must be promptly discontinued from further study drug.


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Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
participants included in the study will be reported as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
Adverse Events of Special Interest
The following AEs are considered to be of special interest in this study:

Cataplexy (sudden, transient episode of muscle weakness accompanied by conscious 
awareness)

Sleep paralysis (the experience of not being able to move, react, or speak when falling 
asleep/awakening)

Complex, sleep-related behaviors/parasomnias such as confusional arousals, somnambulism 
(sleep walking), sleep terrors, bruxism (teeth grinding), sleep sex, sleep-related eating 
disorder, and catathrenia (REM-associated end-inspiratory apnea/breath holding)

Fall (defined as an event which results in a person coming to rest inadvertently on the ground 
or floor or other lower level; falling, loss of posture, falling down)

Motor vehicle accident (also referred to as a road traffic accident, traffic collision, or a car 
accident, occurs when a motor vehicle strikes or collides another vehicle, a stationary object, 
a pedestrian, or an animal)
Investigators are instructed to inquire about the occurrence of such events during the collection of 
AEs at each visit. When reported, the investigator will be required to complete additional eCRF 
pages for AESI. Note: If the event meets the seriousness criteria (see Section 10.4, Appendix 4:
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting), the Serious Adverse Events Form must also be completed according to the SAE
reporting timeline described in Section 8.3.1, ie, within 24 hours of having become aware of the 
event, even if all details are not available.
8.4.
Treatment of Overdose
For this study, any dose of seltorexant greater than the number of tablets assigned for each day 
within a 12-hour time period will be considered an overdose. 
In the event of an overdose, the investigator or treating physician should:

Contact the sponsor’s study responsible physician/scientist or designee immediately.

Monitor the participant for AEs/SAEs until seltorexant and its M12 metabolite can no longer 
be detected systemically (at least 3 days).

Obtain a blood sample for PK analysis within 1 day from the date of the last dose of study 
drug if requested by the sponsor’s study responsible physician/scientist or designee 
(determined on a case-by-case basis). The study team will be blinded to the result.


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
Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF.
Decisions regarding dose interruptions or modifications should be made by the investigator in 
consultation with the Study responsible physician/scientist or designee based on the clinical 
evaluation of the participant.
8.5.
Pharmacokinetics
Evaluations
Blood samples of approximately 3 mL, for the determination of plasma concentrations of 
seltorexant and its M12 metabolite, will be collected from participants per the SoA.
In addition, blood samples (3 mL) will be collected for determination of plasma concentrations of 
seltorexant, its M12 metabolite, and alpha-1-acid glycoprotein in participants who discontinue 
study drug for an AE, have an AESI, or have an SAE if the sample can be obtained within 15 hours 
of the last study drug administration. 
Blood samples will be collected to determine alpha-1-acid glycoprotein levels at each PK 
collection day (as indicated in the SoA) to calculate the unbound concentrations.
During the DB phase, blood samples for PK will be collected from all participants, including 
placebo-treated participants, but samples from placebo-treated participants will not be analyzed 
for PK. These samples will be stored and may be analyzed if needed (eg, suspicion of an incorrect 
treatment assignment). 
Additional information about the collection, handling, and shipment of biological samples can be 
found in the laboratory manual.
The exact date and time of PK blood sample collection must be recorded, along with all 
concomitant medications (dose, drug, start and stop date). Study drug dosing time on the day before 
each PK collection will be accurately recorded by exact dosing date and time by the participant in 
the diary. 
Analytical Procedures 
Pharmacokinetics
Plasma samples will be analyzed to measure concentrations of seltorexant and its M12 metabolite 
using a validated, specific, and sensitive liquid chromatography/mass spectrometry/mass 
spectrometry (LC-MS/MS) method by or under the supervision of the sponsor.
Alpha-1-acid glycoprotein levels will be determined.
Pharmacokinetic Parameters and Evaluations
Plasma concentration-time data will be displayed by visit date and time for seltorexant and its M12 
metabolite. The alpha-1-acid glycoprotein levels will be tabulated for each participant.


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8.6.
Biomarkers
Cortisol concentration has a strong diurnal pattern, with peak concentrations present upon 
awakening and low concentrations in the evening hours. 
Blood samples for the assessment of biomarkers related to immune system activity, growth factors, 
metabolic, and HPA axis activation will be collected during the DB treatment phase. 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.
Menstrual cycle will be tracked in premenopausal women who are still having their menses during 
the study as indicated in the SoA.
8.7.
Pharmacogenomics
Participation of pharmacogenomic blood sample collection is optional. Participants must sign a 
separate ICF if he or she agrees to participate in the optional DNA/RNA sample collection for 
research (where local regulations permit). Refusal to give consent for the optional DNA/RNA
research samples does not exclude a participant from the study.
With participant’s consent, blood sample collection per the SoA will be performed to allow for the 
potential identification of genetic (DNA and RNA), epigenetic factors, and/or transcription factors 
that may influence the PK, efficacy, safety, or tolerability of seltorexant and to identify genetic 
and/or epigenetic factors associated with MDDIS. The RNA will be collected pre- and 
posttreatment will allow examination of changes in gene transcription related to administration of 
seltorexant and/or changes in other biomarkers collected during the study (eg, cortisol, cytokines, 
etc.).
8.8.
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
Statistical analysis will be performed by the sponsor or under the authority of the sponsor. A 
general description of the statistical methods to be used to analyze the efficacy and safety data is 
outlined below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1.
Statistical Hypotheses
This study is designed to show that the treatment effect in improving depressive symptoms (as 
measured by change from baseline on Day 43 in MADRS total score) of seltorexant as an 
adjunctive MDD treatment is superior to placebo in participants with MDDIS.
If µT is the mean change in MADRS total score for seltorexant group and µP is the mean change 
in MADRS total score for the placebo group, then the hypothesis can be written as follows:
H0: µT – µP ≥0 vs.
H1: µT – µP <0


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Superiority can be concluded if the two-sided p-value for the testing of the hypothesis above is 
less than 0.05.
9.2.
Sample Size Determination
Approximately 386 participants (randomized in 1:1 ratio to placebo and seltorexant 20 mg) are 
planned to be enrolled in the DB treatment phase. The enrollment is targeted to achieve 
approximately 374 participants eligible to be included in FAS1. Assuming treatment difference of 
4.4 points in change from baseline in MADRS total score between seltorexant and placebo, 
standard deviation of 12, 1-sided significance level of 0.025 (equivalently, two-sided 0.05), this 
sample size will provide approximately 90% power in a comparison between seltorexant and 
placebo in the primary efficacy analysis, accounting for a drop-out rate of approximately 15%. 
The assumed treatment difference and standard deviation used in this calculation are based on 
Phase 2 (42847922MDD2001) study results, as well as on clinical judgment.
9.3.
Populations for Analyses
Two full analysis sets (FAS) will be defined.

FAS1: defined as all participants who were randomly assigned to study drug and received at 
least 1 dose of study drug and met pre-specified stratification criteria (included in a separate 
document). FAS1 will be used for primary efficacy analysis for all submissions, with the 
exception of the European Union (EU) dossier.

FAS2: defined as all participants who were randomly assigned to study drug and received at 
least 1 dose of study drug. FAS2 will be used for primary efficacy analysis for the EU dossier.
The analyses of primary and key secondary endpoints (and other efficacy analyses) will be based 
on FAS (FAS1 for the non-EU dossier, and FAS2 for the EU dossier). For the EU dossier, the 
primary analysis will be based on FAS2, and the FAS1 will be used for supplementary analyses; 
for the non-EU dossier, the primary analysis will be based on FAS1, and the FAS2 will be used 
for supplementary analyses.
Safety analyses will be based on the safety analysis set, which consists of all participants who were 
randomly assigned to study drug and received at least 1 dose of study drug.
For all participants who are randomly assigned to study drug, descriptive statistics (eg, study 
completion/withdrawal information, demographic and baseline data) will be provided.
9.4.
Statistical Analyses
Efficacy Analyses
The analyses of primary and key secondary endpoints (and other efficacy analyses) will be based 
on FAS1 and FAS2.
The primary efficacy endpoint is the change in MADRS total score from baseline to Day 43.
The first key secondary endpoint is the change in MADRS-WOSI from baseline to Day 43. The 
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There are two primary estimands defined for the primary efficacy endpoint:
Estimand 1:
Population: participants with MDDIS who have had an inadequate response to current 
antidepressant therapy with a SSRI/SNRI, as reflected by the inclusion/exclusion criteria
(participants need to have meet pre-specified stratification criteria [included in a separate 
document] for this estimand).
Endpoint: change in MADRS total score from baseline to Day 43.
Intercurrent events and corresponding strategies: 

Treatment discontinuation of add-on study drug only (Hypothetical strategy: as if the 
intercurrent event had not occurred)

Treatment discontinuation of both underlying antidepressant and add-on study drug 
(Hypothetical strategy: see above)

Switch of add-on treatment and/or underlying antidepressant (Hypothetical strategy: see 
above)
Summary measure: difference in treatment means.
Estimand 2:
Population: participants with MDDIS who have had an inadequate response to current 
antidepressant therapy with a SSRI/SNRI, as reflected by the inclusion/exclusion criteria.
Endpoint: change in MADRS total score from baseline to Day 43.
Intercurrent events and corresponding strategies: 

Treatment discontinuation of add-on study drug only (Treatment policy strategy: all observed 
values of the endpoint are used regardless of whether or not the participant had experienced 
this intercurrent event)

Treatment discontinuation of both underlying antidepressant and add-on study drug 
(Hypothetical strategy: as if the intercurrent event had not occurred)

Switch of add-on treatment and/or underlying antidepressant (Hypothetical strategy: as if the 
participant had discontinued treatment instead of switching)
A supplementary estimand will be defined with the same components as Estimand 2, with the 
hypothetical strategy being replaced by a treatment policy strategy for the intercurrent event of 
treatment discontinuation of both underlying antidepressant and add-on study drug.
With the exception of the European Union (EU) dossier, the primary estimand is Estimand 1, and 
the supplementary estimand is Estimand 2. For the EU dossier, the primary estimand is Estimand 
2, and the supplementary estimand is Estimand 1.


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Under Estimand 2, MADRS will need to be collected after study drug discontinuation for 
participants who did not withdraw consent and will be included in the analyses when the treatment 
policy strategy is applied.
Main Analysis Under Estimand 1
The comparison between seltorexant and placebo will be performed using the appropriate contrasts 
in a MMRM with main comparison at Day 43. The MMRM will include country, age group (adults 
[<65 years] and elderly [≥65 years]), baseline rumination level (RRS total score <54, ≥54), time, 
treatment (placebo and seltorexant), and, treatment by time interaction as factors, baseline 
MADRS total score as a covariate. 
Sensitivity Analysis Under Estimand 1
For Estimand 1, delta adjustment with a tipping point will be conducted as a sensitivity 
analysis.34,39
Main Analysis Under Estimand 2
The copy reference (CR) multiple imputation (MI) method will be performed. A mixed model 
(which will include country, age group [adults {<65 years} and elderly {≥65 years}], baseline 
rumination level [RRS total score <54, ≥54], time, treatment [placebo and seltorexant], and, 
treatment by time interaction as factors, and baseline MADRS total score as a covariate) will be 
applied to each imputed dataset (with the CR MI method), and the Rubin’s rule will be used to 
compile results from each imputed dataset.
Sensitivity Analysis Under Estimand 2
For Estimand 2, the Copy Increment from Reference (CIR) MI method7 will be performed as a 
sensitivity analysis.
Key Secondary Efficacy Endpoints
The same estimands (except the endpoint) and corresponding analyses as for the primary endpoint 
will be used for the key secondary endpoints.
Testing Procedure for Primary and Key Secondary Endpoints
The fixed sequence testing procedure will be applied to control the familywise error rate (FWER) 
at two-sided 0.05 level accounting for multiplicity due to the primary (MADRS total score) and 
key secondary efficacy endpoints (MADRS-WOSI and PROMIS-SD). The fixed sequence testing 
procedure will first test the primary endpoint at two-sided 0.05 level. If the hypothesis 
corresponding to the primary endpoint is rejected, then the first key secondary endpoint 
(MADRS-WOSI) will be tested at the two-sided 0.05 level; if the hypothesis corresponding to the 
primary endpoint is not rejected, then the testing procedure will stop. If the hypothesis 
corresponding to MADRS-WOSI is rejected, then the second key secondary endpoint 
(PROMIS-SD) will be tested at two-sided 0.05 level; if the hypothesis corresponding to 
MADRS-WOSI is not rejected, then the testing procedure will stop.


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Other efficacy endpoints
The analyses for other efficacy endpoints will be described separately in the SAP. There is no 
multiplicity adjustment for other efficacy endpoints.
Safety Analyses
Safety analyses will be based on the safety analysis set, which consists of all participants who were 
randomly assigned to study drug and received at least 1 dose of study drug.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse events are 
AEs with onset during the DB treatment phase or that are a consequence of a pre-existing condition 
that has worsened since baseline. All reported TEAEs will be included in the analysis. For each 
TEAE, the percentage of participants who experience at least 1 occurrence of the given event will 
be summarized by treatment group. Serious adverse events will be summarized separately.
Adverse events occurring during the follow-up phase will be summarized separately.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for any 
participants who die, who discontinue treatment due to an AE, or who experience a severe or an
SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test and treatment. 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 for 
observed values and changes from baseline at each scheduled time point. A listing of participants
with any markedly abnormal laboratory results will be provided.
Electrocardiogram (ECG)
The effects on ECG measurements (heart rate, PR interval, QT interval, and QTc interval) will be 
evaluated using descriptive statistics and frequency tabulations. QTc intervals will be calculated 
using the Bazett and Fridericia correction methods and summarized accordingly. 
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each 
scheduled time point. The percentage of participants with QTc interval higher than pre-specified 
levels will be summarized, as will the percentage of participants with QTc interval increases from 
baseline >30 milliseconds or >60 milliseconds.
A listing of participants with abnormal ECG findings will be presented.


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Vital Signs
Descriptive statistics of pulse, sitting blood pressure (systolic and diastolic), and temperature for 
observed values will be provided and changes from baseline will be summarized at each scheduled 
time point by treatment. The percentage of participants with values beyond clinically important 
limits will be summarized. Changes in body weight and BMI will be summarized descriptively.
Physical Examination
Participants with abnormal findings in physical examination will be presented in a data listing. 
C-SSRS
Suicide-related thoughts and behaviors based on the C-SSRS will be summarized by treatment. 
Withdrawal Effects
Withdrawal effects based on the PWC-20 will be summarized by treatment.
ASEX
Effects on sexual functioning based on the ASEX will be summarized by treatment.
Other Analyses
Biomarkers Analysis
The exploratory biomarkers will be tabulated by treatment and summary statistics will be 
calculated. Posttreatment changes in exploratory biomarkers will be summarized by treatment
group. Associations between baseline biomarker levels and clinical endpoints may be explored.
Results may be presented in a separate Biomarker report. 
Pharmacogenomic Analyses
A composite genotype may be derived from the raw genotyping data for the analyzed genes, as 
appropriate. Specific analyses will include, but are not limited to, interrogation of single nucleotide 
polymorphisms in whole blood DNA at discrete loci implicated in mood. The relationship between 
efficacy measures and gene transcription will also be explored. The relationship between genetic 
subgroups and seltorexant PK endpoints may be examined through descriptive statistics or 
graphically.
Pharmacokinetic Analysis
Plasma concentration-time data will be displayed by visit date, and time for seltorexant and its 
M12 metabolite. 
A population PK analysis using PK data from a selection of clinical studies will be performed at 
the completion of the study. Using actual sampling and dosing times, concentration-time data will 
be analyzed using population PK modeling. Empirical Bayes estimates (ie, individual PK 
parameters estimates) will be used to derive individual estimates of the exposure parameters (eg, 
AUC) for seltorexant, and if necessary, for metabolites). As part of the population PK modeling, 
the effect of intrinsic (eg, age, gender, body weight) and extrinsic factors (eg, concomitant 


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medications) affecting the PK of seltorexant may be evaluated if needed. The results of the 
population PK analysis will be reported separately. 
In addition, plasma concentrations of seltorexant, its M12 metabolite, and alpha-1-acid 
glycoprotein in participants who discontinue study drug for an AE, have an AESI, or have an SAE 
if the sample can be obtained within 15 hours of the last dose will be tabulated.
The alpha-1-acid glycoprotein levels will be tabulated for each participant by visit date and time 
and will be used to calculate the unbound concentrations.
9.5.
Interim Analysis
One unblinded interim analysis (IA) will be conducted to evaluate futility for Studies 
42847922MDD30011 (another seltorexant Phase 3 study) and 42847922MDD3002 (with 2 sets of 
data evaluated at the same time combined and for each study separately). Both the pooled analyses 
of data from 2 studies and the analysis of individual study data will be used in evaluating futility. 
Details of the IA will be included in the Independent Data Monitoring Committee (IDMC) Charter 
and the IA SAP. For including this IA for futility, there will be no adjustment to overall type I 
error level for Studies 42847922MDD3001 and 42847922MDD3002.
9.6.
Independent Data Monitoring Committee 
An IDMC will be established as noted in Committee Structure in Section 10.3, Appendix 3: 
Regulatory, Ethical, and Study Oversight Considerations. The IDMC will meet periodically to 
review safety data and will meet once to evaluate the unblinded efficacy data at the IA and make 
recommendation on whether to declare futility.
                                                
1
A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Study to Evaluate the Efficacy 
and Safety of Seltorexant 20 mg as Adjunctive Therapy to Antidepressants in Adult and Elderly Patients with 
Major Depressive Disorder with Insomnia Symptoms Who Have Responded Inadequately to Antidepressant 
Therapy.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.
Appendix 1: Abbreviations
ADR
adverse drug reaction
AE
adverse event
AESI
adverse event(s) of special interest
ALT
alanine aminotransferase
ASEX
Arizona Sexual Experiences Scale
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BCRP
breast cancer resistant protein
BMI
body mass index 
Cmax
maximum drug concentration
CGI-S
Clinical Global Impression-Severity 
CR
copy reference
CrCl
creatinine clearance
CSD
Consensus Sleep Diary
CSF
cerebrospinal fluid 
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
cytochrome P450
DB
double-blind
DNA
deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders-5th Edition
ECG
electrocardiogram
eCRF
electronic case report form
eDC
electronic data capture
EQ-5D-5L
European Quality of Life, 5-Dimension, 5-Level questionnaire
EU
European Union
FAS
full analysis set
FSH
follicle stimulating hormone
FT4
free thyroxine
GCP
Good Clinical Practice
HbA1c
hemoglobin A1c
HDRS-17
Hamilton Depression Rating Scale 17 item
HPA
hypothalamic-pituitary-adrenal
IA
interim analysis
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IS
insomnia symptom
ISI
Insomnia Severity Index
IWRS
interactive web response system
MADRS
Montgomery-Asberg Depression Rating Scale
MADRS-WOSI
Montgomery-Asberg Depression Rating Scale without Sleep Item
MDD
major depressive disorder
MDDIS
major depressive disorder with insomnia symptoms
MGH-ATRQ
Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire
MI
multiple imputation
MMRM
mixed model for repeated measures
MMSE
Mini-Mental State Examination
NOAEL
no observed adverse effect level
NREM
non-rapid eye movement
OATP
organic-anion-transporting polypeptide
OSA
Obstructive Sleep Apnea
OX2R
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PBPK
physiologically-based PK
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PHQ-9
Patient Health Questionnaire, 9-item
PK
pharmacokinetic(s)
PQC
product quality complaint
PRO
patient-reported outcome
PROMIS-SD
Patient Reported Outcome Measurement Information System-Sleep Disturbance
PWC-20
Physician Withdrawal Checklist, 20-items
PT
prothrombin time
QTc
Corrected QT
QTcF
Corrected QT interval by Fridericia
RBC
red blood cell
REM
Rapid Eye Movement
RNA
ribonucleic acid
RRS
Ruminative Response Scale
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCID-CT
Structured Clinical Interview for DSM-5 Axis I Disorders– Clinical Trials Version
SDS
Sheehan Disability Scale
SIGMA
structured interview guide for the Montgomery-Asberg Depression Rating Scale
SNRI
serotonin-norepinephrine reuptake inhibitor
SoA
schedule of activities
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TEAE
treatment-emergent adverse event
tmax
time to maximum drug concentration
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
WOCBP
women of childbearing potential
XR
extended-release


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10.2.
Appendix 2: Clinical Laboratory Tests
The following tests will be performed according to the Schedule of Activities:
Protocol-Required Safety Laboratory Assessments

Hematology Panel
-hemoglobin
-platelet count
-hematocrit
-percent reticulocytes
-red blood cell (RBC) count
-white blood cell count with differential
Note: A white blood cell evaluation may include any abnormal cells, which will then be
reported by the laboratory. A RBC evaluation may include abnormalities in the RBC count,
RBC parameters, or RBC morphology, which will then be reported by the laboratory.
In addition, any other abnormal cells in a blood smear will also be reported.

Serum Chemistry Panel
-sodium
-gamma-glutamyltransferase (GGT)
-potassium
-total and direct bilirubin
-chloride
-alkaline phosphatase
-bicarbonate
-creatine phosphokinase (CPK)
-blood urea nitrogen (BUN)
-uric acid
-creatinine
-calcium
-glucose
-phosphate
-insulin
-albumin
-aspartate aminotransferase (AST)
-total protein
-alanine aminotransferase (ALT)

Lipid Panel
-total cholesterol
-low-density lipoprotein cholesterol
-triglycerides
-high-density lipoprotein cholesterol

Urinalysis
Sediment if initial result is abnormal
-specific gravity
-red blood cells
-pH
-white blood cells
-glucose
-epithelial cells
-protein
-crystals
-blood
-casts
-ketones
-bacteria
-bilirubin
-urobilinogen
-nitrite
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Note: If initial result is abnormal, flow cytometry will be used to measure sediment. In case 
of discordance between the initial results and the flow cytometric results, the sediment will 
be examined microscopically.

For WOCBP, a serum pregnancy test must be performed at screening, and urine pregnancy 
tests must be performed as indicated in the Schedule of Activities to establish absence of 
pregnancy. Additional serum and urine pregnancy tests may be conducted as needed per the 
investigator’s judgment.

Urine 
drug 
screen: 
opiates 
(including 
methadone), 
cocaine, 
amphetamines, 
methamphetamines, cannabinoids, barbiturates, MDMA and benzodiazepines. Urine drug 
screens will be done by the site.

A urine and/or blood sample will be collected and sent to the central laboratory to assess 
compliance with background antidepressant medications. In some countries, SSRI/SNRI 
background antidepressants may also be assessed in a qualified local laboratory.

TSH (screening only) for any participant (regardless of thyroid history), if the thyroid 
stimulating hormone (TSH) value is out of range or for participants with known 
hypothyroidism who have been on stable treatment for at least 3 months prior to screening, a 
free thyroxine (FT4) will be conducted. If the FT4 value is abnormal and considered to be 
clinically significant (after discussion with the study responsible physician/scientist or 
designee) the participant is not eligible. For participants with abnormal TSH or taking thyroid 
medication, FT4 should be performed whenever the TSH is performed.

Alcohol breath test

Hemoglobin A1c

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10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
Regulatory And Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the participants, in which case the amendment must 
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
listed in the Contact Information page(s), which will be provided as a separate document. Except 
in emergency situations, this contact should be made before implementing any departure from the 
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the 
situation and agree on an appropriate course of action. The data recorded in the eCRF and source 
documents will reflect any departure from the protocol, and the source documents will describe 
this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:


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
Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, participant compensation programs. This approval must clearly identify the 
specific protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated Clinical Trial Agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first 
participant:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the participants)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved participant recruiting materials

Information on compensation for study-related injuries or payment to participants for 
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
Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for participants

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
Approval for the collection of optional samples for research and for the corresponding ICF must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component. 
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 participants, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to participants

If applicable, new or revised participant recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug

New information that may adversely affect the safety of the participants or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the participants

Report of deaths of participants 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 participants, data or study conduct), the amendment and applicable ICF revisions 


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must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help 
ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 4.2.7, Study-Specific Ethical Design 
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.7, Study-Specific Ethical 
Design Considerations.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
Informed Consent Process 
Each participant must give signed consent according to local requirements after the nature of the 
study has been fully explained. Study sites may be asked by the sponsor to obtain informed consent 
using a validated electronic system instead of a paper-based process. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved by 
both the sponsor and by the reviewing IEC/IRB and be in a language that the participant can read 
and understand. The informed consent should be in accordance with principles that originated in 
the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, 
and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential participants the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Participants will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the participant will receive. Finally, they will be told that the investigator will 


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maintain a participant identification register for the purposes of long-term follow-up if needed and 
that their records may be accessed by health authorities and authorized sponsor personnel without 
violating the confidentiality of the participant, to the extent permitted by the applicable law(s) or 
regulations. By signing the ICF the participant is authorizing such access. It also denotes that the 
participant agrees to allow his or her study physician to recontact the participant for the purpose 
of obtaining consent for additional safety evaluations, and subsequent disease-related treatments, 
if needed. 
The participant will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded by 
means of the participant's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the participant.
Participants who are rescreened are required to sign a new ICF.
Participants will be asked for consent to provide optional samples for genetic research (where local 
regulations permit). After informed consent for the study is appropriately obtained, the participant 
will be asked to sign and personally date a separate ICF indicating agreement to participate in the 
optional genetic research component. Refusal to participate in the optional research will not result 
in ineligibility for the study. A copy of this signed ICF will be given to the participant.
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original medical 
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and 
regulatory inspection. This consent also addresses the transfer of the data to other entities and to 
other countries.
The participant has the right to request through the investigator access to his or her personal data 
and the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
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Exploratory biomarker and PK research is not conducted under standards appropriate for the return 
of data to participants. In addition, the sponsor cannot make decisions as to the significance of any 
findings resulting from exploratory research. Therefore, exploratory research data will not be 
returned to participants or investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.
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 seltorexant, to understand 
MDDIS, to understand differential study drug responders, and to develop tests/assays related to 
seltorexant and MDDIS. The research may begin at any time during the study or the post-study 
storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples).
Committee Structure 
The IDMC will consist of at least 1 medical expert in the relevant therapeutic area and at least 
1 statistician. The IDMC responsibilities, authorities, and procedures will be documented in its 
charter.
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding seltorexant 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 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 seltorexant, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of 
pharmacogenomic or biomarker analyses performed after the Clinical Study Report has been 


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issued will be reported in a separate report and will not require a revision of the Clinical Study 
Report.
Study participant identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from copyright 
protection (except any publication by the investigator as provided for below) shall be the property 
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter) 
data and information without approval from the investigator. The investigator has the right to 
publish study site-specific data after the primary data are published. If an investigator wishes to 
publish information from the study, a copy of the manuscript must be provided to the sponsor for 
review at least 60 days before submission for publication or presentation. Expedited reviews will 
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will 
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and substudy approaches, secondary results generally should not be 
published before the primary endpoints of a study have been published. Similarly, investigators 
will recognize the integrity of a multicenter study by not submitting for publication data derived 
from the individual study site until the combined results from the completed study have been 
submitted for publication, within 18 months after the study end date, or the sponsor confirms there 
will be no multicenter study publication. Authorship of publications resulting from this study will 
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations 
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which 
state that the named authors must have made a significant contribution to the conception or design 
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required 
by law. The disclosure of the final study results will be performed after the end of study in order 
to ensure the statistical analyses are relevant.
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 


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study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central 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 the eCRF for accuracy and completeness during 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. 
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. All data relating to the study must be recorded in the eCRF. All CRF entries, corrections, 
and alterations must be made by the investigator or authorized study-site personnel. The 
investigator must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Data must be entered into the eCRF in English. The CRF must be completed as soon as possible 
after a participant visit and the forms should be available for review at the next scheduled 
monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the 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’s delegate can generate a query for resolution by the investigator and study-
site personnel.
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all AEs and follow-up of AEs; concomitant medication; study 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 
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The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).
The following data will be recorded directly into the eCRF and will be considered source data: 

Race

History of all nicotine use, eg, cigarettes (including e-cigarettes or the equivalent of 
e-cigarettes), cigars, chewing tobacco, patch, gum, etc.

Blood pressure and pulse/heart rate

Height and weight

Details of physical examination
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and 
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol-required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents.
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as the 
clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If an electronic source is utilized, references made to the eCRF 
in the protocol include the electronic source system but information collected through the 
electronic source may not be limited to that found in the eCRF. Data in this system may be 
considered source documentation. Centralized and/or remote data will be identified as source from 
the vendor and the collected information used (eg, questionnaires, scales, or other tools) will be 
considered as source and maintained centrally by the vendor(s). In these cases, original entries will 
be made electronically via a tablet or other device. The data (ie, clinical study-specific data fields 
as determined by the protocol) will not be maintained in a hospital or clinic record as source 
documentation. The site’s data will be made available to the site via a portal for review and will 
also be provided as a final data transfer at the end of the study.
Monitoring
The sponsor will use a combination of monitoring techniques including central, remote, or on-site 
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The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the eCRF with the source documents 
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
eCRF are known to the sponsor and study-site personnel and are accessible for verification by the 
sponsor study-site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying 
that the recorded data are consistent with the original source data. Findings from this review will 
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the 
relevant study-site personnel will be available, the source documents will be accessible, and a 
suitable environment will be provided for review of study-related documents. The monitor will 
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study-site personnel will be available to provide an update on the progress of the 
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Participant privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and available 
for consultation during routinely scheduled study-site audit visits conducted by the sponsor or its
designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each participant, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 


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investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports.
Study And Site Start And Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further seltorexant development

Study terminated by sponsor due to interim analysis results.


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10.4.
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Adverse Event Definitions And Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the study drug. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that medicinal 
(investigational or non-investigational) product. (Definition per International Council for
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 AEs starting with the signing of the ICF (refer to All Adverse Events 
under Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information, for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe).

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship 
between the study drug and the event (eg, death from anaphylaxis), the event must be reported as 


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a serious and unexpected suspected adverse reaction even if it is a component of the study endpoint 
(eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product 
reference safety information. For seltorexant, the expectedness of an AE will be determined by 
whether or not it is listed in the Investigator's Brochure. For baseline selective serotonin reuptake 
inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) treatment that is required 
to be continued along with the study drug and with a marketing authorization, the expectedness of 
an AE will be determined by whether or not it is listed in the applicable product information sheet 
(eg, package insert/summary of product characteristics). 
Attribution Definitions
Assessment of Causality
The causal relationship to study treatment is determined by the Investigator. The following 
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study treatment administration and the AE.
Not Related
There is not a reasonable causal relationship between study treatment administration and the AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the participant (eg, laboratory abnormalities).
Special Reporting Situations
Safety events of interest on a sponsor study drug in an interventional study that may require 
expedited reporting or safety evaluation include, but are not limited to:

Overdose of a sponsor study drug


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
Suspected abuse/misuse of a sponsor study drug

Accidental or occupational exposure to a sponsor study drug

Medication error intercepted medication error, or potential medication error involving a 
Johnson & Johnson medicinal sponsor product (with or without patient exposure to the 
Johnson & Johnson medicinal product, eg, product name confusion, product label confusion, 
intercepted prescribing or dispensing errors)

Exposure to a sponsor study drug from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
Procedures
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document and the eCRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory 
infection"). Investigators must record in the eCRF their opinion concerning the relationship of the 
AE to study therapy. All measures required for AE management must be recorded in the source 
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following: 

Study number

Statement, in the local language(s), that the participant is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical personnel only)

Site number

Participant number

Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the participant's participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes


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
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 (participant or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a participant's participation in a study must be reported as an SAE, except 
hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending 
placement in long-term care facility).

Surgery or procedure planned before entry into the study (must be documented in the eCRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.

For convenience the investigator may choose to hospitalize the participant for the duration of 
the treatment period. 
The cause of death of a participant in a study within 30 days of the last dose of study drug, whether 
or not the event is expected or associated with the study drug, is considered an SAE.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
Product Quality Complaint Handling
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of participants, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates will 
be conducted in accordance with those procedures.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.


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If the defect is combined with an SAE, the study-site personnel must report the PQC to the sponsor 
according to the SAE reporting timelines (refer to Section 8.3.1, Time Period and Frequency for 
Collecting Adverse Event and Serious Adverse Event Information). A sample of the suspected 
product should be maintained for further investigation if requested by the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.


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10.5.
Appendix 5: Contraceptive and Barrier Guidance and Collection of 
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria. 
Pregnancy information will be collected and reported as noted in Section 8.3.4, Pregnancy and 
Section 10.4, Appendix 4 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential

premenarchal
A premenarchal state is one in which menarche has not yet occurred.

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. In women who are <40 years old and have amenorrhea, FSH should be performed to 
determine post-menopausal status, based on the reference range of central laboratory. In 
women who are ≥40 years old and have amenorrhea for less than 12 months, FSH test may be 
performed at investigator’s judgment to assist in determining their post-menopausal status. In 
women who are ≥40 years old and have amenorrhea for ≥12 months, FSH is not required.
If there is a question about menopausal status in women on HRT, the woman will be required 
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if 
she wishes to continue HRT during the study.

permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal 
occlusion/ligation procedures, and bilateral oophorectomy. No FSH testing is required.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually 
active becomes active), a woman must begin a highly effective method of contraception, as 
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations 
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should 
be consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.


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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT 
Highly Effective Methods That Are User Independent Failure rate of ≤1% per year when used 
consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 74 days.)
USER-DEPENDENT
Highly Effective Methods That Are User-Dependent Failure rate of <1% per year when used 
consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationb
oral
injectable

Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 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 participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not 
considered to be highly effective - failure rate of ≥1% per year)

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action.

Male or female condom with or without spermicidec

Cap, diaphragm, or sponge with spermicide

A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus-interruptus)

Spermicides alone

Lactational amenorrhea method (LAM)


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a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce 
the efficacy of the contraceptive method. In addition, consider if the hormonal contraception may 
interact with the study drug.
c) Male condom and female condom should not be used together (due to risk of failure with friction).


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10.6.
Appendix 6: Examples of Concomitant Drugs to be Avoided (Strong 
Inhibitors and Moderate/Strong Inducers of CYP3A4 or CYP2C9 or Dual 
Inhibitors/Inducers of CYP3A4 and CYP2C9. In Addition, Moderate CYP3A4 
or CYP2C9 Inhibitors for Participants with Creatinine Clearance 
<60 mL/min or Clinically Significant Hepatic Disease).
Enzymes
Inhibitors
Inducers
Dual Inhibitors or 
Inducers of 
CYP3A4 and 
CYP2C9
Strong
Strong
Moderate
CYP2C9
None known
None known
rifampin, 
enzalutamide
fluconazole 
rifampin
enzalutamide
CYP3A4
boceprevir
clarithromycin 
indinavir/ritonavir
itraconazole 
ketoconazole
lopinavir/ritonavir
mibefradil 
nefazodone 
nelfinavir
posaconazole 
ritonavir
saquinavir/ritonavir
telaprevir/tipranavir/ ritonavir
telithromycin
voriconazole
idelalisib
cobicistat 
danoprevir/ritonavir 
elvitegravir/ritonavir
paritaprevir/ritonavir 
paritaprevir and ritonavir and 
(ombitasvir and/or dasabuvir)
troleandomycin  
high-dose, double strength 
grapefruit juicea
avasimibe
apalutamide 
enzalutamide 
mitotane
carbamazepine 
phenytoin 
rifampin
St. John’s wort
bosentan
efavirenz
etravirine 
modafinil
nafcillin
phenobarbital 
primidone.
In addition to the above list, moderate CYP3A4 or CYP2C9 inhibitors for participants with creatinine 
clearance <60 mL/min or clinically significant hepatic disease
Enzymes
Inhibitors
Moderate
CYP2C9
Amiodarone
miconazole
piperine
CYP3A4
Aprepitant
Ciprofloxacin
Conivaptan
Crizotinib
Cyclosporine
Diltiazem
Dronedarone
Erythromycin
Fluvoxamine
Imatinib
Tofisopam
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Notes:

This is not an exhaustive list.

No “strong CYP2C9” inducers or inhibitors are known, but if any were to emerge, those should be excluded 
as well.

aThe effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength)
Source: USFDA - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm
093664.htm. Accessed 04 April 2020


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10.7.
Appendix 7: Administration of a PRO at Scheduled Visits
Following guidance will be followed to administer a PRO:

Provide a quiet, semi-private location for the participant to complete the PROs

Ensure participants have access to study staff for questions

Instruct participants to complete all PRO assessments using a blue or black ballpoint pen

Explain that all of the information on the PRO assessment(s) is confidential, and that someone 
from the study staff will only check for completeness and not share the results with other 
clinical staff

Explain to participants the reasons why they are being asked to complete the PRO 
assessment(s), ie, they are part of the overall medical assessment and are designed to find out 
more information about how having their disease has affected their life

Allow as much time as the participant needs to orient themselves and complete all PRO 
assessments

Instruct the participants to

Read the instructions for each questionnaire carefully

Note the recall period for each questionnaire

Complete all PROs; 

Instruct the participant not to skip any questions/or questionnaires

Participants must interpret questions and complete the PRO assessment(s) without help from 
anyone. If asked for help interpreting or completing the PRO assessment by the participant, 
please simply reply that there are no right or wrong answers and he/she should use his/her best 
judgment to complete each question (based on what the participant thinks the question is 
asking).

Do not attempt to interpret or explain the instructions, questions, or response options

If the participant has difficulty choosing between two response options, simply state “choose 
the answer that most closely matches your experience.”


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10.8.
Appendix 8: Benzodiazepine Equivalence Table (30 mg diazepam or 3 mg 
lorazepam)
Benzodiazepines
Approximately Equivalent
Oral dosages (mg)
Alprazolam (Xanax, Xanor, Tafil)
1.5
Bromazepam (Lexotan, Lexomil)
18
Chlordiazepoxide (Librium)
75
Clobazam (Frisium) 
60
Clonazepam (Klonopin, Rivotril) 
1.5
Clorazepate (Tranxene)
45
Diazepam (Valium)
30
Estazolam (ProSom, Nuctalon)
6
Flunitrazepam (Rohypnol)
3
Flurazepam (Dalmane)
90
Halazepam (Paxipam)
60
Ketazolam (Anxon)
90
Loprazolam (Dormonoct)
6
Lorazepam (Ativan, Temesta, Tavor)
3
Lormetazepam (Noctamid)
6
Medazepam (Nobrium)
30
Nitrazepam (Mogadon)
30
Nordazepam (Nordaz, Calmday)
30
Oxazepam (Serax, Serenid,
Serepax, Seresta)
60
Prazepam (Centrax, Lysanxia)
60
Quazepam (Doral)
60
Temazepam (Restoril, Normison,
Euhypnos)
60
Triazolam (Halcion)
1.5
The Resource Site for Involuntary Benzodiazepine Tranquiliser Addiction, Withdrawal & Recovery. 
URL: https://benzo.org.uk. Accessed: 04 April 2020.


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10.9.
Appendix 9: Changes in Study-Related Procedures as a Result of the 
COVID-19 Pandemic 
Background
Since December 2019, an outbreak of respiratory disease caused by a novel coronavirus, first 
detected in Wuhan City, Hubei Province, China, has been detected in nearly all countries of the 
world. The virus has been named “SARS-CoV-2” and the disease it causes has been named 
“Coronavirus Disease 2019” (COVID-19). On 8 March 2020, the World Health Organization 
(WHO) declared the COVID-19 outbreak a global pandemic. The processes detailed in this 
appendix may be applied to the COVID-19 public health crises or other emergencies.
In response to the pandemic, various health authorities have issued guidelines to maintain the 
integrity of ongoing clinical studies. For example, the US Food and Drug Administration (FDA) 
and the European Medicines Agency (EMA) / national Heads of Medicines Agencies (HMA)
recognize that the COVID-19 pandemic may impact the conduct of clinical trials of medical 
products. Challenges may arise, for example, from quarantines, site closures, travel limitations, 
interruptions to the supply chain of the investigational product, or other considerations if site 
personnel or study participants become exposed to or infected with SARS-CoV-2. These 
challenges may lead to difficulties in meeting protocol-specified procedures, including 
administering or using the investigational product, or adhering to protocol-mandated visits and 
laboratory/diagnostic testing. The US FDA recognizes that protocol modifications may be required 
and that there may be unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 
control measures. Although the necessity for, and impact of, COVID-19 control measures on 
studies will vary depending on many factors, including the nature of disease under study, the study 
design, and region(s) in which the study is being conducted, the US FDA outlines general 
considerations to assist sponsors in assuring the safety of study participants, maintaining 
compliance with good clinical practice (GCP), and minimizing risks to study integrity. The EMA 
published a guidance to serve as an EU-level harmonized set of recommendations but advises that 
there might be specific national legislation and guidance in place, which the study sites should 
consult. These national guidance and recommendations can be used to complement or, with respect 
to particular matters, may take priority over the EMA recommendations. There may be a need to 
close study sites affected by COVID-19 and/or transfer participants to investigational sites away 
from risk zones, to sites already participating in the study, or to new ones. In case of urgent 
shortage of study drug at some sites or following transfer of study participants from one site to 
another site, there might be a need to potentially re-distribute study drug between sites or direct 
study medication shipments to participants. Study drug blinding should not be compromised. 
Furthermore, protocol-related and other critical laboratory tests, imaging, or other diagnostic tests 
to be performed for patient safety might be done at a participant’s home or local laboratory in case 
a participant cannot reach the site. 
If due to the public health or other emergency, the discontinuation rate is higher than expected, the 
sample size may be increased to ensure a sufficient number of participants for the evaluation of 
the primary outcome. In addition, if the variability of the primary endpoint is higher than the one 
used in the sample size calculation, the sample size may be increased (evaluated in a blinded 


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fashion) to achieve the pre-specified level of power for detecting assumed treatment effect of the 
investigational product.
Summary of Changes
To assure the safety of study participants, maintain compliance with GCP, and minimize risks to 
study integrity, if necessary, the method of assessments may be changed (eg, paper assessments 
replaced by electronic assessments) at the discretion of the sponsor. In addition, site visits may be 
replaced with telephone, internet-based video-conferencing applications, or home visits. 
Furthermore, study sites may be asked by the sponsor to obtain informed consent using a 
validated electronic system or by telephone or video instead of an in-person (face to face) process, 
as permitted by local regulations. 
These procedures will be implemented in consultation with the sponsor. For this study, except in 
an urgent situation, changes in study conduct need to be approved by the sponsor before being 
initiated. The specific changes to be implemented will be based on the current conditions in the 
country/region and will be reassessed on an ongoing basis. Not all countries or all sites in a country 
may be impacted. Normal procedures, as detailed in this protocol, will be resumed as soon as 
possible thereafter. 
If the safety of the participants may be affected and/or key outcome measures cannot be adequately 
monitored, the sponsor will evaluate the impact of the emergency on an ongoing basis and may 
decide to close study centers or participating countries. Enrolment of new participants may need 
to be suspended. Furthermore, the sponsor may decide to delay or cancel the initiation of sites 
during an emergency.
COVID-19 vaccines 
This study allows the use of locally approved (including emergency use-authorized [or country 
specific equivalent emergency use approved]) COVID-19 vaccines.
When considering use of locally approved or authorized COVID-19 vaccines in study participants, 
follow applicable local labelling and guidelines.
For participants who receive an approved or authorized vaccine, it is recommended that this 
occurs at least 5 days prior to the start of dosing, or once randomized at least 5 days prior to the 
next scheduled visit.
If any vaccine (COVID-19 or other eg, Influenza vaccines) are administered, these should be 
recorded in the source documents and entered in the eCRF. All adverse events, including those 
following vaccination, should be included in the source and entered in the eCRF.
Informed Consent Form
Each participant must give consent according to local requirements after the nature of the study 
has been fully explained (ie, face to face, phone or video call by the PI or a designee) and before 
the performance of any study-related activity. If permitted by investigative site procedures and 


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local regulations, the informed consent form can be mailed to the potential participant and/or 
delivered electronically. Despite the flexibility of the suggested informed consent process, all care 
must be taken to ensure that adequate time was provided to review and understand the document, 
all questions were answered, no study procedures occurred prior to consent and proper signed 
documentation was maintained. The participant can sign the consent at home and mail it to the 
study site; or if e-consent is used then electronically sign within the study app, if allowed by local 
regulations. Alternatively, the PI or designee can visit the participant at home to present the study 
and obtain the informed consent form signature at the participant’s home. If the participant has 
any questions about the study prior to providing their signature, they will be provided with an 
opportunity to discuss these questions with the PI or designee. The 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. Once the participant understands all 
aspects of the consent, consent should be appropriately recorded by means of the participant’s 
personally dated signature or via electronic signature, if allowed by local regulations. After having 
obtained the consent, a copy of the signed consent must be sent to or stay with the participant.
The Study Procedures During the Emergency Period
Home visits: If visiting health care professionals (HCP; site staff or qualified designee) are allowed
based on local regulations, certain study procedures and medical assessments can be conducted at
the participant’s home. The Principal Investigator continues to be responsible for reviewing all 
protocol-related assessments.
Medical procedures: A qualified HCP can perform study-related procedures as per the SoA during 
home visits, including but not limited to collection of body weight, vital signs, physical 
examinations, ECGs, blood and urine samples drug screening tests, alcohol breath tests and 
pregnancy tests.
Patient-reported questionnaires and diaries: Paper-based PROs will be either mailed/couriered or 
otherwise delivered to the home and administered according to the instructions of the site staff or 
qualified designee. The sponsor may decide to initiate an ePRO device which will be 
mailed/couriered to the home and completed as instructed. On completion, they may be returned
to the study site using similar methods. The study site may contact the participant to facilitate 
completion of the paper-based PROs or ePROs. Of note, the CSD is always completed as an ePRO.
Clinician-reported questionnaires: Clinician-reported questionnaires can be completed via phone 
or video call or can be collected during the home visit by a trained, certified rater. Generally, it is 
preferred that the MADRS primary endpoint assessment is to be administered in the clinic; 
however, in the event of an emergency, it may be performed by a trained site rater over the 
telephone or video, or at patient’s home. The MMSE scale can only be administered at the site or 
at the participant’s home.
Study Drug and Accountability
Dispensing of study drug and medication diary may be done by certified provider or directly to the 
participant, if allowed by local authorities. Study medication and diary may be returned by similar 
methods. Drug accountability will be performed by the study site. 


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Prioritization of Visits and Assessments  
If home visits are not available and participants are not able to travel to the site during the course 
of the study, assessments by phone or video should be completed. 
If home visits are restricted, the screening and End of Treatment/Early Withdrawal in the 
double-blind phase visits should be prioritized.
At a minimum, the MADRS, PROMIS-SD, ISI, C-SSRS, study medication accountability, and 
assessment of AEs and concomitant medications should be performed. 
Attempts should be made to complete other medical assessments, such as vital signs, clinical 
laboratory assessments, ECGs, weight, and physical examinations. If the participant has completed 
or withdrawn from the treatment phase, the final medical assessments of the End of 
Treatment/Early Withdrawal visit should be completed (even if it is outside of the assessment
window). 
Documentation
Changes in the administration of the clinical outcome assessments supporting the key endpoints 
(eg, primary and key secondary) will be documented in the eCRF. Other changes in administration 
of other assessments should also be documented.
Discontinuations related to COVID-19 should be captured in the eCRF.
Communication with the sponsor concerning implementation of these changes must be 
documented in the source documents.
Data Quality Assurance
During the period of travel restrictions or social distancing, the sponsor may implement remote 
monitoring in place of on-site visits to assure the accuracy and completeness of the data captured.


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10.10. Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment 1 (29 October 2020)
Overall Rationale for the Amendment: To address health authority feedback in regards to the assumption 
of treatment difference and increase in sample size determination, the addition of the Montgomery-Asberg 
Depression Rating Scale without Sleep Item (MADRS-WOSI) as a key secondary endpoint, European 
Union (EU)-specific statistical analyses, use of approved selective serotonin reuptake inhibitor (SSRI)/ 
serotonin-norepinephrine reuptake inhibitor (SNRI) as a background antidepressant in the participating 
country, language of restrictions on driving and alcohol use, disallowed concomitant medications, addition 
of brief neurological examinations, and adjustment of concomitant therapy following study drug stoppage, 
and study discontinuation for participants.
Section Number
and Name
Description of Change
Brief Rationale
1.1. Synopsis: Objectives 
And Endpoints, Statistical 
Methods;
3. Objectives And 
Endpoints;
4.2.4. Efficacy Measures;
8.1.1. Montgomery-
Åsberg Depression Rating 
Scale (MADRS);
9.4.1. Efficacy Analyses.
Updated ‘MADRS-WOSI’ endpoint as a ‘key 
secondary endpoint’ from ‘secondary endpoint’. 
To demonstrate that the 
antidepressant effect of 
seltorexant is present when 
the sleep item is removed 
from the 10-item MADRS 
scale. Placed MADRS-WOSI 
endpoint above the 
PROMIS-SD endpoint in the 
testing hierarchy as requested 
by the United States Food 
and Drug Administration 
(USFDA).
1.1. Synopsis: Statistical 
Methods;
9.4.1. Efficacy Analyses.
The testing procedure for primary and key 
secondary endpoints was updated to consider 
MADRS-WOSI as the first key secondary endpoint 
above the Patient Reported Outcome Measurement 
Information System-Sleep Disturbance (PROMIS-
SD).
1.1. Synopsis: Statistical 
Methods; 
9.2. Sample Size 
Determination.
The assumed treatment difference was changed 
from 4.8 to 4.4.
To update the assumed 
treatment difference.
1.1. Synopsis: Number of 
Participants, Statistical 
Methods; 
4.1. Overall Design;
9.2. Sample Size 
Determination
1.2. Schema
The sample size was updated as follows:
Total planned enrolled: approximately 386
350 participants
Total planned in the full analysis set 1 
(FAS1): approximately 374 340. 
Participants.
Also, updated the number of participants in each 
arm from 175 to 193 in Figure 1.
The increase in sample size 
by 10% was made in relation 
to reassessment of the 
assumed effect size of 
seltorexant 20 mg. 
1.1. Synopsis: Statistical 
Methods;
9.3. Populations for 
Analyses.
Defined the full analysis set in the following 
categories: FAS1 and FAS2.
To change analysis set labels 
to keep consistency with 
other seltorexant Phase 3 
study protocols and to clarify 
the primary efficacy analysis 
sets for EU dossier (FAS2) 
and non-EU dossier (FAS1).
1.1. Synopsis: Statistical 
Methods;
9.2. Sample Size 
Determination;
9.4.1. Efficacy Analyses
Updated the text to clarify the type of full analysis 
sets used for EU dossier and non-EU dossier.


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Section Number
and Name
Description of Change
Brief Rationale
1.1. Synopsis: Statistical 
Methods; 
9.4.1. Efficacy Analyses
Clarified wording for Estimand 2 and clarified that 
Estimand 2 is the primary estimand for EU dossier 
and Estimand 1 is the primary estimand for non-EU 
dossier.
Added a supplementary estimand.
To clarify the primary 
estimands for EU dossier and 
non-EU dossier, and to add a 
supplementary estimand.
1.1. Synopsis: Statistical 
Methods;
9.6. Independent Data 
Monitoring Committee.
Clarified that the Independent Data Monitoring 
Committee (IDMC) will periodically review safety 
data and meet once to evaluate unblinded data for 
the interim analysis.
To clarify the frequency of 
reviewing safety and efficacy 
data by the IDMC.
1.1. Synopsis, Overall 
Design;
1.2. Schema, footnote;
1.3. Schedule of 
Activities (SoA),
Footnote a;
4.1. Overall Design;
7.1. Discontinuation of 
Study Intervention.
Clarified the text to specify that 
“All participants who discontinue study drug in the 
DB treatment phase, will have an Early Withdrawal 
visit (Visit 8 in the SoA) and a Follow-up visit 
(Visit 10 in the SoA). Participants who discontinue 
study drug prior to Day 35 may continue after the 
Follow-up visit (Visit 10 in the SoA) with 
additional follow-up visits every 2 weeks per the 
SoA until Day 50-57.”
To ensure consistency across 
different sections of the 
protocol in the description of 
procedures to be performed 
after early withdrawal from 
the study drug.
1.3. Schedule of 
Activities (SoA), 
Footnote z;
8.2.6. Columbia Suicide 
Severity Rating Scale 
(C-SSRS).
Added new Footnote z and new text in the C-SSRS 
scale description:
“Sites should specify the date of C-SSRS suicidal 
ideation with intent or plan history within the past 6 
months and/or suicidal behavior with in the past 1 
year prior to screening in the eCRF. Participants are 
excluded if they have serious suicidal ideation 
(corresponding to a positive response to C-SSRS 
item 4 or 5) within 3 months or suicidal behavior 
within 6 months of study entry.” 
To ensure that the date of 
serious suicidal ideations 
which occurred within 3 
months or suicidal behavior 
within 1 year of study entry 
is documented in the eCRF. 
As seltorexant did not 
increase suicidal behavior in 
Phase 2 studies, participants 
with prior suicidal behavior 
reported >6 months prior to 
the study may be included at 
the discretion of the 
investigator. 
5.2. Exclusion Criteria 
(Criterion 8)
Clarified the Exclusion Criterion 8 for suicidal 
behavior prior to the study is within 6 months prior 
to the screening visit.
5.1. Inclusion Criteria 
(Criterion 4)
Added a note in Inclusion Criterion 4 to clarify that 
the SSRI/SNRI needs to be approved for the 
treatment of major depressive disorder (MDD)
according to the local label of the country where the 
clinical site is located.
To clarify that only approved 
SSRI/SNRI as a background 
antidepressant in the 
participating country is 
allowed.
5.1. Inclusion Criteria 
(Criterion 5)
Modified Inclusion Criterion 5 to indicate Hamilton 
Depression Rating Scale 17 item (HDRS-17) total 
score of ≥22 is required at the first screening visit 
and deleted text mentioning the HDRS-17 total 
score is ≥18 at the end of screening (Day -5 to -2 
visit).
To clarify that a HDRS-17 
total score of ≥22 is required 
at the first screening visit and 
must not demonstrate an 
improvement of >20% on 
their HDRS-17 total score 
from the beginning to end of 
screening and to remove 
mention of required score at 
the end of screening.
5.2. Exclusion Criteria 
(Criterion 1)
Updated the glucose level limit for controlled Type 
1 or Type 2 diabetes mellitus to ≤150 136 mg/dL
To update the glucose level 
limit for controlled Type 1 or 
Type 2 diabetes mellitus 
given high variability of 
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Section Number
and Name
Description of Change
Brief Rationale
5.2. Exclusion Criteria 
(Criteria 12 and 13)
Updated Exclusion Criterion 12 to clarify that 
participants who have a history of fibromyalgia but 
have been in remission for at least 1 year are not 
excluded.
Deleted ‘fibromyalgia’ from Exclusion 
Criterion 13.
To allow participants with 
fibromyalgia who have been 
in remission for at least 
1 year.
5.2. Exclusion Criteria 
(Criterion 20)
Added a note in the Exclusion Criterion 20 to 
clarify that participants who previously had taken 
up to 2 doses of ketamine/esketamine can be 
considered for enrollment.
To allow participants who 
previously had taken up to 2 
doses of 
ketamine/esketamine.
6.5. Concomitant Therapy
Clarified disallowed medication as follows (new 
text in bold):
“Ketamine or esketamine within 5 years prior to 
and during the study (up to 2 doses are allowed in 
lifetime prior to screening).”
6.5. Concomitant Therapy
Added new text in bold:
“When possible, all sleep medication should be 
stopped within 21 days after signing the ICF 
(including sedative-hypnotics from the 
benzodiazepine, non-benzodiazepine and 
antihistamine classes as well as prazosin, if it is 
being used for the treatment of sleep problems).”
To clarify that prazosin is not 
allowed if it is being used for 
the treatment of sleep 
problems.
1.3. Schedule of 
Activities (SoA),
Footnote g
Modified Footnote g to clarify that one retest may 
be performed if the urine and/or blood sample test is 
negative for antidepressant compliance. Also, 
clarified other means of accessing antidepressant 
adherence.
To clarify that one retest is 
allowed during screening and 
the methods for assessing 
compliance with background 
antidepressant medications. 
5.2. Exclusion Criteria 
(Criterion 15)
Added following note in Exclusion Criterion 15:
“One retest during screening is allowed at 
investigator’s judgment.”
5.3. Lifestyle 
Considerations
The alcohol consumption allowed during the study 
was added for female and elderly participants; and 
the existing criteria was updated for male 
participants.
To clarify limited amounts of 
alcohol allowed for males, 
females, and elderly 
participants.
2.3. Benefit/Risk 
Assessment;
5.3. Lifestyle 
Considerations.
Removed the time element of sleep duration on 
restriction on driving, operating machinery, or 
engaging in hazardous activity.
To address health authority 
feedback not to use specific 
sleep duration as an activity 
restriction but instead to refer 
to insufficient sleep.
6.5. Concomitant 
Therapy;
6.6. Intervention After the 
End of the Study;
7.1. Discontinuation of 
Study Intervention.
Added text to permit the use of disallowed 
medication during the extended follow-up period 
(after the first follow-up visit [Visit 10 in the SoA]) 
and, if needed, after the End-of-Phase/Early 
Withdrawal visit to treat adverse events or 
breakthrough symptoms prior to the first follow-up 
visit.
To clarify the use of 
concomitant treatment when 
a participant stops study drug 
but continues to participate in 
the study.
7.1. Discontinuation of 
Study Intervention
Removed the recommendation for the Investigator 
to consult the Sponsor’s study responsible 
physician/scientist before withdrawing a participant
for lack of efficacy.
To clarify that the 
investigator should have full 
authority to discontinue 
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Section Number
and Name
Description of Change
Brief Rationale
7.2. Participant 
Discontinuation/Withdra
wal From the Study
Clarified that a participant should discontinue from 
the study if the investigator believes it to be in the 
best interest of the participant, in consideration of 
the recommended withdrawal criteria, or for safety 
or tolerability reasons.
To clarify that the 
investigator may discontinue 
a participant from study 
participation, if it is in the 
best interest of the 
participant.
1.1. Synopsis: Safety 
Evaluations;
4.1. Overall Design;
4.2.6. Safety Evaluations;
5.1. Inclusion Criteria 
(Criterion 9);
8.2.1. Physical 
Examination
Mentioned about a brief neurological examination 
as a part of a standard physical examination.
To clarify that a brief 
neurological examination 
will be included as part of a 
standard physical 
examination.
1.3. Schedule of 
Activities (SoA), 
Footnote aa
Added new Footnote aa as follows:
“A physical examination should include a brief 
neurological examination”
1.3. Schedule of 
Activities (SoA), 
Footnote bb
Added a new Footnote bb:
“Two different versions of the MGH-ATRQ scale 
will be used based on age (for participants <65 
years old and for participants ≥65 years old) at the 
beginning of screening.”
To clarify that there will be 2 
different versions 
MGH-ATRQ scale based on 
age at the beginning of 
screening.
6.5. Concomitant Therapy
Clarified that concurrent antidepressant treatment(s) 
will also be included on the appropriate version of 
the MGH-ATRQ.
4.2.4. Efficacy Measures;
8.1.13. Massachusetts 
General Hospital 
Antidepressant Treatment 
Response Questionnaire 
(MGH-ATRQ) –
Screening Only.
Clarified that 2 different versions of the scale will 
be used: for participants <65 years old and for 
participants ≥ 65 years old.
1.3. Schedule of 
Activities (SoA), 
Footnote p
Added below text in the existing Footnote p:
“Minor variations in the sequence and timing of 
assessments on the second screening visit (Day -5 
to Day -2) may be allowed. All assessments must be 
completed and scored prior to randomization.”
Also, added a visit window of “+1 day” for the 
second screening visit (Day -5 to Day -2).
To clarify that minor 
variations in the sequence 
and timing of assessments on 
the second screening visit 
(Day -5 to Day -2) may be 
allowed. 
4.1. Overall Design
Updated text as follows:
“A participant will not be eligible for study 
participation if they had an inadequate response to 
the current antidepressant, ie, if there was an initial 
response of ≥50% for more than 4 weeks a week 
but a subsequent reduction in response to <50% (ie, 
tachyphylaxis to the current SSRI/SNRI).”
To align the definition of 
tachyphylaxis in the protocol 
with the definition used in 
clinical practice and adopted 
by Massachusetts General 
Hospital - Clinical Trials 
Network and Institute
(MGH-CTNI).
5.1. Inclusion Criteria 
(Criterion 16)
Deleted below Inclusion Criterion 16:
“Must be willing and able to adhere to the 
prohibitions specified in this protocol.”
To remove inclusion criterion 
which is referring to the 
lifestyle considerations which 
are guidelines and not 
inclusion criteria.
Throughout the protocol
Minor editorial, grammatical, formatting, or 
spelling changes were made.
Minor errors were noted.


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Status: Approved,  Date: 25 June 2021
11.
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SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 10 August 2022
Janssen Research & Development Statistical Analysis Plan
A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Study to 
Evaluate the Efficacy and Safety of Seltorexant 20 mg as Adjunctive Therapy to 
Antidepressants in Adult and Elderly Patients with Major Depressive Disorder with
Insomnia Symptoms Who Have Responded Inadequately to Antidepressant Therapy
Protocol 42847922MDD3002; Phase 3 
JNJ-42847922 (seltorexant)
Status:
Approved
Date:
10 August 2022
Prepared by:
Janssen Research & Development,
LLC Document No:
EDMS-RIM-121671, 2.0
Compliance:  The study described in this report was performed according to the principles of Good Clinical Practice (GCP).
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04532749


JNJ-42847922 (seltorexant)
Statistical Analysis Plan 42847922MDD3002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 10 August 2022
TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................2
VERSION HISTORY......................................................................................................................................5
1.
INTRODUCTION..................................................................................................................................7
1.1.
Objectives and Endpoints .................................................................................................................7
1.2.
Study Design ....................................................................................................................................9
2.
STATISTICAL HYPOTHESES...........................................................................................................10
3.
SAMPLE SIZE DETERMINATION.....................................................................................................10
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS......................................................................11
5.
STATISTICAL ANALYSES................................................................................................................11
5.1.
General Considerations ..................................................................................................................11
5.1.1.
Visit Windows..............................................................................................................................11
5.1.2.
Analysis Phases ..........................................................................................................................13
5.1.3.
Imputation of Efficacy..................................................................................................................13
5.1.4.
Pooling Algorithm ........................................................................................................................14
5.2.
Participant Dispositions ..................................................................................................................14
5.3.
Primary Endpoint(s) Analysis..........................................................................................................15
5.3.1.
Definition .....................................................................................................................................15
5.3.2.
Estimand 1 ..................................................................................................................................16
5.3.2.1.
Analysis Methods .....................................................................................................................17
5.3.2.1.1.
Primary Analysis ...................................................................................................................17
5.3.2.1.2.
Sensitivity Analysis ...............................................................................................................18
5.3.3.
Estimand 2 ..................................................................................................................................19
5.3.3.1.
Analysis Methods .....................................................................................................................21
5.3.3.1.1.
Primary Analysis ...................................................................................................................21
5.3.3.1.2.
Sensitivity Analysis ...............................................................................................................21
5.3.4.
Estimand 1a ................................................................................................................................22
5.3.4.1.
Analysis Methods .....................................................................................................................22
5.3.4.1.1.
Primary Analysis ...................................................................................................................22
5.3.5.
Estimand 2a ................................................................................................................................22
5.3.5.1.
Analysis Methods .....................................................................................................................23
5.3.5.1.1.
Primary Analysis ...................................................................................................................23
5.3.6.
Estimand 2b ................................................................................................................................23
5.3.6.1.
Analysis Methods .....................................................................................................................23
5.3.6.1.1.
Primary Analysis ...................................................................................................................23
5.4.
Secondary Endpoint(s) Analysis.....................................................................................................24
5.4.1.
Key Secondary Endpoint(s).........................................................................................................24
5.4.1.1.
MADRS – WOSI (Without Sleep Item).....................................................................................24
5.4.1.1.1.
Definition...............................................................................................................................24
5.4.1.1.2.
Estimand(s)...........................................................................................................................24
5.4.1.1.3.
Analysis Methods..................................................................................................................24
5.4.1.2.
PROMIS-SD.............................................................................................................................25
5.4.1.2.1.
Definition...............................................................................................................................25
5.4.1.2.2.
Estimand(s)...........................................................................................................................26
5.4.1.2.3.
Analysis Methods..................................................................................................................26
5.4.2.
Other Secondary Endpoint(s)......................................................................................................26
5.4.2.1.
MADRS-6 .................................................................................................................................27
5.4.2.1.1.
Definition...............................................................................................................................27
5.4.2.1.2.
Analysis.................................................................................................................................27
5.4.2.2.
Response Based on MADRS Total Score ...............................................................................27
NCT04532749


JNJ-42847922 (seltorexant)
Statistical Analysis Plan 42847922MDD3002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved, Date: 10 August 2022
5.4.2.2.1.
Definition...............................................................................................................................27
5.4.2.2.2.
Analysis.................................................................................................................................27
5.4.2.3.
Patient Health Questionnaire - 9 Item (PHQ-9) .......................................................................28
5.4.2.3.1.
Definition...............................................................................................................................28
5.4.2.3.2.
Analysis.................................................................................................................................28
5.5.
Tertiary/Exploratory Endpoint(s) Analysis.......................................................................................28
5.5.1.
Consensus Sleep Diary...............................................................................................................28
5.5.1.1.
Definition ..................................................................................................................................28
5.5.1.2.
Analysis....................................................................................................................................29
5.5.2.
Remission Based on MADRS Total Score..................................................................................29
5.5.2.1.
Definition ..................................................................................................................................29
5.5.2.2.
Analysis....................................................................................................................................29
5.5.3.
European Quality of Life (EuroQol) Group, 5 Dimension, 5-Level questionnaire (EQ-5D-5L) ...30
5.5.3.1.
Definition ..................................................................................................................................30
5.5.3.2.
Analysis....................................................................................................................................30
5.5.4.
Sheehan Disability Scale (SDS)..................................................................................................30
5.5.4.1.
Definition ..................................................................................................................................30
5.5.4.2.
Analysis....................................................................................................................................31
5.5.5.
Insomnia Severity Index (ISI) (Patient Version) ..........................................................................31
5.5.5.1.
Definition ..................................................................................................................................31
5.5.5.2.
Analysis....................................................................................................................................31
5.5.6.
Patient Global Impression of Severity (PGI-S) for Insomnia.......................................................32
5.5.6.1.
Definition ..................................................................................................................................32
5.5.6.2.
Analysis....................................................................................................................................32
5.5.7.
Patient Global Impression of Change (PGI-C) for Depression ...................................................32
5.5.7.1.
Definition ..................................................................................................................................32
5.5.7.2.
Analysis....................................................................................................................................32
5.5.8.
Clinical Global Impression – Severity (CGI-S) ............................................................................33
5.5.8.1.
Definition ..................................................................................................................................33
5.5.8.2.
Analysis....................................................................................................................................33
5.5.9.
Ruminative Response Scale (RRS)............................................................................................33
5.5.9.1.
Definition ..................................................................................................................................33
5.5.9.2.
Analysis....................................................................................................................................34
5.5.10.
Correlation between MADRS total score and PROMIS-SD T-score...........................................34
5.5.11.
Subgroup Analyses .....................................................................................................................34
5.5.12.
Analysis of Efficacy data in the Follow-up Phases......................................................................34
5.6.
Safety Analyses ..............................................................................................................................35
5.6.1.
Extent of Exposure......................................................................................................................35
5.6.1.1.
Intervention Compliance...........................................................................................................35
5.6.2.
Adverse Events ...........................................................................................................................36
5.6.3.
Additional Safety Assessments...................................................................................................36
5.6.3.1.
Clinical Laboratory Tests..........................................................................................................36
5.6.3.2.
Vital Signs and Physical Examination Findings .......................................................................38
5.6.3.3.
Electrocardiogram....................................................................................................................39
5.6.3.4.
Other Safety Parameters .........................................................................................................40
5.6.3.4.1.
Columbia Suicide Severity Rating Scale (C-SSRS) .............................................................40
5.6.3.4.2.
Arizona Sexual Experiences Scale (ASEX)..........................................................................41
5.6.3.4.3.
Physician Withdrawal Checklist (20 items; PWC-20) ...........................................................42
5.6.3.4.4.
Menstrual Cycle Tracking .....................................................................................................42
5.7.
Other Analyses ...............................................................................................................................42
5.7.1.
Pharmacokinetics........................................................................................................................42
5.7.2.
Biomarkers ..................................................................................................................................43
5.7.3.
Definition of Subgroups...............................................................................................................43
5.8.
Interim Analyses .............................................................................................................................44
5.8.1.
Independent Data Monitoring Committee (IDMC).......................................................................44
NCT04532749


JNJ-42847922 (seltorexant)
Statistical Analysis Plan 42847922MDD3002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved, Date: 10 August 2022
6.
SUPPORTING DOCUMENTATION...................................................................................................45
6.1.
Appendix 1 List of Abbreviations ....................................................................................................45
6.2.
Appendix 2 Changes to Protocol-Planned Analyses......................................................................47
6.3.
Appendix 3 Demographics and Baseline Characteristics...............................................................48
6.4.
Appendix 4 Protocol Deviations......................................................................................................50
6.5.
Appendix 5 Prior and Concomitant Medications ............................................................................51
6.6.
Appendix 6 Adverse Events of Special Interest..............................................................................52
6.7.
Appendix 7 Medications of Special Interest....................................................................................53
6.8.
Appendix 8 Conversion of Raw Score to T-Score for PROMIS-SD ...............................................54
6.9.
Appendix 9 Criteria for Treatment-emergent Markedly Abnormal Laboratory Values....................55
6.10.
Appendix 10 Analyses for Assessing and Mitigating the Impact of COVID- 19 on Study
Outcome .........................................................................................................................................58
7.
REFERENCES ...................................................................................................................................59
NCT04532749


JNJ-42847922 (seltorexant)
Statistical Analysis Plan 42847922MDD3002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved, Date: 10 August 2022
VERSION HISTORY
Table – SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
Not Applicable
Initial release
1.1
Fixed Formatting Errors
Section 5.1: Update visit names for 
follow-up visits. Minor edits to the 
analysis windows
Section 5.3: Specified the 
intercurrent event “switch of add-on 
treatment and/or underlying 
antidepressant” separately to three 
distinct events to improve clarity. 
Clarified the summary measure and 
added rules for handling multiple 
intercurrent events at the same time.
Clarified data to be used under each 
estimand
Section 5.3.2 Added a supportive 
analysis excluding Ukrainian 
subjects ongoing in DB phase as of 
Feb. 24, 2022
Section 5.4.2.2: Updated analyses to 
be consistent with not imputing 
percent reduction from 
baseline(DB) to Day 43 in MADRS 
total score
Section 5.5.1.2: Clarified that 
sQUALwill be analyzed using the 
ANCOVA on actual change (not on 
ranked data). 
Section 5.5.6.2 Changed analysis 
method for PGI-S from ANCOVA 
on ranked data to MMRM on actual 
data. In addition, similar change 
applied to PGI-C in section 5.5.7.2 
and CGI-S in Section 5.5.8.2
Section 5.6: Updated safety analyses 
to be based on planned intervention 
received
Section 5.6.1: Updated compliance 
calculation for study intervention.
Added rule for handling missing 
Made the analysis plan consistent 
with the protocol objectives. 
NCT04532749


JNJ-42847922 (seltorexant)
Statistical Analysis Plan 42847922MDD3002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved, Date: 10 August 2022
data of the last dose of study 
intervention
Section 5.6.3: Clarified definition of 
Treatment emergent markedly 
abnormal value. Clarified that only 
participants with baseline (DB) 
values that don’t meet criteria or if 
baseline value is missing will be 
eligible for analyses of hepatic 
toxicity. Added RR Interval to ECG 
table
Section 5.6.3.4: Clarified scoring 
rule for C-SSRS. Clarified the visit 
to which follow-up symptoms will 
be compared for PWC.
Section 5.7.3 Updated region 
categorization
Appendix 3: Added HDRS-17 to 
baseline disease characteristic table
Appendix 5: Added summary of 
antidepressants taken during the DB 
phase
Appendix 6: Updated preferred term 
based on MEDRA 24.1.
Appendix 9: Updated units for 
Hemoglobin A1c, removed LDH
Appendix 10: Specified that if 
number of non-site visits is small, 
then sensitivity analysis may not be 
performed
NCT04532749


JNJ-42847922 (seltorexant)
Statistical Analysis Plan 42847922MDD3002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
7
Status: Approved, Date: 10 August 2022
1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analyses for study 42847922MDD3002.
1.1.
Objectives and Endpoints
For the following objectives and endpoints, major depressive disorder with insomnia symptoms 
(MDDIS) is defined as: Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-
5) diagnosis of Major Depressive Disorder (MDD) and a) moderate to severe IS by a patient version 
Insomnia Severity Index (ISI) total score of ≥15 at the end of screening and b) a positive response for
IS (MDD symptoms Item 4) on the Structured Clinical Interview for DSM-5 Axis I Disorders Clinical
Trials Version (SCID-CT). In addition, the clinician version ISI total score ≥15 is also required since
this version was used in the Phase 2 program.
Double-blind Treatment Phase
Objectives
Endpoints
Efficacy
Primary

To assess the efficacy of seltorexant 20 
mg compared with placebo as adjunctive 
therapy to an antidepressant in improving 
depressive symptoms in participants with 
MDDIS who have had an inadequate 
response to current antidepressant therapy 
with an SSRI or SNRI

Change from baseline to Day 43 in the 
MADRS total score in participants with 
MDDIS.
Key Secondary

MDD symptoms other than insomnia 
symptoms

Change from baseline to Day 43 in the 
MADRS without sleep item (MADRS-
WOSI) total score.

To assess the efficacy of seltorexant 
compared with placebo in participants 
with MDDIS, as adjunctive therapy to an 
antidepressant 
on 
patient-reported 
assessment of sleepoutcomes

Change from baseline to Day 43 in sleep 
disturbance using the Patient Reported 
Outcome 
Measurement 
Information 
System-Sleep Disturbance (PROMIS-SD) 
Short Form (8a) T-score in participants 
with MDDIS.
Secondary
To assess the efficacy of seltorexant compared with placebo as adjunctive therapy to an 
antidepressant in participants with MDDIS on the following:

Core symptoms of depression

Change from baseline to Day 43 in the 
MADRS-6 total score.
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
Response of depressive symptoms

Proportion of responders on depressive 
symptoms   scale, defined   as   a  ≥50% 
improvement in MADRS total score from 
baseline to Day 43.

Patient-reported symptoms of depression

Change from baseline to Day 43 in Patient 
Health Questionnaire, 9-Item (PHQ-9) 
Exploratory
To assess the efficacy of seltorexant compared with placebo as adjunctive therapy to an 
antidepressant on the following:

Patient-reported sleep diary

Change from baseline to Day 43 in 
subjective sleep parameters as measured 
by the Consensus Sleep Diary (CSD).

Remission of depressive symptoms

Proportion of participants with remission 
of depressive symptoms, defined as a 
MADRS total score ≤12 at Day43.

Patient-reported health-related quality of 
life

Change from baseline to Day 43 in health-
related quality of life and health status, as 
assessed by the European Quality of Life, 
5 
Dimension, 
5-Level 
(EQ-5D-5L)
questionnaire.

Patient-reported
global
functioning 
(work/school, social, and family life)

Change from baseline to Day 43 in the 
Sheehan Disability Scale (SDS) total 
score.

Patient-reported insomnia symptoms

Change from baseline to Day 43 in the 
patient-reported ISI total score.

Patient-reported
assessment
of
sleep 
outcomes

Change from baseline over time in sleep 
symptoms using the Patient Global 
Impression of Severity(PGI-S).

Patient-reported assessment of change in 
depressive symptoms

Change from baseline over time in 
depressive symptoms using the Patient 
Global Impression of Change (PGI-C).

Clinical symptom severity of depression

Change from baseline over time in the 
Clinical 
Global 
Impression-Severity 
(CGI-S) score.

Patient-reported rumination symptoms

Change from baseline to Day 43 in the 
RRS total score.
Safety
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
To assess the safety and tolerability of 
seltorexant as adjunctive therapy to an 
antidepressant in participants with MDD 
in the short-term compared with placebo

Adverse events (AEs) including AEs of 
special interest (AESI)

Vital signs

Suicidality assessment using the C-SSRS

Withdrawal symptoms assessment using 
the Physician Withdrawal Checklist 20-
items (PWC-20)

Laboratory values and ECG

Patient-reported sexual functioning using 
Arizona 
Sexual 
Experiences 
Scale 
(ASEX)
Additional exploratory objectives:

To identify diagnostic biomarkers and to investigate changes in MDD-related biomarkers (eg, 
HPA axis, metabolic function, and biomarkers of immune system activation) in relation to 
clinical response on depression and IS upon adjunctive treatment with seltorexant.

To identify genetic (eg, CYP genes) and other factors that may influence the PK, safety, or 
tolerability of seltorexant.

To assess the plasma exposure of seltorexant and its M12 metabolite along with alpha-1-acid 
glycoprotein levels in participants with MDDIS when used as adjunctive treatment.
Statistical hypotheses pertaining to the primary and the key secondary endpoints are described in 
Section 2.
Details about the analysis of biomarker and pharmacokinetic data pertaining to the additional 
exploratory objectives will be described in their respective analysis plans separately.
1.2.
Study Design
This is a multicenter, DB randomized, parallel-group, placebo-controlled, 6-week, study with 
seltorexant 20 mg study to assess the efficacy and safety of seltorexant as an adjunctive therapy in 
adults (18 to 64 years, inclusive) and elderly (65 to 74 years, inclusive) participants with MDDIS, who 
have had an inadequate response to current antidepressant therapy with a SSRI/SNRI.
The study will consist of 3 phases: a screening phase (up to 30 days), a DB treatment phase (43 days), 
and a posttreatment follow-up phase (7 to 14 days after double-blind treatment phase).
Approximately 386 participants with MDDIS will be randomly assigned to receive placebo or 
seltorexant 20 mg in a 1:1 ratio for 6 weeks in the DB treatment phase. Randomization will be 
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stratified by country, age group (adults [<65years] versus elderly [≥65 years]), baseline rumination 
level (RRS total score <54, ≥54), and by baseline MADRS group (MADRS total score <24, ≥24).
Participants who discontinue early from study intervention in the DB treatment phase will be further 
assessed during additional Follow-up visits every 2 weeks until Day 50-57, if they do not withdraw 
the consent.
Participants will take their assigned study intervention at home, once daily at bedtime during DB 
treatment phase. Participants will continue to take their baseline SSRI/SNRI antidepressant (at the 
same dose, without change, and at approximately the same time of the day as prior to entering the 
study) during the study starting at screening, and through the DB treatment phase and the follow- up
phase.
2.
STATISTICAL HYPOTHESES
This study is designed to show that the intervention treatment effect in improving depressive 
symptoms (as measured by change from baseline on Day 43 in MADRS total score) of seltorexant as 
an adjunctive MDD treatment is superior to placebo in participants with MDDIS.
If µT is the mean change in MADRS total score for seltorexant group and µP is the mean change in 
MADRS total score for the placebo group, then the hypothesis can be written as follows:
H0: µT – µP ≥0 
vs.
H1: µT – µP <0
Superiority can be concluded if the two-sided p-value for the testing of the hypothesis above is less 
than 0.05.
3.
SAMPLE SIZE DETERMINATION
Approximately 386 participants (randomized in 1:1 ratio to placebo and seltorexant 20 mg) are 
planned to be enrolled in the DB treatment phase. The enrollment is targeted to achieve approximately
374 participants eligible to be included in the full analysis set 1 (FAS1). Assuming a treatment
difference of 4.4 points in change from baseline in MADRS total score between seltorexant and
placebo, a standard deviation of 12, and a 1-sided significance level of 0.025 (equivalently 2-sided 
0.05), this sample size (ie.,374 in FAS1) will provide approximately 90% power in a pairwise 
comparison between seltorexant and placebo in the primary efficacy analysis, accounting for a drop-
out rate of approximately 15%. The assumed treatment difference and standard deviation used in this 
calculation are based on Phase 2 (42847922MDD2001) study results, as well as on clinical judgment.
An interim analysis (IA) for futility is planned when a combined total of 276 participants with MDDIS 
have completed the DB phase in 42847922MDD3002 and another phase 3 study, 
42847922MDD3001. Details about the interim analysis are presented in a separate IA SAP.
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4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Analysis Sets
Description
Enrolled
All participants who sign the ICF
Randomized
The randomized analysis set includes all participants who were randomized in the study.
Full Analysis Set 1 
(FAS1)
The full analysis set 1 (FAS1) includes all randomized participants who received at least 1 dose 
of study intervention in the DB phase and had baseline MADRS total score ≥24 (per IWRS).
Full Analysis Set 2 
(FAS2)
The full analysis set 2 (FAS2) includes all randomized participants who received at least 1 dose 
of study intervention in the DB phase.
Safety
The safety analysis set includes all randomized participants who received at least 1 dose of 
study intervention in the DB phase.
Follow-up 
Analysis Set
The follow-up analysis set includes all randomized participants who entered the follow-up 
phase.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
5.1.1.
Visit Windows
As participants do not always adhere to the protocol visit schedule, the following rules are applied to
assign actual visits to analysis visits. Listed below are the visit windows and the target days for each 
visit. The reference day is Study Day 1. If a participant has 2 or more actual visits in 1 visit window, 
the visit closest to the target day will be used as the protocol visit for that visit window. The other
additional visit(s) will not be used in the summaries or analyses, but they can be used for determination 
of clinically important endpoints. If 2 actual visits are equidistant from the target day within a visit 
window, the later visit is used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit window,
it will no longer be used for a later time point except for the endpoint. Listed below (
Table 1:
Visit Windows
Parameter
Analysis Phase
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point
(Day)*
MADRS 
PROMIS-SD 
CGI-S
PGI-S
PHQ-9
DB
3
Baseline (DB)
<=1
1
6
Day 15
2 to 22
15
7
Day 29
23 to 36
29
8
Day 43
37 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
FU (DB)
10
Day 50-57
End of DB + 1 to 
End of FU
10
Day 15 EW
2 to 22
15
Day 29 EW
23 to 36
29
Day 43 EW
37 to 48
43
Day 50-57 EW
49 to End of DB
54
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Parameter
Analysis Phase
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point
(Day)*
CSD**
DB
3
Average Baseline
<=1
1
8
Day 43
2 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
FU (DB)
Day 50-57
End of DB + 1 to 
End of FU
10
ISI (patient)
SCR
1
Screening 1
<= -7
-19
2
Screening 2
-6 to -1
-3
DB
3
Baseline (DB)
<=1
1
8
Day 43
2 to End of DB
43
DB final visit
Endpoint (DB)
2 to End of DB
SDS
RRS
ASEX
DB
3
Baseline (DB)
<=1
1
8
Day 43
2 to End of DB
43
DB final visit
Endpoint (DB)
2 to End of DB
PGI-C
DB
6
Day 15
2 to 22
15
7
Day 29
23 to 36
29
8
Day 43
37 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
FU (DB)
10
Day 50-57
End of DB + 1 to 
End of FU
10
Day 15 EW
2 to 22
15
Day 29 EW
23 to 36
29
Day 43 EW
37 to 48
43
Day 50-57 EW
49 to End of DB
54
EQ-5D-5L
DB
3
Baseline (DB)
<=1
1
8
Day 43
2 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
ECG
Lab
SCR
1
Screening
<1
DB
3
Average Predose
<=1
1
8
Day 43
2 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
Vital Signs
Weight
SCR
1
Screening
<1
DB
3
Baseline (DB)
<=1
1
6
Day 15
2 to 22
15
7
Day 29
23 to 36
29
8
Day 43
37 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
FU (DB)
10
Day 50-57
End of DB + 1 to 
End of FU
10
Day 15 EW
2 to 22
15
Day 29 EW
23 to 36
29
Day 43 EW
37 to 48
43
Day 50-57 EW
49 to End of DB
54
C-SSRS
SCR
1
Screening
<1
DB
3
Baseline (DB)
<=1
1
5
Day 8
2 to 11
8
6
Day 15
12 to 22
15
7
Day 29
23 to 36
29
8
Day 43
37 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
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Parameter
Analysis Phase
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point
(Day)*
FU (DB)
10
Day 50-57
End of DB + 1 to 
End of FU
10
Day 8 EW
2 to 11
8
Day 15 EW
12 to 22
15
Day 29 EW
23 to 36
29
Day 43 EW
37 to 48
43
Day 50-57 EW
49 to End of DB
54
PWC
DB
8
Endpoint (DB)
2 to End of DB
43
FU (DB)
9
Follow-up 1 (DB)
1 to 5
1
10
Follow-up 2 (DB)
6 to End of FU
10
) are the analysis visit windows and the target days for each visit defined in the protocol.
Table 1:
Visit Windows
Parameter
Analysis Phase
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point
(Day)*
MADRS 
PROMIS-SD 
CGI-S
PGI-S
PHQ-9
DB
3
Baseline (DB)
<=1
1
6
Day 15
2 to 22
15
7
Day 29
23 to 36
29
8
Day 43
37 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
FU (DB)
10
Day 50-57
End of DB + 1 to 
End of FU
10
Day 15 EW
2 to 22
15
Day 29 EW
23 to 36
29
Day 43 EW
37 to 48
43
Day 50-57 EW
49 to End of DB
54
CSD**
DB
3
Average Baseline
<=1
1
8
Day 43
2 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
FU (DB)
Day 50-57
End of DB + 1 to 
End of FU
10
ISI (patient)
SCR
1
Screening 1
<= -7
-19
2
Screening 2
-6 to -1
-3
DB
3
Baseline (DB)
<=1
1
8
Day 43
2 to End of DB
43
DB final visit
Endpoint (DB)
2 to End of DB
SDS
RRS
ASEX
DB
3
Baseline (DB)
<=1
1
8
Day 43
2 to End of DB
43
DB final visit
Endpoint (DB)
2 to End of DB
PGI-C
DB
6
Day 15
2 to 22
15
7
Day 29
23 to 36
29
8
Day 43
37 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
FU (DB)
10
Day 50-57
End of DB + 1 to 
End of FU
10
Day 15 EW
2 to 22
15
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Parameter
Analysis Phase
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point
(Day)*
Day 29 EW
23 to 36
29
Day 43 EW
37 to 48
43
Day 50-57 EW
49 to End of DB
54
EQ-5D-5L
DB
3
Baseline (DB)
<=1
1
8
Day 43
2 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
ECG
Lab
SCR
1
Screening
<1
DB
3
Average Predose
<=1
1
8
Day 43
2 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
Vital Signs
Weight
SCR
1
Screening
<1
DB
3
Baseline (DB)
<=1
1
6
Day 15
2 to 22
15
7
Day 29
23 to 36
29
8
Day 43
37 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
FU (DB)
10
Day 50-57
End of DB + 1 to 
End of FU
10
Day 15 EW
2 to 22
15
Day 29 EW
23 to 36
29
Day 43 EW
37 to 48
43
Day 50-57 EW
49 to End of DB
54
C-SSRS
SCR
1
Screening
<1
DB
3
Baseline (DB)
<=1
1
5
Day 8
2 to 11
8
6
Day 15
12 to 22
15
7
Day 29
23 to 36
29
8
Day 43
37 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
FU (DB)
10
Day 50-57
End of DB + 1 to 
End of FU
10
Day 8 EW
2 to 11
8
Day 15 EW
12 to 22
15
Day 29 EW
23 to 36
29
Day 43 EW
37 to 48
43
Day 50-57 EW
49 to End of DB
54
PWC
DB
8
Endpoint (DB)
2 to End of DB
43
FU (DB)
9
Follow-up 1 (DB)
1 to 5
1
10
Follow-up 2 (DB)
6 to End of FU
10
*Relative to the first day of the respective phases for DB and FU (DB) phase; Assignment of visits to the 
FU (DB) will be made to the assessments that were recorded after double-blind treatment stop date. 
Participants who discontinue DB prior to Day 35 will have additional follow-up visits performed every 2 
weeks until Day 50-57 - the follow-up data from these participants are assigned relative to the first day of 
DB phase with visit labels ending with EW.
** The analysis windows for CSD pertains to the average of the assessments that were performed 7 days 
prior to and including the study visit.
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5.1.2.
Analysis Phases
Double-Blind Analysis Phase
The analysis reference start date of the double-blind analysis phase is the date of the first dose of 
double-blind study intervention. The analysis reference end date of the double-blind analysis phase is 
the maximum of the date of the last visit in the double-blind phase and date of completion or early 
withdrawal from the double-blind phase. For randomized participants who did not receive any study 
intervention in the double-blind phase, both analysis reference start and end dates are missing for the 
double-blind analysis phase.
Assignment of adverse events to double-blind analysis phase is described separately in Section 5.6.2.
Follow-up Phase
Start and end dates for the follow-up phase are only defined for participants who continued into the 
follow-up phase. The analysis reference start date of the follow-up analysis phase is the day after the
reference end date for the double-blind analysis phase. The analysis reference end date of the follow-
up analysis phase is the maximum of the last follow-up visit date or the disposition date at follow-up.
5.1.3.
Imputation of Efficacy
Imputation method for missing data will include the following methods (Table 2).
Table 2:
Imputation of Missing Efficacy Data
Imputation
Method/Rule
Multiple Imputation (MI) 
method
1) Copy Reference
2) Copy Increment from Reference
3) Delta Adjustment
Non-Responder
Participants with missing values will be imputed as non-responders for 
analyses that use imputed data.
Non-Remitter
Participants with missing values will be imputed as non-remitters for 
analyses that use imputed data.
Imputation of total scores will be performed for the following efficacy scales as shown in Table 3
below. If the number of items with missing scores is greater than the maximum number of items 
presented in the table, the total score will be missing.
For the remaining efficacy assessments which require adding multiple item scores, the total score will 
be missing if any item score is missing.
Table 3:
Imputation of Total Score for Efficacy Scales
Efficacy Scale
Total 
Number of 
Items
Maximum Number 
of Items That Can Be 
Missing
Formula for Total Score
MADRS
10
1
Sum of non-missing item scores * (10 / 
number of non-missing items)
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MADRS-WOSI
9
1
Sum of non-missing item scores * (9 / 
number of non-missing items)
PROMIS-SD
8
4
Sum of non-missing item scores * (8 / number of 
non-missing items). If the result is a fraction, the 
imputed total score will be rounded up to the 
nearest whole number.
5.1.4.
Pooling Algorithm
If low enrollment were to occur in a country, it may be combined with other countries in the similar 
geographic region for analysis.
5.2.
Participant Dispositions
The number of screened participants and reason for screen failures will be summarized overall
The number of participants in the following disposition categories will be summarized throughout the
study by intervention group and overall for the all randomized, FAS1, FAS2, safety and follow- up 
analysis sets pertinent to each phase:

Participants randomized

Participants who received studyintervention

Participants who completed, discontinued and reasons for discontinuation of study intervention 
during double-blind phase

Participants who completed, terminated and reasons for termination from the follow-up phase of 
the study

Intercurrent events in the double-blind phase
The distribution of the time to discontinuation of study intervention in double-blind phase will be 
displayed with Kaplan-Meier curves. A participant who discontinues study intervention during at 
any time will be considered as an event, and the date of study intervention discontinuation will be 
used in the time to event calculation. A participant who completes study intervention will be 
censored and the date of last dose of study intervention will serve as the time of censoring.
Listings of participants will be provided for the following categories:

Participants who discontinued double-blind study intervention

Participants who were unblinded during the study period

Participants who were randomized yet did not receive study intervention.
Additional analyses of disposition data for assessing and mitigating the impact of COVID-19 on study 
outcome are presented in Appendix 10.
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5.3.
Primary Endpoint(s) Analysis
The primary analysis will be based on full analysis set 1 (FAS1) using the MADRS total score 
collected during the double-blind phase for submissions other than the EU dossier. For the EU dossier, 
the primary analysis set will be based on full analysis set 2 (FAS2).
5.3.1.
Definition
The primary efficacy endpoint is the change in MADRS total score from baseline (DB) to Day 43.
The MADRS is a clinician-administered scale designed to measure depression severity and detects 
changes due to antidepressant intervention (Montgomery 1979). The scale consists of10 items, each 
of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the
symptoms).Higherscoresrepresent amoreseverecondition.TheMADRSevaluates reported sadness, 
apparent sadness, inner tension, reduced sleep, reduced appetite, concentration
difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. The test exhibits 
high inter-rater reliability. The typical recall period for the MADRS is 7 days.
The MADRS total score is the sum of scores from individual question items at a given time point, and
ranges from 0 to 60. Higher scores represent a more severe condition. Imputation of total score is 
presented in Section 5.1.3.
Negative changes in MADRS total score indicate improvement.
Five estimands are defined for the primary endpoint: Estimand 1, Estimand 2a using the FAS1 
analysis set, and Estimand 2, Estimand 2b, and Estimand 1a using the FAS2 analysis set. With the 
exception of the European Union (EU) dossier, the primary estimand is Estimand 1, and the 
supplementary estimands are Estimand 1a, Estimand 2, Estimand 2a and Estimand 2b. For the EU 
dossier, the primary estimand is Estimand 2, and the supplementary estimands are Estimand 1, 
Estimand 1a, Estimand 2a and Estimand 2b.
The sections below describe the primary and sensitivity analyses performed for each primary and 
supplementary estimand.
5.3.2.
Estimand 1
Estimand 1 will be the primary estimand for submissions other than the EU dossier, and a
supplementary estimand for the EU dossier.  The analysis will be performed on FAS1.
Primary Trial Objective: To evaluate the efficacy of seltorexant 20 mg compared with placebo as 
adjunctive therapy to an antidepressant in improving depressive symptoms in participants with 
MDDIS who have had an inadequate response to current antidepressant therapy with a SSRI or SNRI.
Estimand Scientific Question of Interest: What is the antidepressant benefit from seltorexant 20 mg 
versus placebo as adjunctive treatment to a SSRI or SNRI in adults and elderly participants with 
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interest. This approach was discussed and agreed upon at the End of Phase 2 meeting with FDA 
(February 2020).
The hypothetical strategy attempts to estimate the treatment effect in the hypothetical scenario as if 
the intercurrent events had not occurred. As such, any data observed after an intercurrent event of 
switch of treatment is excluded. Otherwise, data observed up to and including DB disposition day 
will be included.
5.3.2.1.
Analysis Methods
5.3.2.1.1.
Primary Analysis
Descriptive statistics of the actual values and the change from baseline (DB) to each postbaseline 
time point in the double-blind phase will be presented for MADRS total score by intervention group.
MADRS total score will be analyzed by a Mixed-Effect Model for Repeated Measures (MMRM) 
based on observed case. The fixed terms included in the model will be intervention group, country, age 
group (adults [<65 years] and elderly [≥65 years]), baseline(DB) rumination level (RRS total score
<54, ≥54), time, and time-by-intervention interaction, and baseline(DB) MADRS total score as a 
covariate. The within-subject covariance between visits will be estimated via an unstructured 
variance-covariance matrix. In case of convergence problems, alternative variance-covariance 
structures will be tried in the following order, with the first structure that converges being used in the 
analysis: heterogeneous Toeplitz, standard Toeplitz, and AR(1) with separate subject random effect. 
The Kenward-Roger method will be used for approximating the denominator degrees of freedom. 
Comparison between seltorexant and placebo at Day 43 will be performed using the appropriate 
contrast. Difference in least square means and 2-sided 95% CI will be presented.
Least squares mean changes from baseline(DB) (+/- SE) will be presented graphically over time.
A supportive analysis excluding Ukrainian participants ongoing in Double-blind phase on February 
24, 2022 will be conducted using the same MMRM model used for the primary analysis. Comparison 
between seltorexant and placebo at Day 43 will be performed using the appropriate contrast. 
Difference in least square means and 2-sided 95% CI will be presented.
Justification of MMRM: Based on data from the short-term phase 2b study MDD2001, it was observed 
that within each treatment group, there was no obvious difference in MADRS change trajectories 
between completers and drop-outs, and for each drop-out reason, MADRS trajectories do not follow 
a specific pattern. In addition, in the 20mg group (the dose being studied in phase 3 program), those 
who dropped out generally showed in improvement prior to discontinuation. Based on these 
observations, it is considered reasonable to assume missing at random (MAR) as the missingness 
mechanism.
MAR assumption cannot be tested vs. MNAR using observed data, however, simulation findings 
(Siddiqui 2009). indicate that in the presence of a mixture of the three missing mechanisms (MCAR, 
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MAR, MNAR) with differential dropout rates between treatment groups, the MMRM approach is 
able to re-estimate the true treatment difference consistently with a negligible bias and control Type 
I error rate. Therefore, the primary analysis in this phase 3 study will be MMRM, with sensitivity 
analyses (tipping point) (Section 5.3.2.1.2) to stress test the efficacy findings under MNAR 
assumption. This approach was discussed and agreed upon at the End of Phase 2 meeting with FDA 
(February 2020)
5.3.2.1.2.
Sensitivity Analysis
The sensitivity analysis for Estimand 1 will include the delta adjustment multiple imputation 
method which will be implemented on the MADRS total score. This method will employ the 
following 3 steps:
Step 1 – Multiple Imputation (MI)
If there are participants with a non-monotone missing data pattern, datasets with only monotone 
missing data patterns will be created first by imputing the intermediate missing values using 
methods such as the MCMC (Markov Chain Monte Carlo) method. 500 imputations will be 
performed to create 500 unique datasets which now have monotone missing (ie., missing data after 
the participant experienced an intercurrent event) data pattern.
Analysis assumptions: Missing at random (MAR) is assumed for intermediate missing data (i.e., 
missing data between non-missing observations). Monotone missing data will first be imputed by 
MAR-based MI regression, and the imputed scores in the experimental intervention group will be 
adjusted to be worse than the other participants in same group with non-missing data as discussed 
below.
The imputed values will be adjusted by adding 8c to the imputed values for participants randomized 
to the control group and adding 8A to the imputed values for participants randomized to the
experimental intervention group. Delta-adjusted fully imputed datasets will be generated for different 
combinations of 8c  and 8A   values as defined below:

8c = 0 and 8A = 0 to ∆∗ in increments of 1 (experimental group-only adjustment 
analysis)
- Adding positive values results in higher (worse) scores. ∆∗represents the adjustments leading to the
‘tipping point’, so the smallest delta adjustments values at which conclusions change from favorable 
(i.e. statistically significant: 2-sided p-value ≥0.05) to unfavorable (fail to reject the null hypothesis 
of no intervention difference).

Imputed values in both the experimental and the control groups will be adjusted using a range of
delta values, and delta-adjusted fully imputed datasets will be generated for each combination.
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3. Switch of add-on study drug
Hypothetical strategy: as if the participant had 
discontinued treatment instead of switching
4. Switch of underlying 
antidepressant
Hypothetical strategy: as if the participant had 
discontinued treatment instead of switching
5. Switch of add-on study drug and 
underlying antidepressant
Hypothetical strategy: as if the participant had 
discontinued treatment instead of switching
For participants experiencing multiple intercurrent events at the same time, intercurrents in categories 
3-5 will override the rest. For example, if a patient starts a new add-on study drug the day after taking 
the last dose of their previous add-on study medication, this intercurrent event will be considered a 
switch of add-on study drug, and not a discontinuation. However, if more than one day passes between 
the last dose of their previous add-on medication and the first dose of the new add-on medication, 
this situation will be considered a discontinuation of add-on study drug intercurrent event followed 
by a switch of add-on study drug intercurrent event.
The treatment policy strategy attempts to estimate the treatment effect irrespective of the intercurrent 
event.  Therefore, follow-up data will be used in the analysis for patients who discontinue add-on 
study drug only.  The hypothetical strategy attempts to estimate the treatment effect in the 
hypothetical scenario as if the intercurrent events had not occurred. As such, any data observed after 
an intercurrent event of switch of treatment is excluded. Otherwise, data observed up to and including 
DB disposition day will be included.
5.3.3.1.
Analysis Methods
Once monotone missing datasets are created after imputing intermediate missing data using the 
MCMC method as described in Section 5.3.2.1.2, the monotone missing data will be imputed using the 
following 2 methods: (i) Copy Reference (CR) MI method for the primary analysis (ii) Copy 
Increment from Reference (CIR) MI method as a sensitivity analysis. Each method has a different set 
of assumptions as described in the sections below.
Steps 2 and 3 from Section 5.3.2.1.2 will then be implemented: performing MMRM analysis on each 
imputed dataset, and pooling of the results from the imputed datasets.
5.3.3.1.1.
Primary Analysis
The primary analysis for Estimand 2 will include implementation of Copy Reference (CR) MI 
method.
Analysis assumptions: MAR is assumed for intermediate missing data. Missing not at random 
(MNAR) is assumed for monotone missing (i.e., data that is deemed missing after the participant 
experienced an intercurrent event under hypothetical strategy, or missing data after the occurrence of 
an intercurrent event under treatment policy) in the experimental intervention group, where efficacy 
scores are assumed as if participant had always been in the control group. MAR is assumed for 
missing data in the control group.
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The efficacy data that is either missing or not used after the intercurrent event at a given timepoint will 
be imputed using the imputation model of the control group, i.e., conditional on the data observed or
imputed at previous timepoints relative to the mean of the model for the control group.
This approach does not assume a sustained benefit of experimental intervention for the efficacy data 
that is either missing or not used after the intercurrent event, and uses an imputation method that is 
based on the control group distribution and the estimated correlations between time points in the 
control group.
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point will be presented for MADRS total score by intervention group. Under the treatment policy 
strategy, data from participants who discontinued the add-on study drug only (intercurrent event 1 
under this estimand) and provided additional follow-up data every 2 weeks until Day 43 will be 
included in this analysis.
Least squares mean changes from baseline(DB) (+/- SE) will be presented graphically over time.
5.3.3.1.2.
Sensitivity Analysis
The sensitivity analysis for Estimand 2 will include implementation of Copy Increment from 
Reference (CIR) MI method.
Analysis assumptions: MAR is assumed for intermediate missing data. MNAR will be assumed for 
monotone missing (i.e., data that is deemed missing after the participant experienced an intercurrent 
event under hypothetical strategy, or missing data after the occurrence of an intercurrent event under 
treatment policy) in the experimental intervention group, where it will be assumed that the efficacy 
data that is not missing or not used after the intercurrent event in these participants immediately adopt 
a distribution with predicted mean values at future visits where change in mean from visit to visit is 
similar to those in the control group. MAR is assumed for missing data in the control group.
This approach assumes that the participant’s efficacy under the experimental intervention versus the 
control group is maintained as at the last time for which the efficacy scores are available.
Least squares mean changes from baseline(DB) (+/- SE) will be presented graphically over time.
5.3.4.
Estimand 1a
Estimand 1a will be a supplementary estimand for all submissions. The analysis will be performed 
on FAS2.
Estimand 1a is similar to Estimand 1 (Section 5.3.2) in all but the population component. The 
population under this estimand includes participants with MDDIS who have had an inadequate 
response to current antidepressant therapy with a SSRI/SNRI, as reflected by the inclusion/exclusion 
criteria (i.e., regardless of the baseline MADRS total score).
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5.3.4.1.
Analysis Methods
5.3.4.1.1.
Primary Analysis
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point in the double-blind phase will be presented for MADRS total score by intervention group.
The primary analysis under Estimand 1a is the same as the primary analysis under Estimand 1 
(Section 5.3.2.1.1) where an MMRM analysis will be performed.
5.3.5.
Estimand 2a
Estimand 2a will be a supplementary estimand for all submissions. The analysis will be performed 
on FAS1.
Estimand 2a is similar to Estimand 2 (Section 5.3.3) in all but the population component. The 
population under this estimand includes participants with MDDIS who have had an inadequate 
response to current antidepressant therapy with a SSRI/SNRI, as reflected by the inclusion/exclusion 
criteria, and who have a baseline MADRS total score ≥24.
5.3.5.1.
Analysis Methods
5.3.5.1.1.
Primary Analysis
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point will be presented for MADRS total score by intervention group. Under the treatment policy 
strategy, data from participants who discontinued the add-on study drug only (intercurrent event 1 
under this estimand) and provided additional data every 2 weeks until Day 43 will be included in this 
analysis.
The primary analysis under Estimand 2a is the same as the primary analysis under Estimand 2 
(Section 5.3.3.1.1) where CR MI will be implemented.
5.3.6.
Estimand 2b
Estimand 2b will be a supplementary estimand for all submissions. The analysis will be performed 
on FAS2.
Estimand 2b is similar to Estimand 2 (Section 5.3.3) in all but the strategy for the intercurrent event
of treatment discontinuation of both underlying antidepressant and add-on study drug; under this 
estimand, treatment policy strategy will be implemented – under this strategy all observed values of 
the endpoint will be used regardless of whether or not the participant had experienced this intercurrent 
event. The strategy for the other 2 intercurrent events will be the same as that of Estimand 2.
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5.3.6.1.
Analysis Methods
5.3.6.1.1.
Primary Analysis
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point will be presented for MADRS total score by intervention group. Under the treatment policy 
strategy, data from participants who discontinued the add-on study drug only, and from those who
discontinued both underlying antidepressant and add-on study drug (intercurrent events 1 and 2 under 
this estimand) and provided additional follow-up data every 2 weeks until Day 43 will be included in 
this analysis.
The primary analysis under Estimand 2b is the same as the primary analysis under Estimand 2 
(Section 5.3.3.1.1) where CR MI will be implemented.
Additional analyses of the primary endpoint for assessing and mitigating the impact of COVID- 19 
on study outcome are presented in Appendix 10.
5.4.
Secondary Endpoint(s) Analysis
5.4.1.
Key Secondary Endpoint(s)
Similar to the primary endpoint, the primary analysis of the key secondary endpoints will be based on 
full analysis set 1 (FAS1) for submissions other than the EU dossier. For the EU dossier, the primary 
analysis will be based on full analysis set 2 (FAS2).
5.4.1.1.
MADRS – WOSI (Without Sleep Item)
5.4.1.1.1.
Definition
The first key secondary endpoint is the change in MADRS-WOSI from baseline(DB) to Day 43.
MADRS-WOSI is defined as the full MADRS without the sleep item (Montgomery 1979).
The MADRS-WOSI total score is the sum of scores of the remaining 9 items at a given time point, 
ranging from 0 to 54. Higher scores represent a more severe condition. Imputation of total score is 
presented in Section 5.1.3.
Negative changes in MADRS-WOSI total score indicate improvement.
5.4.1.1.2.
Estimand(s)
The same estimands as defined for the primary endpoint in Section 5.3 are defined for MADRS-
WOSI, with the variable being the following: Change in MADRS-WOSI total score from baseline to 
Day 43.
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5.4.1.1.3.
Analysis Methods
Same analyses as for the estimands under the primary endpoint, and the corresponding sensitivity and 
supplementary analyses will be implemented for change in MADRS-WOSI total score. The MMRM 
model will include baseline(DB) MADRS-WOSI total score as the covariate.
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point in the double-blind phase will be presented for MADRS-WOSI total score by intervention
group. Under the treatment policy strategy for Estimand 2, Estimand 2a and Estimand 2b, MADRS-
WOSI data from participants who discontinued the add-on study intervention only (intercurrent event 
1 under these estimands), and from participants who discontinued both underlying antidepressant and 
add-on study drug (intercurrent event 2 under Estimand 2b) and provided additional data every 2
weeks until Day 43 will be included in the analyses corresponding to each estimand.
Least squares mean changes from baseline(DB) (+/- SE) will be presented graphically over time.
The fixed sequence testing procedure will be applied to control the familywise error rate (FWER) at 
two-sided 0.05 level accounting for multiplicity due to the primary and key secondary efficacy 
endpoints. The fixed sequence testing procedure will first test the primary endpoint at two-sided 0.05 
level. If the hypothesis corresponding to the primary endpoint is rejected, then the MADRS-WOSI 
will be tested at the same alpha level. If the hypothesis corresponding to the primary endpoint is not 
rejected, then the testing procedure will stop.
5.4.1.2.
PROMIS-SD
5.4.1.2.1.
Definition
The second key secondary endpoint is the change in PROMIS-SD T-score from baseline(DB) to Day 
43.
Developed under a National Institutes of Health (NIH) initiative, the Patient Reported Outcomes 
Measurement Information System captures self-reported, qualitative health aspects in the domains of 
physical, mental, and social health (Yu L 2011).
The PROMIS-SD (Short Form 8a) subscale consists of a static 8-item questionnaire. The PROMIS-
SD instruments assess self-reported perceptions of sleep quality, sleep depth, and restoration
associated with sleep. This includes perceived difficulties and concerns with getting to sleep or staying
asleep, as well as perceptions of the adequacy of and satisfaction with sleep. Sleep Disturbance does
not focus on symptoms of specific sleep disorders, nor does it provide subjective estimates of sleep 
quantities (total amount of sleep, time to fall asleep, amount of wakefulness during sleep). The Sleep 
Disturbance short form is universal rather than disease-specific. It assesses sleep disturbance over the
past 7 days.
Each question has five response options ranging in value from one to five. To find the total raw score
for a short form with all questions answered, sum the values of the response to each question. For the
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8-item form, the lowest possible raw score is 8; the highest possible raw score is 40. Lower scores 
indicate less sleep disturbance. The “direction” of the responses is not the same for all questions, i.e., 
sometimes a response of “not at all” indicates more sleep disturbance and sometimes a response of
“not at all” indicates less sleep disturbance.
“My sleep quality was” ranges from 5=very poor to 1=very good “My sleep was refreshing” ranges 
from 5=not at all to 1=very much
“I had a problem with my sleep” ranges from 1=not at all to 5=very much “I had difficulty falling 
asleep” ranges from 1=not at all to 5=very much “My sleep was restless” ranges from 1=not at all to 
5=very much
“I tried hard to get to sleep” ranges from 1=not at all to 5=very much
“I worried about not being able to fall asleep” ranges from 1=not at all to 5=very much “I was satisfied 
with my sleep” ranges from 5=not at all to 1=very much
A score can be approximated if a participant skips a question. Imputation of total score is presented 
in Section 5.1.3.
The total raw score or pro-rated raw score will be converted into a T-score for each participant based 
on the table in Appendix 6.8. The T-score rescales the raw score into a standardized score with a 
mean of 50 and an SD of 10.
5.4.1.2.2.
Estimand(s)
The same estimands as defined for the primary endpoint in Section 5.3 are defined for PROMIS- SD, 
with the variable being the following: Change in PROMIS-SD T-score from baseline to Day 43.
5.4.1.2.3.
Analysis Methods
Same analyses as for the estimands under the primary endpoint, and the corresponding sensitivity and
supplementaryanalyses will be implemented for change in PROMIS-SD T-score. The MMRM model 
will include baseline(DB) PROMIS-SD T-score as the covariate.
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time
point in the double-blind phase will be presented for PROMIS-SD raw score and the T-score by 
intervention group. Under the treatment policy strategy for Estimand 2, Estimand 2a and Estimand
2b, PROMIS-SD T-score data from participants who discontinued the add-on study drug only 
(intercurrent event 1 under these estimands), and from participants who discontinued both underlying 
antidepressant and add-on study drug (intercurrent event 2 under Estimand 2b) and provided 
additional follow-up data every 2 weeks until Day 43 will be included in the analyses corresponding 
to each estimand.
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Least squares mean changes from baseline(DB) (+/- SE) for T-score will be presented graphically over
time.
Similar to the first key secondary endpoint, a fixed sequence testing procedure will be applied to 
control the FWER at two-sided 0.05 level accounting for multiplicity due to the primary and key 
secondary efficacy endpoints. If the hypothesis corresponding to MADRS-WOSI is rejected, then the 
PROMIS-SD T-score key will be tested at the same alpha level of 2-sided 0.05. If the hypothesis 
corresponding to the MADRS-WOSI is not rejected, then the testing procedure will stop.
Additional analyses of the key secondary endpoint for assessing and mitigating the impact of COVID-
19 on study outcome are presented in Appendix 10.
5.4.2.
Other Secondary Endpoint(s)
The following analyses will be performed on the FAS1 and FAS2 populations.
5.4.2.1.
MADRS-6
5.4.2.1.1.
Definition
The 6-item MADRS is a clinician-administered scale designed to measure the core symptoms of 
depression severity and detects changes due to antidepressant intervention (Montgomery 1979). It is
a subset of MADRS (10-item). The MADRS scale is a validated, reliable scale and acceptable to 
regulatory health authorities as a primary scale to determine efficacy in major depression.
The MADRS-6 subscale score is the sum of scores for the following MADRS items: reported sadness, 
apparent sadness, inner tension, lassitude, inability to feel, and pessimistic thoughts.
Negative changes in MADRS-6 total score indicate improvement.
5.4.2.1.2.
Analysis
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point in the double-blind phase will be presented for MADRS-6 total score by intervention group.
The change from baseline(DB) in MADRS-6 total score at Day 43 will be analyzed using the same 
MMRM model as described for the primary endpoint with baseline(DB) MADRS-6 total scoreas the
covariate.
Least squares mean changes from baseline (+/- SE) will be presented graphically over time.
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5.4.2.2.
Response Based on MADRS Total Score
5.4.2.2.1.
Definition
A participant is defined as a responder at a given time point if the percent improvement from 
baseline(DB) in MADRS is ≥50% at that time point (i.e., percent change ≤-50%). Participants who 
do not meet such criterion will be considered as non-responders. Imputation of missing response 
status is presented in Section 5.1.3.
5.4.2.2.2.
Analysis
The number and percentage of participants who achieve a response will be summarized at each time
point during the double-blind phase byintervention group. The analysis will be performed on observed 
as well as imputed data (participants with missing values will be imputed as non- responders).
Response rates over time will be plotted.
The cumulative response rate, defined as the percentage of participants experiencing at least a given 
value of percent reduction from baseline(DB) to Day 43 in MADRS total score, will be presented 
graphically, for observed data.
5.4.2.3.
Patient Health Questionnaire - 9 Item (PHQ-9)
5.4.2.3.1.
Definition
The 9-item Patient Health Questionnaire - 9 Item (PHQ-9) scale scores each of the 9 symptom 
domains of the DSM-5 MDD criteria and it has been used both as a screening tool and a measure of 
response to intervention for depression. Each item is rated on a 4-point scale (0=not at all, 1=several 
days, 2=more than half the days, and 3=nearly every day). The participant’s item responses are 
summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of 
depressive symptoms. The recall period is 2  weeks.
Negative changes in PHQ-9 total score indicate improvement.
5.4.2.3.2.
Analysis
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time
point in the double-blind phase will be presented for PHQ-9 total score by intervention group.
The change from baseline(DB) in PHQ-9 total score at Day 43 will be analyzed using the same 
MMRM model as described for the primary endpoint with baseline(DB) PHQ-9 total score as the 
covariate.
Least squares mean changes from baseline (+/- SE) will be presented graphically over time.
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5.5.
Tertiary/Exploratory Endpoint(s) Analysis
Exploratoryanalyses will be performed for the endpoints described in the sections below for FAS1 and 
FAS2 analysis sets.
5.5.1.
Consensus Sleep Diary
5.5.1.1.
Definition
Subjective sleep parameters are measured by means of Consensus Sleep Diary (CSD).
The CSD (Carney 2012). is a prospective measure that involves daily completion within an hour of 
getting out of bed. The CSD includes: (1) time into bed, (2) time of sleep attempt, (3) time it took to 
fall asleep, (4) number of awakenings during the main sleep period, (5) total estimated duration of
awakenings, (6) time of final awakening, (7) rise time, (8) subjective report of sleep quality (very 
poor, poor, fair, good, very good), and (9) comment (e.g., comments such as “I had a cold last night”)
(this item is not collected in this study). Of these nine items, the first seven are used to derive estimates 
of other sleep indices. The following parameters will beanalyzed:
Consensus Sleep Diary – Sleep Indices
Self-reported sleep 
onset latency (sSOL)
Recorded time to fall asleep (item 3)
Subjective wake after 
sleep onset (sWASO)
Total duration of the nighttime awakenings (item 5)
Subjective total sleep 
time (sTST)
Time of final awakening (item 6) – time into bed (item 1) –
(sSOL + sWASO)
Subjective number of 
nighttime awakenings (s-
nNAW)
Number of awakenings during the sleep period (item 4)
Subjective (sQUAL)
Subjective report of quality of sleep (item 8)
5.5.1.2.
Analysis
As the CSD data will be collected for up to 7 days prior to each scheduled visit, the dataanalyzed will 
be the average of the data pertaining to each visit. The average of the ordinal data pertaining to 
sQUAL (0 = Very Poor to 4 = Very Good) will be rounded to the nearest integer.
Descriptive statistics of the average actual values and the change from average baseline(DB) to each
postbaseline time point in the double-blind phase will be presented by intervention group for sSOL, 
sTST, sWASO, s-nNAW, and sQUAL.
An ANCOVA model will be used to test the difference of change from average baseline(DB) at 
endpoint(DB) in the continuous endpoints (sSOL, sTST, sWASO, and s-nNAW) and sQUAL
between seltorexant and placebo. The model will include intervention, country, age group, and 
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baseline(DB) rumination level as factors, and the respective average baseline(DB) value as a 
covariate. Difference of least square means and 2-sided 95% CI will be presented.
5.5.2.
Remission Based on MADRS Total Score
5.5.2.1.
Definition
A participant is defined as a remitter at a given time point if the MADRS total score is [≤12] at 
that time point. Participants who do not meet such criterion will be considered as non-remitters. 
Imputation of missing remission status is presented in Section 5.1.3.
5.5.2.2.
Analysis
The number and percentage of participants who achieve remission will be summarized at each time 
point during the double-blind phase by intervention group. The analysis will be performed on
observed as well as imputed data (participants with missing values will be imputed as non- remitters).
Remission rates over time will be plotted.
5.5.3.
European Quality of Life (EuroQol) Group, 5 Dimension, 5-Level 
questionnaire (EQ-5D-5L)
5.5.3.1.
Definition
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily 
designed for self-completion by respondents. It is a descriptive system comprised of 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) (EuroQol Group. About EQ-5D.2014).
Participants select an answer for each of the 5 dimensions considering the response that best matches 
their health “today”. Individual scores from the 5 dimensions will be used to obtain a weighted health
status index as shown below: (i) Scores from each dimension will be combined to obtain a 5L profile
score: eg, a score of 1 for each dimension will give a 5L profile score of 11111. Dimension scores will 
be combined in the following order: Mobility, Self-Care, Usual Activities, Pain/Discomfort, 
Anxiety/Depression. (ii) The value set of the Health Status Index (HSI) for various values of 5L 
profile 
scores 
is 
published 
for 
Canada 
in 
the 
following 
website: 
https://www.ncbi.nlm.nih.gov/pubmed/26492214/. (iii) The Canadian value set will be used to get the 
HSI values for all the countries participating in the study.
A sum score, with a possible range of 0 to 100, is derived as follows: (sum of the scores from the 5 
dimensions minus 5) * 5. Negative changes in the sum score indicate improvement.
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5.5.3.2.
Analysis
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point in the double-blind phase will be presented by intervention group for weighted EQ-5D health 
status index, the EQ-VAS, and the sum score.
Individual dimension responses will also be summarized at each visit with frequency counts and 
percentage of participants by intervention group.
5.5.4.
Sheehan Disability Scale (SDS)
5.5.4.1.
Definition
The SDS, a patient-reported outcome measure, is a 5-item questionnaire which has been widely used 
and accepted for assessment of functional impairment and associated disability (Leon 1996). The first 
3 items assess disruption of (1) work/school work, (2) social life/leisure activities, and (3) family 
life/home  responsibilities using a 0-10 rating scale. The total score is the sum of the first 3 items,
ranging from 0 to 30. Higher scores indicate greater impairment. It also
has one item on days lost from school or work and one item on days when underproductive. Negative 
changes in SDS total score indicate improvement.
5.5.4.2.
Analysis
Descriptive statistics of the actual values and the change from baseline(DB) to endpoint (DB) time 
point will be presented for SDS total score by intervention group.
An ANCOVA model will be used to test the difference of change from baseline at endpoint(DB) in
SDS total score between seltorexant and placebo. The model will include intervention, country, age 
group, and baseline(DB) rumination level as factors, and baseline(DB) SDS total score value as a 
covariate. Difference of least square means and 2-sided 95% CI will be presented.
In addition, descriptive statistics of the actual values and the change from baseline, as well as a 
frequency distribution, will be presented by intervention group for each of the 5 SDS individual item 
scores at each time point. The percentage of participants who have not worked/studied at all during 
the past 7 days will be summarized at each time point during the double-blind phase by intervention 
group.
5.5.5.
Insomnia Severity Index (ISI) (Patient Version)
5.5.5.1.
Definition
The ISI is a 7-item questionnaire assessing the nature, severity, and impact of insomnia. The 
dimensions evaluated are: sleep onset, sleep maintenance, early morning awakening problems; sleep 
dissatisfaction; interference of sleep problem with daily functioning; noticeability of sleep problems 
by others; and distress caused by the sleep difficulties. A 5-point Likert scale (0-4) is used to rate 
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each item. The total score is the sum of the 7 item scores, ranging from 0 to 28. The total score is 
interpreted as follows: absence of insomnia (0-7); sub-threshold insomnia (8-14); moderate insomnia 
(15-21); and severe insomnia (22-28).
Negative changes in ISI total score indicate improvement.
5.5.5.2.
Analysis
Descriptive statistics of the patient-reported ISI total score and individual item scores at baseline(DB) 
and endpoint (DB), as well as the change from baseline to Endpoint (DB), will be presented by 
intervention group.
The change from baseline(DB) in ISI total score at endpoint (DB) will be analyzed using the same 
ANCOVA model as described for SDS total score (Section 5.5.4.2) with baseline(DB) ISI total score 
as the covariate. Difference of least square means and 2-sided 95% CI will be presented.
In addition, the shift in ISI score category from baseline to endpoint (DB) will be presented. A 
frequency distribution of the ISI individual item scores at baseline(DB) and endpoint(DB) will be 
provided by intervention group.
5.5.6.
Patient Global Impression of Severity (PGI-S) for Insomnia
5.5.6.1.
Definition
The PGI-S for sleep symptoms consists of 2 patient-reported items to capture the participant’s 
perceived severity of difficulty falling and staying asleep as well as the problem of not feeling rested
the next day. Both items have the recall period of the past 7 days. The 2 dimensions of PGI- S are 
measured on a 5-point scale: 1=no difficulty of falling asleep or staying asleep (for severity of 
difficulty falling and staying asleep), or I did not have this problem (for problem of not feeling rested 
the next day); 2=mild; 3=moderate; 4=severe; 5=very severe.
Negative changes in PGI-S dimension scores indicate improvement.
5.5.6.2.
Analysis
Descriptive statistics of the actual values and the change from baseline(DB) will be presented by 
intervention group at each postbaseline timepoint in the double-blind phase for observed case data for 
each dimension.
The change from baseline(DB) in PGI-S dimension score at each postbaseline timepoint will be 
analyzed using an MMRM model with baseline(DB) PGI-S dimension score as a covariate.
A frequency distribution of the PGI-S dimension scores over time will be provided by intervention 
group. The frequencies of PGI-S scores will be plotted at baseline(DB) and endpoint(DB) for the 2 
dimensions.
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5.5.7.
Patient Global Impression of Change (PGI-C) for Depression
5.5.7.1.
Definition
The PGI-C for depression is a single item that will capture the participant’s perceptions of 
improvement or deterioration in depression symptoms compared with when the participant started 
the study intervention. The change of measured on a 7-point scale: 1=much better; 2=somewhat 
better; 3=a little better; 4=about the same; 5=a little worse; 6=somewhat worse; 7=much worse.
Higher scores indicate deterioration of symptoms.
5.5.7.2.
Analysis
Descriptive statistics of the actual values at each postbaseline time point in the double-blind phase will 
be presented by intervention group for observed case data.
An ANOVA model will be used to test the difference in PGI-C score at each postbaseline time point 
in the double-blind phase between seltorexant and placebo. The model will include the PGI-C score 
as the dependent variable, intervention, country, age group, baseline(DB) rumination level asfactors.
A frequency distribution of the PGI-C over time will be provided by intervention group.
5.5.8.
Clinical Global Impression – Severity (CGI-S)
5.5.8.1.
Definition
The CGI-S (Depression) provides an overall clinician-determined summary measure of the severity 
of the participant's illness that takes into account all available information, including knowledge of 
the participant's history, psychosocial circumstances,  symptoms,  behavior,  and the impact of the 
symptoms on the participant’s ability to function (Guy 1976). The CGI-S evaluates the severity of 
psychopathology on a scale of 1 to 7. Considering total clinical experience with the depression 
population, a participant is assessed on severity of illness at the time of rating  according to: 0=not 
assessed; 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill;
5=markedly ill; 6=severelyill; 7=among the most extremelyill patients.
A score of 0 indicates that the participant was not assessed and will be treated as missing. The score 
will be summarized as recorded.
Negative changes in CGI-S score indicate improvement.
5.5.8.2.
Analysis
Descriptive statistics of the actual values and the change from baseline(DB) will be presented at each 
post-baseline timepoint in the double-blind phase by intervention group for observed case data.
The change from baseline(DB) in CGI-S score at each postbaseline timepoint will be analyzed using 
an MMRM model with baseline(DB) CGI-S score as a covariate.
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A frequency distribution of the CGI-S scores over time will be provided by intervention group. The 
frequencies of CGI-S scores will be plotted at baseline and endpoint(DB).
5.5.9.
Ruminative Response Scale (RRS)
5.5.9.1.
Definition
The RRS assesses rumination as the process of “compulsively focused attention on the symptoms of 
one’s distress, and on its possible causes and consequences, as opposed to its solutions” as established
by Nolen-Hoeksema in 1998. The 22 items of the RRS measure aspects of rumination, brooding and 
reflective pondering (Nolen-Hoeksema 2000). A 4-point Likert scale (1=almost never, 2=sometimes,
3=often, 4=almost always) is used to rate each item.
The RRS total score is the sum of the 22 item scores, ranging from 22 to 88. A higher total score 
indicates higher degree of rumination.
Negative changes in RRS total score indicate improvement.
5.5.9.2.
Analysis
Descriptive statistics of the actual values and the change from baseline(DB) to endpoint(DB) will be 
presented for RRS total score by intervention group.
The change from baseline(DB) in RRS total score at endpoint (DB) will be analyzed using the 
ANCOVA model with intervention, country, age group as factors and baseline(DB) RRS total score 
as a covariate. Difference of least square means and 2-sided 95% CI will be presented.
5.5.10.
Correlation between MADRS total score and PROMIS-SD T-score
Correlation between change in MADRS total score and change in PROMIS-SD T-score at Week 
6 will be explored; Pearson and Spearman correlation coefficients will be calculated. Scatter plot 
of change in scores of the 2 assessment scales at Week 6 will be presented for each intervention 
group.
5.5.11.
Subgroup Analyses
For the subgroups listed in Section 5.7.3, subgroup analyses using MMRM will be performed for the 
change in MADRS total score at Day 43. The fixed terms in the model will be intervention group, 
country, age group (adults, elderly), baseline (DB) RRS level (RRS total score <54, ≥54), time, 
subgroup, time-by-intervention interaction, intervention-by-subgroup interaction, and time- by-
intervention-by-subgroup interaction, and baseline(DB) MADRS total score as a covariate. Point
estimate of the treatment difference and 2-sided 95% CI will be estimated using appropriate contrasts. 
The terms in the model will be adjusted for the subgroups of region and age group II (18-34 years, 
35-54 years, 55-64 years, ≥ 65 years). Country will not be included in the model where the subgroup 
of interest is Region and age group will not be included where the subgroup of interest is Age group
II.
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The analysis results (difference of LS means and 95% CI) of the different subgroups will be displayed 
in a forest plot.
Similar analyses will be performed for the change in PROMIS-SD T-score and the results will be 
displayed in a forest plot. Sub-group analyses for the change in MADRS-WOSI total score may be 
performed if this assessment shows a meaningful difference from MADRS total score.
The analyses will be performed for the FAS1 and FAS2 analysis sets.
5.5.12.
Analysis of Efficacy data in the Follow-up Phases
Descriptive statistics of the actual values and the change from the baseline (DB) for the data collected 
in the follow-up phase will be presented for the following efficacy data:
MADRS total score, MADRS-WOSI score, MADRS-6 score, PROMIS-D raw and T-scores, 
individual domains of CSD, PGI-S (severity of difficulty falling and staying asleep, and problem of 
not feeling rested the next day), PGI-C, CGI-S.
The analyses will be performed for the follow-up analysis set for the follow-up phase.
5.6.
Safety Analyses
All safety analyses will be based on safetyanalysis set based on planned intervention, unless otherwise
specified.
For all continuous safety variables, descriptive statistics by intervention group will include the N, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by intervention group using frequency counts and percentages.
5.6.1.
Extent of Exposure
The number and percentage of participants who receive study intervention will be summarized
Descriptive statistics for duration of study intervention and of the background antidepressant 
intervention (N, mean, SD, median, and range (minimum, maximum)) will be summarized.
Duration of intervention will be summarized in the following duration categories: <=7 days, 8-14 
days, 15-21 days, 22-28 days, 29-35 days, 36-42 days, >42 days.
Study intervention duration is defined as (date of last dose of study intervention – date of first dose of
study intervention) +1. If the date of last dose of study intervention is missing, it will be imputed as the 
day prior to the double-blind disposition date for calculating exposure duration and compliance. Number
of doses is defined as the total number of dose administrations, which is the total number of days that 
study intervention was administered to the participant (excluding days off study intervention).
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Background antidepressant duration is defined as (minimum of end of double blind phase and end of 
antidepressant use – maximum of start of double blind phase and start of antidepressant use) +1.
The analysis will be performed on FAS1, FAS2 and safety analysis set.
5.6.1.1.
Intervention Compliance
Compliance will be summarized descriptively for each study intervention.
The percent compliance will be categorized and the number and percentage of participants in each 
category will be summarized by intervention group for study agent and for the background 
antidepressant.
Compliance will be calculated for the study intervention as:
Compliance (%) = (number of days when participant took the expected number of tablets)/(days 
expected to be dosed (includes days where the antidepressant was not taken) x 100)
Compliance will be calculated for the background antidepressant as:
Compliance (%) = (number of days actually dosed)/(days expected to be dosed (includes days where 
the antidepressant was not taken) x 100
The analysis will be performed on FAS1, FAS2 and safety analysis set.
5.6.2.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the initial 
administration of study intervention through the day of last dose plus 2 days is considered to be 
treatment emergent. AEs with onset date > date of last dose of double-blind study intervention plus 2 
days will be assigned to follow-up phase. If the event occurs on the day of the initial administration 
of study intervention (and action taken is not entered as ‘Not Applicable’ in the database), then the
event will be considered as treatment emergent. If the event date is recorded as partial or completely
missing, then the event will be considered to be treatment emergent unless it is known to be prior to 
the first administration of study intervention based on partial onset date or resolution date. All 
reported adverse events will be included in the analysis. For each adverse event, the number and
percentage of participants who experience at least 1 occurrence of the given event will be summarized 
by intervention group.
Summary tables will be provided for treatment-emergent adverse events:

AEs (all AEs, and AEs with incidence of at least 5% in any treatment group)

Serious AEs (SAEs)

AEs leading to discontinuation of study intervention
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
AEs by severity

AEs by relationship to study intervention

AEs of special interest (See Appendix 6.6 for list of adverse events in eachcategory) 
In addition to the summary tables, listings will be provided for participants who had:

SAEs

AEs leading to discontinuation of study intervention

AEs of special interest
A listing of participants who died will be provided.
5.6.3.
Additional Safety Assessments
5.6.3.1.
Clinical Laboratory Tests
Descriptive statistics will be presented for all chemistry, hematology, and urinalysis laboratory tests 
at scheduled time points in the double-blind phase.
Change from baseline(DB) to all post-baseline visits in the double-blind phase will be summarized for 
chemistry, hematology, and urinalysis tests and displayed by study intervention group.
Clinical laboratory test values will be considered “treatment-emergent markedly abnormal” (TEMA) 
using the criteria defined by the sponsor listed in Appendix 6.9.

If the postbaseline value is above the upper limit of the markedly abnormal criteria and the 
baseline(DB) value is equal to or below the upper limit, then the postbaseline marked 
abnormality will be considered TE. The same applies to the postbaseline value being below 
the lower limit of the markedly abnormal criteria with the baseline value being equal to or 
above the lower limit of the markedly abnormal criteria.

If the baseline(DB) value is missing, a postbaseline marked abnormality will always be 
considered as TE.
The number and percentage of participants with treatment-emergent markedly abnormal values in the 
double-blind phase will be presented by study intervention group.
The incidence of participants with treatment-emergent ALT values >3*upper normal limit (ULN) or 
AST value > 3*ULN will be presented for the double-blind phase. Additionally, incidence of 
treatment-emergent hepatic toxicity (suspected Hy’s Law [U.S. Department of Health and Human
Services 2009] cases) defined as (ALT values >3*ULN or AST values > 3*ULN) AND total bilirubin 
values >2*ULN will be presented for the double-blind phase. Similar to the markedly abnormal
analysis, only participants with baseline(DB) values that don’t meet criteria or if baseline value is 
missing will be eligible for these analyses.
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A listing of participants with markedly abnormal laboratory values will be provided. A listing of 
participants with ALT > 3* ULN or AST values > 3*ULN) and participants with hepatic toxicity 
(suspected Hy’s Law cases) will be provided.
In addition, the number of subjects with the following shifts in chemistry laboratory values from 
baseline(DB) to the maximum postbaseline time point will be presented for the double-blind phase:
Glucose:

from <100 mg/dL  to [≥100 mg/dL - <126 mg/dL] (normal to borderline)

from [≥100 mg/dL - <126 mg/dL] to ≥126 mg/dL (borderline tohigh)

from <100 mg/dL to ≥126 mg/dL (normal to high)
Triglycerides:

from <150 mg/dL to ≥200 mg/dL (normal to high/very high)

from <150 mg/dL to ≥500 mg/dL (normal to very high)

from [≥150 mg/dL - <200 mg/dL] to ≥200 mg/dL (borderline to high/veryhigh)

from [≥150 mg/dL - <200 mg/dL] to ≥500 mg/dL (borderline to very high)

from [≥200 mg/dL - <500 mg/dL] to ≥500 mg/dL (high to very high)
Total Cholesterol

from <200 mg/dL to ≥200 mg/dL (normal to borderline/high)

from <200 mg/dL to ≥240 mg/dL (normal to high)

from <200 mg/dL to [≥200 mg/dL - <240 mg/dL] (normal to borderline)

from [≥200 mg/dL - <240 mg/dL] to ≥240 mg/dL (borderline to high)
HDL Cholesterol

from ≥40 mg/dL to <40 mg/dL (normal tolow).
5.6.3.2.
Vital Signs and Physical Examination Findings
Continuous vital sign parameters including temperature, weight, pulse, blood pressure (systolic and 
diastolic), and Body Mass Index (BMI) will be summarized at each assessment time point. Body 
Mass Index will be calculated as weight (kg)/(height (m))2, at each time point that body weight is
measured. The height measurement collected at screening will be used in the calculation. Change from 
the baseline(DB) will be summarized. Descriptive statistics (mean, standard deviation, median, 
minimum and maximum) will be presented.
Abnormality criteria (based on criteria defined below) will be applied to postbaseline values in the 
double-blind phase.
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Postbaseline values will be considered treatment-emergent if they meet both value and change criteria 
in the table below.
For criteria that do not include an increase or decrease from baseline(DB) for the double-blind phase:

Treatment-emergent will be concluded if the postbaseline value is above the upper limit 
and the baseline(DB) value is below the upper limit (eg, Normal or Low). The same applies
to the postbaseline value being below the lower limit with the baseline value being above 
the lower limit (eg, Normal orHigh).

If the baseline(DB) value is missing, a postbaseline abnormality will always be considered
as TE.
Incidence of treatment-emergent clinically important vital signs during intervention, as defined in 
Table 4, will be summarized for participants who had a baseline(DB) assessment and at least 1 
postbaseline assessment for that vital sign. A listing of participants with treatment-emergent clinically 
important abnormalities in vital signs will be presented, along with a listing of all vital sign
measurements.
Table 4:
Clinically Important Abnormalities in Vital Signs
Vital Sign
Abnormal Category
Criteria
Pulse
Abnormally high
[≥100] bpm and with [≥15] bpm increase from baseline
Abnormally low
[≤50] bpm and with [≥15] bpm decrease from baseline
Systolic blood pressure
Abnormally high
[≥180] mm Hg and with [≥20] mm Hg increase from baseline
Abnormally low
[≤90] mm Hg and with [≥20] mm Hg decrease from baseline
Diastolic blood pressure
Abnormally high
[≥105] mm Hg and with [≥15] mm Hg increase from baseline
Abnormally low
[≤50] mm Hg and with [≥15] mm Hg decrease from baseline
Temperature
Abnormally high
[>37.5]oC
Abnormally low
[<35.5]oC
Weight
Abnormally high
increase [≥7%] from baseline
Abnormally low
decrease [≥7%] from baseline
5.6.3.3.
Electrocardiogram
The ECG parameters that will be analyzed are heart rate, PR interval, QRS interval, QT interval, and
corrected QT (QTc) interval using the following correction methods: Bazett’s formula (QTcB), 
Fridericia’s formula (QTcF).
Bazett’s formula: QTcB (msec) = QT (msec) / (RR (msec)/1000)1/2; if RR is missing, use QT (msec) 
* (HR(bpm)/60)1/2;
Fridericia’s formula: QTcF (msec) = QT (msec) / (RR (msec)/1000)1/3; if RR is missing, use QT 
(msec) * (HR(bpm)/60)1/3;
Baseline ECG is defined as the average of all ECG results collected up to and including the day of the 
first dose of studyintervention.
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The number and percentage of participants with QTc interval increases from average baseline to the 
maximum postbaseline value will be summarized at each time point for double-blind phase. Refer to 
the following Table 5 for summary categories.
Table 5:
Criteria for Abnormal QTc Values and Changes From Baseline
QTc value (msec)
Normal QTc
≤450 for male, ≤470 for female
>450 to ≤480 for male, >470 to ≤480 for female
>480 to ≤500
>500
Clinically significant QTc (msec)
No
≤500
Yes
>500
QTc change from baseline (msec)
No concern
≤30
Concern
>30-60
Clear concern
>60
Descriptive statistics of ECG parameters and change from average baseline will be summarized at 
each scheduled time point for double-blind phase.
Abnormality criteria (based on criteria defined in Table 6 below) will be applied to average baseline 
and postbaseline values.
Postbaseline abnormalities will be compared with their corresponding average baseline result:

Treatment-emergent will be concluded if the postbaseline value is above the upper limit and 
the average baseline value is below the upper limit (eg, Normal or Low). The same applies to 
the postbaseline value being below the lower limit with the average baseline value being above 
the lower limit (eg, Normal or High).

If the average baseline value is missing, a postbaseline abnormality will always be considered 
as treatment-emergent.
The number and percentage of participants with treatment-emergent ECG values outside 
predefined limits will be presented by study intervention over time for DB phase of the study:
Table 6:
Abnormal Limits for ECG Parameters
ECG Parameter
Outside of normal limit if ...
Abnormally low
Abnormally high
Heart Rate (bpm)
50 bpm
100 bpm
PR interval (msec)
120 msec
200 msec
QRS interval (msec)
60 msec
120 msec
QT interval (msec)
200 msec
500 msec
RR interval (msec)
600 msec
1200 msec
The interpretation of the ECGs as determined by a central reader will be displayed by the number and 
percentage of participants meeting the normality criteria. The interpretation will be summarized over 
time.
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A listing of clinically relevant ECG abnormalities will also be provided.
5.6.3.4.
Other Safety Parameters
5.6.3.4.1.
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed to assess severity and track suicidal events through any intervention (Posner 2007). It is a 
clinical interview providing a summary of both suicidal ideation and behavior that can be 
administered during any evaluation or risk assessment to identify the level and type of suicidality
present. The C-SSRS has been used frequently in clinical studies, and is a validated, standard measure 
for suicidal ideation assessment. Using the C-SSRS, the outcomes will be categorized using the 
scoring for the 11 categories:
Suicidal Ideation (1-5)
1
Wish to be dead
2
Non-specific active suicidal thoughts
3
Active suicidal ideation with any methods (not plan) without intent to act
4
Active suicidal ideation with some intent to act, without specific plan
5
Active suicidal ideation with specific plan and intent
Suicidal Behavior (6-10)
6
Preparatory acts or behavior
7
Aborted attempt
8
Interrupted attempt
9
Actual attempt
10
Suicide
Non-suicidal self-injurious behavior (11)
11
Non-suicidal self-injurious behavior
At each time point, an event of suicidal ideation or behavior will be assigned a score of 1 to 10 based 
on the maximum response for the C-SSRS at that visit. If no events qualify for a score of 1 to 10, a
score of 0 will be assigned (0=“no suicidal ideation or behavior that can be assessed on the basis of 
C-SSRS”). A participant with an event of non-suicidal self-injurious behavior only will not be 
considered as having suicidal ideation or behavior; therefore, a score of 0 will be assigned. However, 
an additional score of 11 will be assigned to summarize any participants with an event of non-suicidal 
self-injurious behavior.
Shifts from baseline(DB) to the maximum score pertaining to suicidal ideation or suicidal behavior 
(i.e., scores 1 to 10) will be summarized by intervention for DB phase.
The maximum score (of scores 0 to 10) assigned to each participant will be grouped into one of three 
broad categories: No suicidal ideation or behavior (0), Suicidal ideation (1-5), Suicidal behavior (6-
10). Shifts from baseline(DB) to the maximum category will be summarized by intervention for DB 
phase.
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A frequency distribution of the scores for the 11 categories (0 to 10) will be provided by study 
intervention at each time point for DB phase. In addition, the number and proportion of participants 
with non-suicidal self-injurious behavior (a score of 11) will be provided by study intervention at 
each time point for DB phase.
5.6.3.4.2.
Arizona Sexual Experiences Scale (ASEX)
The ASEX is a patient-reported 5-item rating scale that quantifies sex drive, arousal, vaginal 
lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. The scale has 
shown satisfactory reliability and validity (McGahuey 2000).
Each of the 5 items is rated on a 6-point Likert scale, ranging from 1 to 6. The total score is the sum 
of the 5 items. Higher scores indicate more sexual dysfunction. If any item of the scale is missing at 
a visit, the total score for that scale at that visit will be left blank.
For each of the 5 items, a frequency distribution will be provided by intervention group and gender at 
each time point. In addition, for each of the 5 items, a frequency distribution will be provided by 
intervention group, combining the responses for the genders. For this analysis, “vaginal 
lubrication/penile erection” (question 3) will be summarized as one question. The ASEX total score 
at each time point and the change from baseline(DB) will be summarized with descriptive statistics 
by intervention group.
The number and percentage of participants who have ASEX total score 19 or greater, or a score of 5 
or greater on any item, or a score of 4 or greater on any 3 items, reflecting sexual dysfunction, will 
be summarized at each time point by intervention group for double-blind phase.
5.6.3.4.3.
Physician Withdrawal Checklist (20 items; PWC-20)
The PWC-20 is a reliable and sensitive instrument for the assessment of discontinuation symptoms 
(Rickels 2008). The PWC-20 is a simple and accurate method used to assess potential withdrawal 
symptoms following cessation of studyintervention.
The proportion of participants with withdrawal symptoms at the end of DB phase and follow-up visits 
will be presented by intervention group.
In addition, symptoms at follow-up will be compared to endpoint (DB) and will be summarized using 
the following categories: new or worsened symptoms, symptoms present and unchanged, no 
symptoms, and improved.
Additionally, PWC-20 total score will be computed, and summary statistics of the total score at each 
visit will be provided.
Bar chart of the incidence of withdrawal symptoms (i.e, severity of mild or worse) over time for all 
20 items will be provided for each item.
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5.6.3.4.4.
Menstrual Cycle Tracking
Menstrual cycle in premenopausal women will be tracked during the double-blind and follow-up 
phases. Participants who are experiencing menses during the screening evaluation belonging to the 
safety analysis set will be included in the analysis.
Descriptive summary statistics (n, mean, SD, median, minimum, and maximum) of the duration of 
menses and the length of menstrual cycle will be provided for the duration of the double-blind phase. 
This analysis will be repeated for the following 2 sub-groups: women who use contraception, and 
those who don’t use contraception. Duration of menses in the follow-up phase will be summarized 
for the follow-up analysis set.
5.7.
Other Analyses
5.7.1.
Pharmacokinetics
PK analyses will be performed on the safety analysis set.
Descriptive statistics (N, mean, SD, median, range, CV (%) and IQ range) will be used to summarize
plasma concentrations at each sampling time point and for each PK parameter of Active Study
Intervention.
5.7.2.
Biomarkers
Analysis of biomarker data will be discussed in a separate SAP.
5.7.3.
Definition of Subgroups
Subgroup analyses of the primary and key secondary endpoints will be performed for the FAS1 
and FAS2 analysis sets for the following subgroups:
Subgroup
Definition
Sex
Male 
Female 
Other
Race
Asian 
Black 
White 
Other
Ethnicity
Hispanic  or  Latino 
Not Hispanic or Latino
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Country
Argentina 
Denmark 
Finland 
Korea 
Malaysia 
Poland 
Chile 
Ukraine 
USA
Slovakia
Region
European Union
North America 
Rest of World
Age Group
Adult (<65 years) 
Elderly (≥ 65 years)
Age Group II
18-34 years
35-54 years
55-64 years
≥ 65 years
Baseline BMI
underweight <18.5 kg/m2
normal 18.5-<25 kg/m2
overweight 25-<30 kg/m2 
obese ≥ 30 kg/m2
Number of major 
depressive episodes
< 3
≥ 3
Family history of 
psychiatric disorders
Yes 
No
Unknown
Number of failed prior 
antidepressants
1
2
3 or more
Current antidepressant type
SSRI 
SNRI
Prior use of 
benzodiazepines
Yes 
No
Baseline RRS per IWRS
<54
≥ 54
5.8.
Interim Analyses
One interim analysis of the primary endpoint is planned for this study. The aim of the IA is to 
make recommendations to continue the study, or stop the study for futility. Details about the 
analysis will be discussed in an IA SAP.
5.8.1.
Independent Data Monitoring Committee (IDMC)
An independent data monitoring committee will monitor the SAEs on a bi-monthly basis. 
Additionally, the IDMC will meet periodically to review safety data and meet once to evaluate the 
unblinded efficacy data at the IA and make recommendation on whether to declare futility. Details 
about the membership of the IDMC and its roles and responsibilities are discussed in a separate IDMC
charter.
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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
adverse event
AESI
adverse event(s) of special interest
ALT/SGPT
alanine aminotransferase
ANCOVA
analysis of covariance
ASEX
Arizona Sexual Maturity Scale
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic class
BMI
body mass index
C-SSRS
Columbia Suicide Severity Rating Scale
CGI-S
Clinical Global Impression-Severity
CI
confidence interval
CIR
copy increment from reference
CR
copy reference
CRF
case report form
CSD
consensus sleep diary
CV
coefficient of variation
DB
double-blind
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
electrocardiogram
EQ-5D-5L
European Quality of Life, 5-Dimension, 5-Level
EQ-VAS
European Quality of Life-Visual analog Scale
EU
European Union
FAS1
full analysis set 1
FAS2
full analysis set 2
FWER
familywise error rate
HSI
health status index
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IQ
interquartile
IS
insomnia symptoms
ISI
Insomnia Sleep Index
IWRS
interactive web response system
LS
least squares
MADRS
Montgomery-Asberg Depression Rating Scale
MADRS-WOSI
Montgomery-Asberg Depression Rating Scale-Without Sleep Item
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MDD
major depressive disorder
MDDIS
major depressive disorder with insomnia symptoms
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
MMRM
mixed model for repeated measures
MNAR
missing not at random
NIH
National Institutes of Health
PGI-C
Physician Global Impression-Change
PGI-S
Physician Global Impression-Severity
PHQ-9
Patient Health Questionnaire-9 Item
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PK
pharmacokinetic(s)
PWC-20
Physician Withdrawal Checklist-20
RRS
Ruminative Response Scale
s-nNAW
subjective number of nighttime awakenings
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCID-CT
Structured Clinical Interview for DSM-5-Clinical Trial Version
SD
standard deviation
SDS
Sheehan Disability Scale
SE
standard error
SNRI
selective norepinephrine reuptake inhibitors
sQUAL
subjective quality of sleep
SSRI
selective serotonin reuptake inhibitors
sSOL
subjective sleep onset latency
sTST
subjective total sleep time
sWASO
subjective wake after sleep onset
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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
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6.3.
Appendix 3 Demographics and Baseline Characteristics
The number of participants in each analysis set will be summarized and listed by intervention group 
and overall. In addition, the distribution of participants by region, country, and site ID will be 
presented unless otherwise noted.
Table 7 presents a list of the demographic variables that will be summarized by intervention group and 
overall for the FAS1 and FAS2 analysissets.
Table 7:
Demographic Variables
Continuous Variables
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables
Frequency distribution with the 
number and percentage of 
participants in each category.
Age Group (Adult [<65 years], Elderly [≥65 years])
Age Group II (18-34 years, 35-54 years, 55-64 years, and ≥65 years)
Sex (male, female, unknown, undifferentiated)
Racea (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Multiple, Not 
Reported)
Ethnicity (Hispanic or Latino, not Hispanic or Latino, Not Reported, 
Unknown)
BMI (underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, overweight 25-
<30 kg/m2, obese ≥30 kg/m2)
Country
Region
a
If multiple race categories are indicated, the Race is recorded as 'Multiple'
Table 8 presents a list of the baseline disease characteristics variables that will be summarized by 
intervention group and overall for the FAS1 and FAS2 analysis sets.
Table 8:
Baseline Disease Characteristics
Continuous Variables
Summary Type
Age (years) when diagnosed with MDD
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Duration (weeks) of current depressive episode
Baseline MADRS total score
Baseline CGI-S score
Baseline patient-rated ISI total score per eDC
Baseline clinician-rated ISI total score per eDC
Baseline RRS total score per eDC
Baseline HDRS-17 total score
Categorical Variables
Frequency distribution with the 
number and percentage of 
participants in each category.
Baseline CGI-S (Depression) score (Normal (not at all ill), Borderline 
mentally ill, Mildly ill, Moderately ill, Markedly ill, Severely ill, Among 
the most extremely ill patients)
Baseline RRS per IWRS (54, ≥54)
Baseline RRS per eDC (54, ≥54)
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Categorical Variables
Summary Type
Current antidepressant type (SSRI, SNRI)
Frequency distribution with the number 
and percentage of participants in each 
category.
Number of failed prior antidepressants (1, 2, 3 or more)
SCID-CT DSM-5 specifiers for MDD
Prior medication use of benzodiazepines
Number of major depressive episodes to date, including current episode (<3, ≥ 
Family history of alcohol abuse (Yes, No)
Family history of anxiety disorder (Yes, No)
Family history of bipolar disorder (Yes, No)
Family history of depression (Yes, No)
Family history of schizophrenia (Yes, No)
Family history of substance abuse (Yes, No)
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6.4.
Appendix 4 Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical study. 
Participants with major protocol deviations will be identified prior to database lock and the 
participants with major protocol deviations will be summarized by category for safety analysis sets.

Developed withdrawal criteria but not withdrawn

Entered but did not satisfycriteria

Received a disallowed concomitanttreatment

Received wrong treatment or incorrectdose

Other
Number of participants not meeting inclusion criteria, or meeting exclusion criteria will be 
summarized by study intervention group for the safety analysis set.
Additional analyses of protocol deviations for assessing and mitigating the impact of COVID-19 on 
study outcome are presented in Appendix 10.
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6.5.
Appendix 5 Prior and Concomitant Medications
Prior medications and concomitant medications will be coded using the World Health Organization 
Drug Dictionary (WHO-DD). Prior medications are defined as any therapy used before the day of 
first dose (partial or complete) of study intervention. Concomitant medications are defined as any 
therapy used on or after the same day as the first dose of study intervention, including those that 
started before and continue on after the first dose of study intervention.
Summaries of concomitant medications will be presented by ATC level 2 and level 4 terms and base
preferred term for the double-blind and follow-up phases for safety and follow-up analysis sets,
respectively. The proportion of participants who receive each concomitant medication will be 
summarized as well as the proportion of participants who receive at least 1 concomitant medication. 
Antidepressant medications taken during the double-blind phase will be summarized. In addition, 
concomitant medications of special interest will be summarized. See Appendix 7 Medications of 
Special Interest for list of categories of medications of special interest.
Prior antidepressant medications, prior medications other than antidepressants, and prior medications 
of special interest will be summarized by ATC level 2 and level 4 terms and base preferred term.
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6.6.
Appendix 6 Adverse Events of Special Interest
AE Special Interest 
Category
Event Type
Cataplexy
Cataplexy
Sleep paralysis
Sleep paralysis
Complex, sleep-related 
behaviors/parasomnias
Confusional arousal
Somnambulism
Sleep terror
Bruxism
Sleep sex
Sleep-related eating 
disorder
Rapid eye movement sleep 
behaviour disorder
Catathrenia
Fall
Fall
Motor vehicle accident
Road traffic accident
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6.7.
Appendix 7 Medications of Special Interest
Categories for medications of special interest are defined as follows:
Medications of Special Interest 
Category
Antidepressants
Benzodiazepines
Hypnotic/sedative including z-drugs
Antipsychotics
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6.8.
Appendix 8 Conversion of Raw Score to T-Score for PROMIS-SD
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6.9.
Appendix 9 Criteria for Treatment-emergent Markedly Abnormal Laboratory
Values
Laboratory Parameter
Unit
Low
High
Clinical Chemistry
Albumin
g/dL
2.4
6.0
Albumin
g/L
24
60
Alkaline phosphatase
U/L
N/A
250
Alanine transaminase (SGPT)
U/L
N/A
200
Aspartate transaminase (SGOT)
U/L
N/A
250
Bicarbonate
mEq/L
15.1
34.9
Bicarbonate
mmol/L
15.1
34.9
Bilirubin (direct)
mg/dL
N/A
3.0
Bilirubin (direct)
mol/L
N/A
51.3
Bilirubin (total)
mg/dL
N/A
3.0
Bilirubin (total)
mol/L
N/A
51.3
Blood urea nitrogen
mg/dL
N/A
50
Blood urea nitrogen
mmol/L
N/A
17.9
Calcium
mg/dL
6
12
Calcium
mmol/L
1.497
2.994
Chloride
mEq/L or mmol/L
94
112
Cholesterol
mg/dL
N/A
300
Cholesterol
mmol/L
N/A
7.758
Creatine kinase
U/L
N/A
990
Creatinine
mg/dL
N/A
3
Creatinine
mol/L
N/A
265.2
Gamma glutamyl transferase
U/L
N/A
300
Glucose Plasma
mg/dL
40
300
Glucose Plasma
mmol/L
2.204
16.653
Hemoglobin A1c
Fraction of 1
0.04
0.08
High-density lipoprotein cholesterol (HDL)
mg/dL
35
N/A
High-density lipoprotein cholesterol (HDL)
mmol/L
0.905
N/A
Low-density lipoprotein cholesterol (LDL)
mg/dL
89
160
Low-density lipoprotein cholesterol (LDL)
mmol/L
2.3015
4.1376
Phosphate
mg/dL
2.2
8.1
Phosphate
mmol/L
0.71038
2.61549
Potassium
mmol/L
3.0
5.8
Sodium
mEq/L
125
155
Sodium
mmol/L
125
155
Total protein
g/L
50
N/A
Triglycerides
mg/dL
N/A
500
Triglycerides
mmol/L
N/A
5.645
Uric acid
mg/dL
1.5
10
Uric acid
mol/L
89.22
594.8
Hematology
Hematocrit - female
%
0.28
0.50
- male
%
0.24
0.55
Hemoglobin
g/dL
8
19
Hemoglobin
g/L
80
190
Neutrophils
%
30
90
Monocytes
%
N/A
20
Eosinophils
%
N/A
10
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Basophils
%
N/A
6
Lymphocytes
%
10
60
Reticulocytes
%
0.5
1.5
Platelet count
109/L; giga/L
100
600
Red blood cell (RBC) count - female
1012/L; tera/L
3.0
5.5
- male
1012/L; tera/L
3.0
6.4
White blood cell (WBC) count
109/L; giga/L
2.5
15.0
Y
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Laboratory Parameter
Unit
Low
High
Urinalysis
Urine pH
N/A
6.5
Urine specific gravity
< 1.001
> 1.035
Note: Values should be flagged as markedly abnormally low if the value is less than the value indicated in the 
“Low” column. Likewise, values should be flagged as markedly abnormally high if the value is greater than the 
value indicated in the “High” column.
Note:  The same limits apply to both males and females unless gender is indicated.
N/A = Not applicable.
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6.10.
Appendix 10 Analyses for Assessing and Mitigating the Impact of COVID- 19 
on Study Outcome
The following measures will be taken to handle the impact of COVID-19 on study outcome:
1.
Listing and summary of treatment discontinuation and study discontinuation including 
reasons due to COVID-19 will be presented.
2.
Protocol deviation related to COVID-19 including missing visits and remote visits due    to 
COVID will be summarized; corresponding listing will be provided.
3.
Additional analyses to assess the potential impact of COVID-19 in the primary and key 
secondary endpoints.
a.
Mean summaries over time by types of collection (remote, home, site,etc).
b. Sensitivity analyses will be provided by including types of collection in the primary 
models for MADRS, MADRS-WOSI, and PROMIS-SD. If the number of non-site 
visits is small, then the sensitivity analysis may not be conducted as the results 
would not be expected to differ from the main analyses.
4.
Sensitivity analysis for Estimand 1: Additional tipping analysis will be performed for 
Estimand 1 where the delta adjustments will be applied to all missing data under 
hypothetical strategy including those caused by discontinuation reasons due to COVID-
19; delta adjustments will not be applied to missing data due to discontinuation reasons not 
related to study intervention including Lost to Follow-Up, Withdrawal by Subject or Other.
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7.
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