Conditions: Alzheimer Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 88
Healthy volunteers: no

Brief summary:
The purpose of this study is to investigate the effect of seltorexant versus placebo on the sum of Agitation and Aggression domain scores (A plus A) of the Neuropsychiatric Inventory-Clinician rating (NPI-C) in participants with probable Alzheimer's Disease (AD) with clinically significant agitation/aggression.

Detailed description:

Arms:
arm 1: Participants will receive single oral dose of seltorexant 20 milligrams (mg) tablet once daily from Day 1 to Day 42. arm 2: Participants will receive single oral dose of matching placebo tablet once daily from Day 1 to Day 42.

Interventions: intervention 1: Seltorexant intervention 2: Placebo
Intervention descriptions: intervention 1: Seltorexant 20 mg will be administered orally as a tablet. intervention 2: Matching placebo will be administered orally as a tablet.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 8 April 2023
Janssen Research & Development *
Clinical Protocol
A Multicenter, Randomized, Placebo-Controlled, Double-Blind Study to Investigate the
Safety, Tolerability, and Clinical Efficacy of Seltorexant (JNJ-42847922) on Behavioral
and Psychological Symptoms of Dementia in Patients with Probable Alzheimer’s Disease.
Protocol 42847922ALZ2001; Phase 2a
Amendment 1
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).
Pre-IND:  157146
Status: 
Approved
Date: 
8 April 2023
Prepared by: Janssen Research & Development, LLC
EDMS number: 
EDMS-RIM-436692, 3.0
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.
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Clinical Protocol 42847922ALZ2001 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 8 April 2023
DOCUMENT HISTORY
Document 
Country/Territory Affected  
Date
Amendment 1 
United States 
8 April 2023
Original Protocol 
United States 
8 December 2021
Amendment 1 (8 April 2023)
Overall Rationale for the Amendment: To make cognitive impairment severity requirement more
consistent between MMSE and CDR global score, and to correct errors and improve clarity of the protocol.
The changes made to the clinical protocol 42847922ALZ2001 as part of Protocol Amendment 1 are listed
below, including the rationale of each change and a list of all applicable sections.
Section Number 
and Name
Description of Change 
Brief Rationale
Sections 1.1 Synopsis 
Section 4.1 Overall Design  
Section 5.1 Inclusion 
Criteria 
CDR global score modified from CDR of ≥ 2 
(moderate to severe impairment) to CDR of ≥ 1 
(mild, moderate to severe impairment) 
Modified to align with the
required cognitive
impairment defined by the
MMSE scale range (10-24,
mild, moderate to severe)
Section 5.2 
Exclusion Criteria 
Exclusion criterion #28 deleted 
Deleted because it is a
duplication of the same
exclusion criterion #20
Section 5.2 
Exclusion Criteria 
Revised Exclusion criterion #10. 
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 stable, and if on glucose-lowering 
therapy (eg diet, lifestyle or medication),
remaining on a stable regimen for at least 2
months prior to screening.
Clarified Exclusion Criterion
#10 requirements for
glucose-lowering treatment
of diabetes; in alignment with
the protocol clarification note
of December 09, 2022.
Section 6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Note added: ‘Assisted living’ refers to 
participants living in a staffed facility vs. 
‘Community-dwelling’ refers to participants not 
living in a staffed facility (whether or not
needing assistance with activities of daily living)
Clarification in alignment
with the protocol clarification
note of December 09, 2022.
Section 1.1 Synopsis 
Section 9.4.3 Statistical
analysis, Safety analysis
Mentions of waist circumference removed 
Waist circumference is not
to be collected (not
applicable for this study); in
alignment with the protocol
clarification note of
December 09, 2022.
Section 10.2 Appendix 2 
Routine Urinalysis refers to Dipstick  
Urinalysis samples are to be
sent to the central lab for
analysis and are not tested on
site by dipstick; in alignment
with the protocol clarification
note of December 09, 2022.
Section 8.3.1 
Clinical Dementia Rating 
Clarified how CDR global score will be used and 
calculated in the study.
Clarification
Section 10.10 
Provided information on the protocol amendment 
history
Editorial change
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TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................................... 3
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
1. 
PROTOCOL SUMMARY..................................................................................................................... 7
1.1. 
Synopsis........................................................................................................................................... 7
1.2. 
Schema.......................................................................................................................................... 14
1.3. 
Schedule of Activities (SoA)........................................................................................................... 15
2. 
INTRODUCTION................................................................................................................................ 21
2.1. 
Study Rationale.............................................................................................................................. 22
2.2. 
Background.................................................................................................................................... 24
2.3. 
Benefit-Risk Assessment............................................................................................................... 25
3. 
OBJECTIVES AND ENDPOINTS..................................................................................................... 26
4. 
STUDY DESIGN ................................................................................................................................ 29
4.1. 
Overall Design................................................................................................................................ 29
4.2. 
Scientific Rationale for Study Design............................................................................................. 33
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 34
4.3. 
Justification for Dose...................................................................................................................... 35
4.4. 
End of the Study Definition ............................................................................................................ 35
5. 
STUDY POPULATION ...................................................................................................................... 36
5.1. 
Inclusion Criteria............................................................................................................................ 36
5.2. 
Exclusion Criteria........................................................................................................................... 38
5.3. 
Lifestyle Considerations................................................................................................................. 42
5.4. 
Screen Failures.............................................................................................................................. 43
5.5. 
Study Partner/Legal Representative.............................................................................................. 43
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 44
6.1. 
Study Intervention(s) Administered................................................................................................ 44
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 46
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 46
6.4. 
Study Intervention Compliance...................................................................................................... 47
6.5. 
Dose Modification........................................................................................................................... 48
6.6. 
Continued Access to Study Intervention After the End of the Study ............................................. 48
6.7. 
Treatment of Overdose .................................................................................................................. 48
6.8. 
Prior and Concomitant Therapy..................................................................................................... 48
6.8.1. 
Prohibited Medications ............................................................................................................... 49
6.8.2. 
Rescue Medication ..................................................................................................................... 51
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 52
7.1. 
Discontinuation of Study Intervention ............................................................................................ 52
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 52
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 53
7.3. 
Lost to Follow-up............................................................................................................................ 54
8. 
STUDY ASSESSMENTS AND PROCEDURES............................................................................... 54
8.1. 
Efficacy Assessments .................................................................................................................... 56
8.1.1. 
Neuropsychiatric Inventory (NPI-12)........................................................................................... 56
8.1.2. 
Neuropsychiatric Inventory clinician version (NPI-C) ................................................................. 56
8.1.3. 
Sleep Disorder Inventory (SDI)................................................................................................... 57
8.1.4. 
Cohen-Mansfield Agitation Inventory — Community version (CMAI-C)..................................... 57
8.1.5. 
Geriatric Depression Scale, informant version (GDSI)............................................................... 57
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8.2. 
Safety Assessments....................................................................................................................... 57
8.2.1. 
Physical Examination.................................................................................................................. 58
8.2.2. 
Neurological Examination........................................................................................................... 58
8.2.3. 
Vital Signs................................................................................................................................... 58
8.2.4. 
Electrocardiograms..................................................................................................................... 58
8.2.5. 
Clinical Safety Laboratory Assessments .................................................................................... 59
8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring ......................................................................... 59
8.2.7. 
Physician Withdrawal Checklist (PWC)...................................................................................... 59
8.3. 
Other Assessments and Procedures ............................................................................................. 59
8.3.1. 
Clinical Dementia Rating (CDR)................................................................................................. 59
8.3.2. 
Hachinski Ischemic Scale (HIS) ................................................................................................. 60
8.3.3. 
Alzheimer’s Disease Assessment Scale Cognitive subscale 14-item version (ADAS-
Cog-14)....................................................................................................................................... 60
8.3.4. 
Mini-Mental State Examination (MMSE)..................................................................................... 60
8.3.5. 
Brief Psychosocial Therapy (BPST)........................................................................................... 60
8.3.6. 
Objective Sleep and Physical Activity Parameters (Actigraphy) ................................................ 61
8.3.7. 
Off-body touchless sensors ........................................................................................................ 62
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 63
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 63
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 64
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 64
8.4.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 64
8.4.5. 
Pregnancy................................................................................................................................... 64
8.4.6. 
Adverse Events of Special Interest............................................................................................. 65
8.5. 
Pharmacokinetics........................................................................................................................... 65
8.5.1. 
Evaluations ................................................................................................................................. 65
8.5.2. 
Analytical Procedures................................................................................................................. 66
8.5.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 66
8.6. 
Genetic and Pharmacogenomic Evaluations................................................................................. 66
8.7. 
Biomarkers..................................................................................................................................... 67
8.8. 
Immunogenicity Assessments ....................................................................................................... 67
8.9. 
Health Economics .......................................................................................................................... 67
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 67
9.1. 
Statistical Hypotheses.................................................................................................................... 67
9.2. 
Sample Size Determination ........................................................................................................... 67
9.3. 
Populations for Analysis Sets ........................................................................................................ 68
9.4. 
Statistical Analyses ........................................................................................................................ 68
9.4.1. 
Primary Endpoint(s).................................................................................................................... 68
9.4.2. 
Secondary and Tertiary/Exploratory Endpoint(s) ....................................................................... 69
9.4.3. 
Safety Analyses.......................................................................................................................... 69
9.4.4. 
Other Analyses ........................................................................................................................... 71
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS............................ 73
10.1. 
Appendix 1: Abbreviations and Definitions .................................................................................... 73
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 75
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 77
10.3.1. 
Regulatory and Ethical Considerations ...................................................................................... 77
10.3.2. 
Financial Disclosure.................................................................................................................... 80
10.3.3. 
Informed Consent Process ......................................................................................................... 81
10.3.4. 
Long-Term Retention of Samples for Additional Future Research ............................................ 82
10.3.5. 
Publication Policy/Dissemination of Clinical Study Data............................................................ 82
10.3.6. 
Data Quality Assurance.............................................................................................................. 84
10.3.7. 
Case Report Form Completion................................................................................................... 84
10.3.8. 
Source Documents ..................................................................................................................... 85
10.3.9. 
Monitoring ................................................................................................................................... 86
10.3.10. On-Site Audits............................................................................................................................. 86
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10.3.11. Record Retention........................................................................................................................ 87
10.3.12. Study and Site Start and Closure ............................................................................................... 87
10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting................................................................................................................................. 89
10.4.1. 
Adverse Event Definitions and Classifications ........................................................................... 89
10.4.2. 
Attribution Definitions.................................................................................................................. 90
10.4.3. 
Severity Criteria.......................................................................................................................... 90
10.4.4. 
Special Reporting Situations ...................................................................................................... 90
10.4.5. 
Procedures ................................................................................................................................. 91
10.4.6. 
Product Quality Complaint Handling........................................................................................... 92
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality............................................. 93
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ......................................................................... 94
10.6. 
Appendix 6: International Psychogeriatric Association (IPA) consensus clinical and
research definition of agitation in cognitive disorders.................................................................... 97
10.7. 
Appendix 7: 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................................. 98
10.8. 
Appendix 8: Benzodiazepine Equivalence Table......................................................................... 100
10.9. 
Appendix 9: Changes in Study-Related Procedures as a Result of the COVID-19
Pandemic ..................................................................................................................................... 102
10.10. Appendix 10: Protocol Amendment History................................................................................. 106
11. REFERENCES................................................................................................................................. 107
INVESTIGATOR AGREEMENT............................................................................................................... 110
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LIST OF IN-TEXT TABLES AND FIGURES
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 14
Figure 2: Schematic of the Machine Learning Platform........................................................................... 63
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Status: Approved,  Date: 8 April 2023
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Multicenter, Randomized, Placebo-Controlled, Double-Blind Study to Investigate the Safety,
Tolerability, and Clinical Efficacy of Seltorexant (JNJ-42847922) on Behavioral and Psychological
Symptoms of Dementia in Patients with Probable Alzheimer’s Disease.
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), and for the treatment of Behavioral and Psychological Symptoms of Dementia
(BPSD). The clinical program for the latter indication is the focus of this Phase 2 study protocol.
In this study, participants with probable Alzheimer’s disease (AD) with clinically significant
agitation/aggression will be included. The effect of seltorexant on other behavioral and psychological
symptoms of dementia (BPSD) such as sleep disturbances, depression/dysphoria, hallucinations, and
delusions will also be studied.
Preclinical evidence supports a role for the orexin system in modulating stress-responsiveness and arousal.
In addition to a hypothesized role in modulating arousal, the sleep-enhancing effects of a selective OX2R
antagonist, such as seltorexant, are expected to confer benefit in mood disorders and neurodegenerative
diseases. Further, orexin 2 antagonists have shown to promote anti-aggressive behavior in animal models.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To investigate the effect of seltorexant versus placebo 
on the sum of agitation and aggression domain scores 
(A+A) of the Neuropsychiatric Inventory-Clinician
rating (NPI-C) in participants with probable AD with
clinically significant agitation/aggression.
 
Change from baseline to Day 43 on
NPI-C A+A scores.
Secondary –Efficacy
To investigate the effect of seltorexant versus placebo on the following in participants with probable
AD with clinically significant agitation/aggression:
 
Cohen-Mansfield Agitation Inventory community 
version (CMAI-C) total score 
 
Change from baseline to Day 43 on
the total CMAI-C score.
 
Sleep symptoms as assessed by the Sleep Disorder 
Inventory (SDI). 
 
Change from baseline to Day 43 on
SDI total score.
Secondary –Pharmacokinetics
 
To investigate the plasma pharmacokinetics (PK) of 
seltorexant and its M12 metabolite in participants with 
probable 
AD 
with 
clinically 
significant 
agitation/aggression.
 
Plasma concentrations of seltorexant
and its M12 metabolite at Day 15 and
Day 43.
Exploratory –Digital
To investigate the effect of seltorexant versus placebo on the following in participants with probable
AD with clinically significant agitation/aggression:
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Status: Approved,  Date: 8 April 2023
Objectives 
Endpoints
 
Sleep and activity metrics using an actigraphy device.  
Change from baseline on sleep and
activity metrics.
 
Sleep and mobility using an off-body touchless sensor 
in a subset of participants (if feasible and available) 
 
Change from baseline on sleep and
mobility measurements
Exploratory –Biomarkers
 
To investigate the effect of seltorexant versus placebo 
in participants with probable AD with clinically 
significant agitation/aggression on blood biomarkers
including but not limited to:
o biomarkers of AD, eg, p217+tau, Aβ1-42/40
levels and ratio, NfL, and other exploratory
biomarkers
 
Change from baseline in levels of
blood biomarkers of AD
Other Exploratory
To investigate the effect of seltorexant versus placebo on the following in participants with probable AD
with clinically significant agitation/aggression:
 
Variables derived from the NPI-12/NPI-C rating:
o The sum of the NPI-C delusion and
hallucination domain scores (NPI-C D+H)
o Individual NPI-C domain scores for
agitation, aggression, dysphoria, delusions,
and hallucinations
o NPI-12 total score
o NPI-12 Caregiver Distress total score
o All NPI-12 individual item scores
 
Change from baseline over time on
the 
specified 
NPI-12/NPI-C
variables.
 
SDI Caregiver Distress score 
 
Change from baseline over time in
SDI caregiver distress
 
Short-term rebound effects on BPSD  as well as 
withdrawal symptoms 
 
Change in Physician Withdrawal
Checklist (PWC-20)from End of DB
Treatment/EW  to first follow up
visit.
 
Change in NPI-12, NPI-C and SDI
scores 
from 
End 
of 
DB
Treatment/EW  to first follow up
visit.
 
CMAI-C factor scores 
 
Change from baseline over time on
CMAI-C factor scores.
 
Depressive symptoms as assessed by the Geriatric 
Depression Scale, Informant version (GDSI). 
 
Change from baseline on GDSI total
score at Day 43.
 
The 
association 
between 
treatment 
effect 
ofseltorexant in sleep and treatment effect in
agitation/aggression
 
Correlation between change in NPI-
C A+A and change in SDI total score,
and mediation effect on change in
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Objectives 
Endpoints
NPI-C A+A through change in SDI
total score
 
Cognitive symptoms 
 
Change from baseline to Day 43 on
Alzheimer’s Disease Assessment
Scale Cognitive subscale 14-item
version (ADAS-Cog-14) composite
cognitive score and from screening to
Day 43 on the Mini-Mental State
Examination (MMSE) total score.
Safety
To investigate the effect of seltorexant versus placebo on the following in participants with probable
AD with clinically significant agitation/aggression:
 
Safety and tolerability of seltorexant 
 
Change from baseline in vital signs,
Clinical 
Labs 
(chemistry,
hematology, 
urinalysis), 
ECG,
C-SSRS, and Treatment Emergent
Adverse Events (TEAEs) including
AEs of special interest (AESI).
HYPOTHESIS
The hypothesis for this study is that seltorexant 20 mg is superior to placebo in reducing aggression and
agitation as measured by change in NPI-C A+A scores from baseline to Day 43 in participants with probable
AD and clinically significant agitation/aggression.
OVERALL DESIGN
This multi-center randomized, placebo-controlled, double-blind study to investigate seltorexant safety,
tolerability, and clinical efficacy will be the first study with seltorexant in patients with probable AD and
clinically significant agitation/aggression. The primary aim of the study will be to explore seltorexant
clinical efficacy on behavioral and psychological symptoms (eg, agitation, depression/dysphoria, sleep
disturbances, etc.) while also studying the safety and tolerability of seltorexant in patients with probable
AD.
The study will consist of 3 phases: a screening phase (up to 28 days), a DB treatment phase (43 days), and
a post-treatment follow-up phase (14 days after DB treatment phase).
The study population will include participants of 55 to 85 years old who meet Diagnostic and Statistical
Manual of Mental Disorders-5th Edition (DSM-5) criteria for probable AD, and criteria of a syndrome
diagnosis of agitation based on International Psychogeriatric Association (IPA) consensus clinical and
research definition of agitation in cognitive disorders (see Appendix 6), have an MMSE total score from 10
to 24 (inclusive), and a Clinical Dementia Rating (CDR) global score of ≥1. Additionally, patients will be
characterized by the presence of clinically significant agitation/aggression defined by  NPI-12
agitation/aggression (A/A) domain score ≥ 4 with NPI frequency score ≥ 2 at entry and baseline with no
more than 35% of improvement allowed in NPI-12 A/A score during the screening period. NPI-12 will be
used to enrich the study population for sleep problems (targeting for approximately 50% or more of the
participants who should meet baseline NPI-12 sleep domain score of ≥4).
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Each participant in the study will have a designated study partner who will be available to meet with study
staff at each visit. A study partner can be a relative, friend or caretaker indicated by the participant (or legal
representative), who is at least 18 years old, who may or may not live with the participant, who has at least
8 hours of contact with the participant each week (eg, 4 days a week for at least 2 hours per day), and who
is available for contact with the study site staff at each visit.
At the start of the DB treatment phase, participants will be randomly assigned to receive placebo or
seltorexant 20 mg in a 1:1 ratio for 6weeks.
After the last dose of study treatment, all participants should have the End of DB Treatment/EW visit
(Visit 6 in the SoA), preferably the day after the last dose. After completion of this visit, the participant
enters the follow-up phase with a Follow-up visit (Visit 7 in the SoA). All participants who discontinue
study drug in the DB treatment phase will have an Early Withdrawal visit (Visit 6in the SoA) and a Follow-
up visit (Visit 7 in the SoA). Participants who discontinue study drug prior to Day 35 are encouraged to
continue with additional follow-up visits every 2 weeks per the SoA until Day 57 (up to four Early
Withdrawal Follow-up visits will be possible). At least one Early Withdrawal Follow-up visit needs to be
conducted 2 weeks apart from the Early Withdrawal visit (EW Follow-up 1, which will include the
assessments of Visit 7 in the SoA). Please refer to the SoA for additional details.
NUMBER OF PARTICIPANTS
This study will enroll approximately 86participants.
INTERVENTION GROUPS AND DURATION
The assigned study drug (seltorexant or placebo) will be taken by the participant at their residence, often
with the help of a study partner, 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. Each participant in the study will have a designated study partner (a relative,
friend or caretaker indicated by the participant (or legal representative)).
Description of Interventions
Seltorexant 20 mg 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
Clinical efficacy assessments will include assessing effects on BPSD (ie, agitation, aggression, psychosis,
depression/dysphoria, and sleep disturbances). The efficacy of study drug will be evaluated using the
NPI-12, NPI-C, SDI, GDSI, and CMAI-C.
The primary efficacy endpoint is change from baseline on NPI-C A+A scores at Day 43. NPI-C is a clinician
administered instrument that was designed to assess the presence of neuropsychiatric symptoms (NPS)
across many domains, as a standalone measure for specific NPS domains (eg, dysphoria, agitation), or a
combination of both (presence of NPS across domains plus particular focus on one or more specific
domains). In this study, the sum of NPI-C agitation and aggression (A+A) domain scores is the primary
focus of interest.
Change from baseline on CMAI--C total score at Day 43 and endpoints for sleep as assessed by the SDI
are secondary objectives of the study. CMAI-C measures the ability of a drug to reduce overall frequency
of agitation symptoms, including aggressive behaviors. SDI is an expanded version of one item of the
NPI-12, which describes the frequency, severity, and caregiver burden of sleep-disturbed behaviors.
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Other efficacy endpoints include changes from baseline on the specified NPI-12 and NPI-C variables at
Day 43. The NPI-12 is a measure of psychobehavioral disturbances, assessing the frequency and severity
of disturbances in 12 domains, based on a caregiver interview. For each domain, there is also an assessment
of caregiver distress. The study will explore the effect ofseltorexant on other symptoms of BPSD beyond
NPI-C A+A scores including depression/ dysphoria, and hallucinations and delusions. GDSI will also be
used to measure depression.
PHARMACOKINETIC EVALUATIONS
Sparse blood samples will be collected for measurement of plasma concentrations of seltorexant and its
M12 metabolite as per the SoA.
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
Exploratory biomarker assessments will include blood-based biomarkers of AD (including but not limited
to p217+tau, Aβ42/40 levels and ratio, neurofilament light chain (NfL)) and other potential exploratory
biomarkers.
OTHER EVALUATIONS/DIGITAL
Other exploratory endpoints include actigraphy to measure sleep and movement, and off-body touchless
sensors to measure sleep and mobility in a subset of participants.
GENETIC AND PHARMAGENOMIC (DNA) EVALUATIONS
A pharmacogenomic blood sample will be collected from participants who consent separately to this
component of the study to allow (where local regulations permit) for potential identification of factors that
may influence the PK (CYP2C9 and CYP3A4 genotyping), and to allow for apolipoprotein E genotyping.
DNA samples may also be analyzed for pharmacogenomic research, as necessary. Participation in the
genetic and pharmacogenomic research is optional.
SAFETY EVALUATIONS
Safety evaluations will include collection of AEs including AESIs and concomitant medications, as well as
assessment with physical examination, neurological examination, body weight and height, 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). Additional drug and alcohol tests may be conducted as needed per the
investigator’s judgment.
In addition, the emergence of suicidal ideation will be assessed using the Columbia Suicide Severity Rating
Scale (C-SSRS). PWC-20 will also be used to assess potential withdrawal effects.
COGNITION
Change in cognition will be assessed by the MMSE and ADAS-Cog-14.
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STATISTICAL METHODS
Sample Size Calculation
Assuming a treatment difference of 5 points in change from baseline in NPI-C A+A score between
seltorexant 20 mg and placebo, a standard deviation of 10 (effect size of 0.5), 15% drop-out rate during the
6-week double-blind phase, 86participants (randomized in 1:1 ratio to placebo and seltorexant 20 mg) will
need to be enrolled in the double-blind phase, in order to achieve 80% power to detect treatment difference,
at one-sided 0.1 significance level.
Efficacy Analyses
Efficacy analyses will be based on the full analysis set, which is defined as all participants who were
randomly assigned to study intervention and received at least 1 dose of study intervention. For all efficacy
endpoints, descriptive statistics of the actual values and the change from baseline to each postbaseline time
point in the double-blind phase will be presented by intervention group.
The primary efficacy endpoint is the change in NPI-C A+A score from baseline to Day 43.
The primary estimand for the primary efficacy endpoint contains the following components:
Study Intervention:
 
Experimental: seltorexant
 
Control: placebo
Population: participants with probable AD with clinically significant agitation/aggression, as reflected by
the inclusion/exclusion criteria.
Variable: change in NPI-C A+A from baseline to Day 43.
Summary measure: difference in treatment means between placebo and 20 mg.
Intercurrent events and corresponding strategies:
 
Treatment discontinuation of study drug (Hypothetical strategy: as if the intercurrent event had not
occurred)
 
Switch of treatment (Hypothetical strategy: see above)
 
Allowed rescue medication (Treatment policy strategy: all observed values of the endpoint are used
regardless of whether or not the participant had experienced this intercurrent event)
Main Analysis Under Primary Estimand: The comparison between seltorexant 20 mg and placebo will be
performed using the appropriate contrasts in a mixed model repeated measures (MMRM) with main
comparison at Day 43. The MMRM will include stratification factors (country [if applicable], baseline NPI-
12 sleep domain score [<4, ≥4], and community dwelling/assisted living), time, intervention group (placebo
and seltorexant 20 mg), and time-by-intervention interaction as factors, and baseline NPI-C A+A as a
covariate. Difference in least square means and 2-sided 80% CI will be presented.
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, has an AESI, or has 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.
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Safety Analyses
Safety analyses will be based on the safety analysis set, which consists of all participants who were
randomly assigned to study intervention and received at least 1 dose of study intervention.
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 and
AESI will be summarized separately.
Laboratory data will be summarized by type of laboratory test and intervention group. 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), and temperature for observed
values will be provided and changes from baseline will be summarized at each scheduled time point by
intervention group. The percentage of participants with values beyond clinically important limits will be
summarized. 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
C-SSRS will be tabulated by intervention group. For PWC-20, frequency for individual item score and
mean summaries for a total score (based on 8 items) will be provided by intervention group.
Cognition
Descriptive statistics of observed values and change from baseline over time will be provided for
ADAS-Cog-14 and MMSE by intervention group.
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1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
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d. 
If possible, participants should be fasted (ie, no food or beverages [except water]) for at least 8 hours before blood is drawn for clinical chemistry, insulin,
hemoglobin A1c [HbA1c], and hematology.
e. 
Participants and study partners will receive brief psychosocial therapy (BPST) during screening. A number ofsessions will be scheduled during the screening
period and should be completed at Visit 2 (baseline).
f. 
For the remote contact at Visit 3 (Day 8), approximately 7 days after Visit 2, participants and their study partners will be contacted remotely (ie, by telephone or
videoconference) and queried for AEs, overall seltorexant dosing compliance and tolerance, any changes in concomitant therapies, and medication diary
completion.
g. 
Eligible participants who successfully complete Visit 2 will be randomized and receive the study medication to take home until the next visit ofthe double-blind
treatment period, including instructions and a medication diary.
h. 
Participants will wear the actigraphy device continuously throughout the study upon receipt. At Visit 6, participants and study partners will return the actigraphy
device.
i. 
Visits 5 (Day 29) and 7 (Day 57)may be done remotely (eg, tele- or videoconference; optional) or at the research site. It is preferred that Visit 5 (Day 29) is done
on-site; if done remotely, the NPI-C should be conducted by videoconference if possible (with audio-recording)
j. 
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 and last meal time
on the day before each PK sample collection will be accurately recorded by exact dosing date and time and last meal date and time by the participant and/or study
partner in the participant medication 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.
k. 
Participants who discontinue treatment during the double-blind phase prior to Day 35 and do not withdraw consent for further assessments, will have End ofDB
Treatment visit and Follow-up visit, and will be encouraged to have additional Follow-up visits with assessments according to the SoA every 2 weeks until Day 57.
These additional Follow-up visits may be done remotely (eg, tele- or videoconference; optional) or at the research site. If done remotely, the NPI-C should be
conducted by videoconference if possible (with audio-recording).
l. 
For Day 8, 29, and 57 remote contacts and other remote visits, the site will ask about adherence to study drug, but formal drug accountability (pill counts) will not
be done.
m. If the ICF for optional genetic and pharmacogenomic (DNA) research sample is signed, the sample should be collected at the specified time point; however, if
necessary, it may be collected at a later time point without constituting a protocol deviation.
n. 
Study intervention intake ends on the night of Day 42.
o. 
Vital signs collection will be done only if an in-person site visit is conducted.
p. 
An extension of up to 2 weeks of the screening phase may be allowed (eg, if needed to confirm eligibility criteria, taper off a sleep medication or for scheduling
difficulties) with permission from the sponsor’s medical monitor or designee. The minimal screening duration should be 2 weeks to allow the proper conduct of the
BPST.
q. 
Off-body touchless sensors (optional in the study) will be used in a subset of participants. The sensor(s) will be placed in the participants home and be used from
screening to end ofthe study.
r. 
The IWRS will assign medication for 4 weeks at D15 to cover up to D43.
s. 
Screening visit 1 assessments can be split over 2 days, if needed, however they should be conducted no more than three days apart.
t. 
In case of a positive result, one retest is allowed. Furthermore, if the test results contradict to the data obtained from the patient and caregiver, clinical judgement
should be applied.
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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 the adjunctive treatment of major depressive disorder (MDD)
with insomnia symptoms (MDDIS) and behavioral and psychological symptoms of dementia
(BPSD). This Phase 2 study will assess safety, tolerability, and clinical efficacy of seltorexant on
BPSD including agitation and aggression in patients with probable Alzheimer’s Disease (AD).
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 orexin system is implicated in the clinical outcomes and pathophysiology of AD.  There is an
association between orexinergic neurotransmission dysfunction, sleep impairment, and decline in
memory function and cognition in moderate to severe AD patients (Liguori 2014; 2016).
Further, depressive and mood symptoms are common in patients with AD, particularly those with
BPSD, and seltorexant 20 mg has shown efficacy in improving the core symptoms as well as the
overall symptoms of MDD in 4 different studies to date.
Based on the potential of seltorexant to improve multiple symptoms of BPSD and the demonstrated
safety in the elderly population with depression and insomnia disorder, the sponsor plans to initiate
the trial in BPSD in participants of 55 to 85 years of age (inclusive) with probable AD and
clinically significant agitation/aggression.
Currently, there is no efficacious treatment for the underlying causes of AD. Two categories of
medications are used in the treatment or management of symptoms ofAD: drugs that may delay
clinical decline in people living with Alzheimer’s (ie, Aducanumab [Aduhelm™]), and drugs that
may temporarily mitigate some symptoms of Alzheimer’s disease (cognitive [eg, cholinesterase
inhibitors] and non-cognitive [BPSD]). Due to the variability in number, type and severity of
BPSD symptoms between patients there are different symptomatic strategies currently available
for managing these patients, each with limitations and/or risks. Non-pharmacological approaches
(psychological, psychosocial, behavioral or environmental interventions, complimentary
therapies, etc.) are used as a first line in treating behavioral problems associated with dementia.
There is no pharmacological treatment approved in the United States for the management ofBPSD.
In some European countries, risperidone and haloperidol are indicated for the short-term treatment
(up to 6 weeks) of persistent aggression in participants with moderate to severe Alzheimer's
dementia unresponsive to nonpharmacological approaches and when there is a risk of harm to self
or others.
Despite absence of solid evidence about their efficacy on individual neuropsychiatric symptoms
(NPS), several antipsychotics, antidepressants, mood stabilizers, anticonvulsants and
benzodiazepines are used off-label to treat BPSD in people living with Alzheimer’s when non-
pharmacological approaches fail. Their administration is related to high risk of occurrence of
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adverse effects and increased mortality, highlighting an ongoing and serious unmet medical need
in this vulnerable patient population.
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
Currently, around 55 million people worldwide are living with dementia and there are nearly 10
million new cases every year. The number of individuals with dementia is projected to reach about
78 million by 2030 and 139 million in 2050. Of all dementias, Alzheimer’s disease (AD) is the
most common contributor and accounts for up to 70% of all dementia cases (WHO 2021).
As the population ages, the number of people with dementia will rise and a concomitant rise in the
dependency ratio means that the economic burden of AD will increase dramatically. The current
annual cost of dementia is estimated at US $1trillion, a figure set to double by 2030. According to
the Alzheimer’s Association, dementia-related costs range from $157 to $215 billion - higher than
costs associated with cancer or cardiac disease - in the US alone, with roughly $42,000 to $56,000
spent per individual. These costs are driven to a significant extent by behavioral and psychological
symptoms of dementia (BPSD) such as psychosis, apathy, hyperactivity, agitation, sleep disorders
or depression (Ballard 2006). Especially in advanced stages of dementia, BPSD often lead to
hospitalization or admission into long-term care nursing homes (Zuidema 2007). Agitation, one of
the most commonly observed neuropsychiatric symptoms, maybe found in up to 70% of dementia
patients (Ijaopo 2017). In addition to patients’ mobility impairment and high risk of falling,
clinicians are confronted with aberrant motor behavior symptoms, ie, restlessness or circadian
rhythm disturbances (Lyketsos 2011). Unfortunately, only a limited number of pharmacologic
treatments for BPSD are approved in this population. Antipsychotics that are often used in this
population have a black box warning for increased risk of mortality  in elderly patients with
dementia. A wide range of psychotropic medications —  including antipsychotics, mood
stabilizers, antidepressants, and cholinesterase inhibitors — are regularly used in an effort to
manage these symptoms (Ballard 2010).
Researchers have found that circadian rhythms are significantly disturbed in AD, and that this
disturbance is of significant clinical relevance to development of behavioral and psychological
symptoms, as well as decline in memory function and cognition in moderate to severe AD patients
(Musiek et al, 2015; Coogan et al, 2013; Liguori 2014; 2016; Moran 2005; Shin 2014).
Excessive daytime sleepiness, sundowning, and insomnia are among the most common sleep
disturbances in dementia due to AD, and originate from changes in sleep architecture and the
circadian rhythm (Wang & Holtzman, 2020). Neuronal and synaptic damage that occur as a result
of AD pathology in circadian regulating areas of the brain (e.g. hypothalamic suprachiasmatic
nucleus) increase the dysfunction of cellular circadian rhythms. This damage is believed to be an
underlying cause of the sleep disturbances seen in AD, including increase in fragmented daytime
naps, reduced rapid eye movement (REM) and non-rapid eye movement (NREM) slow wave sleep
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(SWS) duration and decreased sleep efficiency, coupled with increased wakefulness after sleep
onset (WASO)(Liguori 2016).
Changed sleep architecture and circadian rhythm dysregulation in AD patients is correlated with
other behavioral manifestations of BPSD, such as depressive mood, apathy, and aggressiveness
(Moran 2005; Shin 2014; Mulin 2011). It has also been suggested that symptoms such as
aggressiveness are consequences of the same underlying problem, e.g., disturbance of rest/activity
and sleep-wake rhythms due to circadian rhythm disturbance (Moran 2005). Recent preclinical
evidence also supports an additional important role of orexin in modulating behavior such as
aggression through the activation of a small population of glutamic acid decarboxylase 2-
expressing neurons in the lateral habenula via OX2R, which is consistent with other evidence of
the role for orexin in other motivated behaviors (Flanigan 2020). In this study, in addition to
demonstrating that cell-type-specific knockdown of OX2R reduces aggression and preference for
aggression-paired contexts without affecting locomotor behavior, it was also seen that systemic
administration of an OX2R antagonist reduces aggression and preference for aggression-paired
contexts without affecting motor behavior in the open field test in mice. Thus, seltorexant as an
orexin 2 antagonist has the potential to have a direct anti-aggression activity in AD patients with
aggression.
Seltorexant has shown consistent results in improving total sleep time, reducing wake after sleep
onset, and improving sleep efficiency in both adults and elderly patients with insomnia disorder as
well as patients with MDD. Further, seltorexant 20 mg has shown the ability to reduce sleep
fragmentation in patients with MDD leading to improved sleep quality and more restful sleep.
The efficacy data from seltorexant studies of MDD and those in insomnia disorder support
potential therapeutic benefit in BPSD in participants with AD. A clinically meaningful reduction
of depressive symptoms based on mixed model repeated measures (MMRM) analysis favored
seltorexant 20 mg as an adjunctive treatment to an SSRI/SNRI over placebo (Study
42847922MDD2001) and as monotherapy (42847922MDD1009) with more benefit being seen in
patients with an at least moderate level of IS. The improvements in depressive symptoms observed
with seltorexant 20 mg were maintained over a 6-month study period in the 42847922MDD2002
study. In supporting studies in insomnia disorder, seltorexant showed efficacy in improving both
objective and subjective measures of sleep onset and sleep maintenance, as well as total sleep time
(TST), in individuals with insomnia disorder. The latency to persistent sleep (LPS) was reduced
by 49.59, 69.86, and 57.38 minutes after single dose of seltorexant in 10 mg, 20 mg, and 40 mg
treatment groups, respectively in patients with MDD treated with an SSRI/SNRI who had insomnia
disorder (Study 42847922EDI1002). Sleep efficiency was significantly higher in the 40 mg
seltorexant dose group, compared with placebo, at both Day 1/2 and Day 5/6 timepoints in patients
with insomnia disorder without significant psychiatric co-morbidity (Study 42847922ISM2002).
Seltorexant 10 and 20 mg provided clinically meaningful improvements over placebo for LPS and
WASO-6 (Wake After Sleep Onset over the first 6 hours) at Night 1. These effects were maintained
over 2 weeks in participants with insomnia disorder (Study 42847922ISM2005) with similar
efficacy in adults and elderly populations.
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In study 42847922EDI1014, elderly participants received seltorexant in single doses of 10, 20 or
40 mg and demonstrated similar pharmacokinetics of seltorexant as adult patients as well as a
similar safety profile. Tolerability of seltorexant in the elderly has further been shown in studies
42847922ISM2005 in patients with insomnia disorder (up to age 85) and MDD2001 and
MDD2002 in patients with MDD (up to age 70) with similar adverse event profile as in the non-
elderly adult population.
In adults, 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.
This multi-center randomized, placebo-controlled, double-blind study to investigate seltorexant
safety, tolerability, and clinical efficacy will be the first study with seltorexant in patients with
probable AD and clinically significant agitation/aggression. Whilst this study will investigate the
safety and tolerability of seltorexant administered for 6 consecutive weeks, the primary aim will
be to explore seltorexant clinical efficacy on behavioral and psychological symptoms (eg,
agitation, sleep disturbances, depression/dysphoria, etc.) while also studying the safety and
tolerability of seltorexant in patients with probable Alzheimer’s dementia with clinically
significant agitation/aggression.
2.2. 
Background
AD is a progressive neurodegenerative disorder affecting wide areas of the cerebral cortex and
hippocampus. Even though psychopathology of AD can differ greatly from one person to another,
it includes both behavioral and psychological symptoms that are common and associated with
distress for patients and caregivers, greater risk of institutionalization, and accelerated progression
to severe dementia and death. The three most common psychopathologies in AD are agitation,
depression and affective symptoms, and psychosis (Tractenberg 2003b). Additionally, sleep and
circadian rhythm disturbances are frequent in AD, and it has been reported that up to 45% of
patients may have sleep issues (Moran 2005; Pistacchi 2014; Cipriani 2015). The most frequent
sleep disturbances include excessive awakenings (23%), early morning awakening (11%),
excessive daytime sleepiness (10%), and napping for more than 1 hour during the day (14%)
(Vitiello 2001). Sleep in AD is often fragmented with patients often having reduced total sleep
times at night leading to significant sleep periods during the day. Such disturbances can appear
early in the course of the disease, and they tend to be correlated with the severity of the cognitive
decline and behavioral and psychological symptoms (Moran 2005).
Seltorexant is a potent and selective antagonist of the human orexin-2 receptor (OX2R) and is
currently being developed by Janssen Research & Development for the adjunctive treatment of
major depressive disorder with IS (MDDIS)and for the treatment of Behavioral and Psychological
Symptoms of Dementia (BPSD). In addition to a hypothesized role in modulating arousal, the
sleep- and mood-enhancing effects of a selective OX2R antagonist, such as seltorexant, are
expected to confer benefit in mood disorders and neurodegenerative diseases.
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2.3. 
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks ofseltorexant may be
found in the seltorexant Investigator’s Brochure (IB)(Investigator’s Brochure).
The currently available data in adults (see Investigator’s Brochure) support a positive benefit-risk
assessment and this clinical study that investigates the safety and tolerability of seltorexant in
patients with probable Alzheimer’s Dementia with clinically significant agitation/aggression. In
clinical trials in the MDD population, the 20 mg dose of seltorexant has shown consistent benefits
in adult and elderly  MDD patients (currently being investigated in adult and elderly  phase 3
studies). 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 including elderly
patients while maintaining normalized sleep parameters.
For the AD patient with BPSD, the potential benefit may include improvements in sleep,
depression, agitation and/or aggression (based on animal models).
In studies with adults, the safety and tolerability data so far accumulated from completed clinical
studies of seltorexant in both healthy participants, and participants with MDD or insomnia disorder
were generally acceptable based on a thorough review of the safety information related to
seltorexant. 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. ADRs 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, in adults, 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 seltorexant is expected in adults or in elderly. Refer to the Investigator’s Brochure
for additional details from the adult program.
In adults, the benefits of seltorexant for MDD include symptoms beyond sleep. In the clinical
studies in adults conducted to date in the MDD study population, clinically  and statistically
significant changes in the core symptoms of depression (HDRS-6 or MADRS-6) have been seen,
which may indicate that seltorexant will help with some of the symptoms of BPSD such as apathy
and depression. Further, seltorexant 20 mg has consistently shown a greater benefit in patients
with at least moderate IS in patients with MDD. However, it is not known if the presence of IS (as
assessed by the sleep disorder inventory [SDI]) will predict efficacy in BPSD. In this study, both
patients with and without sleep problems will be included.
For the elderly, the pharmacokinetics are similar in the elderly and adults (42847922EDI1014). In
terms of safety, elderly and adults were included in the insomnia study 42847922ISM2005 with
both populations having fewer adverse events with seltorexant than with placebo or zolpidem
including no cases of somnolence in the elderly population. In that study, postural stability was
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studied at 4 hours after dosing (waking the participant up in the middle of the night) and the next
morning with no differences between patients treated with seltorexant or placebo.
To ensure safe use of study intervention, besides routine safety monitoring and participant
management, this protocol also includes specific risk mitigation strategies, including: restrictions
on driving, operating machinery, engaging in hazardous activity when participants have had
insufficient sleep or are feeling sedated the next day (Section 5.3, Lifestyle Considerations; and
frequent assessments at the site (every 1-2 weeks), paying special attention to clinically significant
AEs that are known to have been reported with drugs of the same pharmacological class
(Section 8.4.6, Adverse Events of Special Interest), reducing suicidality risk inherent in the
underlying depression by excluding high risk participants, and performing Columbia Suicide
Severity Rating Scale (C-SSRS) prior to dosing and at each study visit. Further, due to the
impairments associated with AD, all participants must have a study partner to help with the
procedures of the protocol and to provide additional feedback about any issues related to the study
treatment.
The information obtained to date regarding seltorexant suggests that the potential benefits to treat
patients with probable AD with clinically significant agitation/aggression in fulfilling an unmet
medical need outweigh the identified risks and potential risks at the dose 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.
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.
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To investigate the effect of seltorexant versus 
placebo on the sum of agitation and aggression 
domain scores (A+A) of the Neuropsychiatric
Inventory-Clinician rating (NPI-C) in participants
with probable AD with clinically significant
agitation/aggression.
 
Change from baseline to Day 43
on NPI-C A+A scores.
Secondary –Efficacy
To investigate the effect of seltorexant versus placebo on the following in participants with
probable AD with clinically significant agitation/aggression:
 
Cohen-Mansfield Agitation Inventory community 
version (CMAI-C) total score 
 
Change from baseline to Day 43
on the total CMAI-C score.
 
Sleep symptoms as assessed by the Sleep Disorder 
Inventory (SDI). 
 
Change from baseline to Day 43
on SDI total score.
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Objectives 
Endpoints
Secondary –Pharmacokinetics
 
To investigate the plasma pharmacokinetics (PK) 
of seltorexant and its M12 metabolite in 
participants with probable AD with clinically 
significant agitation/aggression.
 
Plasma 
concentrations 
of
seltorexant 
and 
its 
M12
metabolite at Day 15 and Day 43.
Exploratory –Digital
To investigate the effect of seltorexant versus placebo on the following in participants with
probable AD with clinically significant agitation/aggression:
 
Sleep and activity metrics using an actigraphy 
device. 
 
Change from baseline on sleep
and activity metrics.
 
Sleep and mobility  using an off-body touchless 
sensor in a subset of participants, (if feasible and 
available)
 
Change from baseline on sleep
and mobility measurements
Exploratory –Biomarkers
 
To investigate the effect of seltorexant versus 
placebo in participants with probable AD with 
clinically significant agitation/aggression on
blood biomarkers including but not limited to:
o biomarkers of AD, eg, p217+tau,
Aβ1-42/40 levels and ratio, NfL, and other
exploratory biomarkers
 
Change from baseline in levels of
blood biomarkers of AD
Other Exploratory
To investigate the effect of seltorexant versus placebo on the following in participants with
probable AD with clinically significant agitation/aggression:
 
Variables derived from the NPI-12/NPI-C rating:
o The sum of the NPI-C delusion and
hallucination  domain scores (NPI-C
D+H)
o Individual NPI-C domain scores for
agitation, 
aggression, 
dysphoria,
delusions, and hallucinations
o NPI-12 total score
o NPI-12 Caregiver Distress total score
o All NPI-12 individual item scores
 
Change from baseline over time
on the specified NPI-12/NPI-C
variables.
 
SDI Caregiver Distress score 
 
Change from baseline over time in
SDI caregiver distress
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Objectives 
Endpoints
 
Short-term rebound effects on behavioral and 
psychological symptoms of dementia (BPSD) as 
well as withdrawal symptoms 
 
Change in Physician Withdrawal
Checklist (PWC-20) from End of
DB Treatment/EW to first follow
up visit.
 
Change in NPI-12, NPI-C and
SDI scores from End of DB
Treatment/EW to first follow up
visit.
 
CMAI-C factor scores 
 
Change from baseline over time
on CMAI-C factor scores.
 
Depressive symptoms as assessed by the Geriatric 
Depression Scale, Informant version (GDSI). 
 
Change from baseline on GDSI
Total score at Day 43.
 
The 
association between 
treatment 
effect 
ofseltorexant in sleep and treatment effect in 
agitation/aggression  
 
Correlation between change in
NPI-C A+A and change in SDI
total score, and mediation effect
on change in NPI-C A+A through
change in SDI total score
 
Cognitive symptoms 
 
Change from baseline to Day 43
on 
Alzheimer’s 
Disease
Assessment 
Scale 
Cognitive
subscale 
14-item 
version
(ADAS-Cog-14) 
composite
cognitive 
score 
and 
from
screening to Day 43 on the Mini-
Mental 
State 
Examination
(MMSE) total score.
Safety
To investigate the effect of seltorexant versus placebo on the following in participants with
probable AD with clinically significant agitation/aggression:
 
Safety and tolerability of seltorexant 
 
Change from baseline in Vital
signs, Clinical Labs (chemistry,
hematology, urinalysis), ECG,
C-SSRS, 
and 
Treatment
Emergent 
Adverse 
Events
(TEAEs) including AEs of special
interest (AESI).
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
The hypothesis for this study is that seltorexant 20 mg is superior to placebo in reducing aggression
and agitation as measured by change in NPI-C A+A scores from baseline to Day 43 in participants
with probable AD and clinically significant agitation/aggression.
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4. 
STUDY DESIGN
4.1. 
Overall Design
This multi-center randomized, placebo-controlled, double-blind study will investigate seltorexant
safety, tolerability, and clinical efficacy in approximately 86 participants with probable AD and
clinically significant agitation/aggression. Participants will be diagnosed with probable AD
(DSM-5), and criteria of a syndrome diagnosis of agitation based on International Psychogeriatric
Association (IPA) consensus clinical and research definition of agitation in cognitive disorders
(see Appendix 6), have an MMSE total score from 10 to 24 (inclusive), and a Clinical Dementia
Rating (CDR) global score of ≥1. Additionally, patients will be characterized by the presence of
clinically significant agitation/aggression defined as NPI-12 agitation/aggression (A/A) domain
score ≥4 with NPI frequency score ≥2 at entry and baseline with no more than 35% of improvement
allowed in NPI-12 A/A score during the screening period. NPI-12 will be used to enrich the study
population for sleep problems (targeting for approximately 50% or more of the participants who
should meet baseline NPI-12 sleep  domain  score of ≥4). Vascular factors associated with the
dementia will be assessed with the Hachinski Ischemia Scale (HIS) score at baseline. Biomarkers
associated with AD will also be assessed at baseline.
Each participant in the study will have a designated study partner who will be available to meet
with study staff at each visit. A study partner can be a relative, friend or caretaker indicated by the
participant (or legal representative), who is at least 18 years old, who may or may not live with the
participant, who has at least 8 hours of contact with the participant each week (eg, 4 days a week
for at least 2 hours per day), and who is available for contact with the study site staff at each visit.
As judged by the investigator, study partners should have adequate literacy to participate and be
judged to have high likelihood of completing the study with the participant. Prior to study
assessments, study partners will receive oral and written information about the study and will sign
a Study Partner Informed Consent Form (ICF).
This study will consist of 3 phases: a screening phase (up to 28 days), a double-blind treatment
phase (43 days), and a post-treatment follow-up phase (14 days after DB treatment phase). Eligible
participants will be randomized in a 1:1 ratio after the screening period to receive either placebo
or seltorexant 20 mg for 6 consecutive weeks.
A diagram of the study design is provided in Section 1.2, Schema.
Sequence and Duration of Study Phases/Periods:
The duration of participation in the study for an individual participant (including screening, DB
treatment, and follow-up phases) will be approximately 12 weeks. There will be up to 7 scheduled
visits (Visit 1, 2, 3 [remote], 4, 5 [optional remote], 6, & 7 [optional remote]) according to the
SoA.
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Screening Period (minimum 2 weeks and up to 28-days before the double-blind treatment period)
Visit 1:
Before performing any screening-related procedures, participants and their study partners will be
fully informed about the purpose and the risks of the study. Informed consent will be obtained for
the participant or, when the participant is unable to consent, from the legal representative, and the
participant’s study partner.
During screening, participants will be assessed for being able to meet the study inclusion criteria
and if they meet any exclusion criteria. Diagnosis will be confirmed based on DMS-5 criteria for
AD, and criteria of a syndrome diagnosis of agitation based on IPA consensus clinical and research
definition of agitation in cognitive disorders, severity of dementia will be assessed, as well as
cognitive functioning, and BPSD symptoms including agitation and aggression. Medical, family
and disease history  will be obtained, including prior and concomitant therapies, and safety
evaluations (eg, physical examination, neurological examination, vital signs, ECG, C-SSRS, urine
drug screen, alcohol breath test, and clinical laboratory tests) will be performed to assess eligibility.
Participants and study partners who successfully completed the other Visit 1 assessments and meet
study participation requirements will receive brief psychosocial therapy (BPST). The first session
should occur in person with the study partner during screening Visit 1, and subsequent sessions
will be scheduled during the screening period and should be completed at Visit 2 (baseline) (see
Section 8.3.5 for more details). Additionally, participants and study partners will be instructed in
the use of the actigraphy device used for at-home recording of activity patterns and sleep patterns.
Participants will wear the actigraphy device continuously throughout the study screening and
double-blind periods when tolerated. Participants may be included in the study even if they are not
able or willing to wear the actigraphy device.
If implemented, the off-body touchless sensor(s) will be placed in the participants home during
the screening period (subset of the participants who agreed for use of the device at screening).
Participants will be monitored for at least 2 weeks during the screening period and eligible
participants will be monitored throughout the end of the study.
Prohibited medications will be tapered and discontinued prior to the start of the DB treatment
phase as described in Section 6.8.1. Treatment of stable medical conditions is allowed as defined
in the concomitant medications section of the protocol (Section 6.8).
Adverse 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.
An extension of up to 2 weeks of the screening phase may be allowed (eg, if needed to confirm
eligibility criteria, taper off a sleep medication or for scheduling difficulties) with permission from
the sponsor’s medical monitor or designee. The minimal screening duration should be 2 weeks to
allow the proper conduct of the BPST.
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For details regarding options for re-testing, see Section 5.4, Screen Failures.
Double-blind treatment period
Eligible participants and study  partners should return to the clinic to start the double-blind
treatment period within 28 days after start of the screening (Visit 1).
Visit 2:
Visit 2 will occur on Day 1 (baseline). Study restrictions and any changes in inclusion/exclusion
criteria will be reviewed, and an alcohol breath test and urine drug screen performed. Other
assessments will be completed as per the SoA at this and subsequent visits.
Upon completion of Visit 2 assessments, eligible participants will be randomized and receive the
study medication to take home for the double-blind treatment period, including instructions and a
medication diary. Participants and study partners will be reminded about the use of the actigraphy
device.
Visit 3
Approximately 7 days after Visit 2 (baseline), the participant and their study partner will be
contacted remotely (ie, by telephone or videoconference) and queried for AEs that may have
occurred between the last visit and remote follow up, and overall study drug dosing compliance
and tolerance, and medication diary completion.
Visit 4
Visit 4 will take place at the end of Week 2 ofthe double-blind treatment period.
Upon completion of Visit 4 assessments, participants and study partners will be reminded about
the use of the actigraphy device.
Visit 5
Visit 5 will be at the end of Week 4 of the double-blind period and is preferred to be done on-site;
if done remotely, the NPI-C should be conducted by videoconference if possible (with audio-
recording)
Visit 6
Visit 6 will be at the end of Week 6 of the double-blind treatment period or at the time of early
withdrawal from study treatment. At Visit 6, participants and study partners will return the
actigraphy device.
All participants who discontinue study drug in the DB treatment phase, will have an Early
Withdrawal visit (Visit 6 in the Schedule of Activities [SoA]), preferably the day after the last
dose. After completion of this visit, the participant enters the follow-up phase. All participants who
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discontinue study drug in the DB treatment phase after Day 35 will have an Early Withdrawal visit
(Visit 6 in the SoA) and a Follow-up visit (Visit 7 in the SoA). Participants who discontinue study
drug prior to Day 35 are encouraged to continue with additional Follow-up visits every 2 weeks
per the SoA until Day 57 (up to four Early Withdrawal Follow-up visits will be possible). At least
one Early Withdrawal Follow-up visit needs to be conducted 2 weeks apart from the Early
Withdrawal visit (EW Follow-up 1, which will include the assessments of Visit 7 in the SoA).
These additional Follow-up visits may be done remotely (eg, tele- or videoconference; optional)
or at the research site. If done remotely, the NPI-C should be conducted by videoconference, if
possible.
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 ofDB Treatment/Early Withdrawal visit assessments (including NPI-C/12) will be
performed per the SoA, preferably on the day after the last dose or as soon as the participant and
study partner are available for the assessment.
Entry to the follow-up phase should not be conducted in participants or study partners who
withdraw consent for further study assessments; however, they should complete the End of DB
treatment/EW visit if they are willing to do so.
Follow-Up Period-
Post-treatment Follow-up period (14 days after completion of the double-blind treatment period)
Visit 7(Follow-up Visit) which may be done remotely or in person.
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 complete follow-up assessments per the SoA
approximately 14 days after the last dose of study drug.
For participants who have completed the DB treatment phase (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 End of DB treatment/EW visit (Visit 6 in the SoA) and a Follow-up visit (Visit
7 in the SoA). Participants who discontinue study drug prior to Day 35 are encouraged to continue
after the Follow-up visit (Visit 7 in the SoA) with additional Follow-up visits, every 2 weeks per
the SoA until Day 57.
The off-body touchless sensor(s) will also be returned from the home subsequent to the last
participant’s study visit (in the subset of the participants who agreed for use of the device at
screening).
At the start of the follow-up phase, further clinical/standard of care for the treatment of BPSD
symptoms should be arranged by the study investigator and/or the participant’s treating physician.
The decision to continue and/or change the BPSD treatment in this phase will be at the discretion
of the investigator and/or participant’s treating physician.
Unscheduled visits
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For unscheduled visits conducted for non-administrative/non-logistic reasons (eg., a safety event
or change 
in 
the 
participant’s 
BPSD 
condition), 
the 
minimum 
recommended
evaluations/assessments include: physical and neurological examinations, vital signs, NPI-C, NPI-
12, SDI, C-SSRS, hematology and chemistry laboratory tests. Additional examinations and scales
can be performed as per the clinical judgement of the investigator and protocol requirements.
4.2. 
Scientific Rationale for Study Design
Blinding, Control, Study Phase/Periods, Intervention Groups
Treatment assignment will be blinded for participants, study partners and investigators to reduce
potential expectation bias during evaluation of clinical endpoints as well as AEs.
A placebo control will be used to establish the frequency and magnitude of changes in clinical
endpoints, both efficacy and safety, that may occur in the absence of active 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.
BPST during screening will be conducted for all participants and study partners in order to reduce
non-specific effects of increased attention/inclusion in the trial (see Section 8.3.5 for more details).
A 14-day follow-up period off treatment will be used to assess short-term rebound effect on BPSD
as well as withdrawal effect after discontinuing seltorexant.
DNA and Biomarker Collection
Pharmacogenomic research may help to explain interindividual variability in clinical outcomes
and may help to identify population subgroups that respond differently to an intervention. The goal
of the pharmacogenomic component is to collect DNA to allow the identification of genetic factors
that may influence the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety, or
tolerability of seltorexant. In this regard, metabolism of seltorexant may be influenced by genetic
variation in CYP2C9 and CYP3A4. An additional goal of the pharmacogenomic component is to
assess APOE genotype.
APOE is involved in several key amyloid beta (Aβ)-mediated processes associated with AD,
including the distribution, clearance and/or metabolism of Aβ, altered lipid-binding properties
leading to an augmentation of Aβ-mediated toxicity (eg, disruption of lysosomal storage), and
formation of aggregates that may promote Aβ nucleation and plaque formation. The APOE ε4
allele is considered the most significant genetic risk factor for AD and is associated with a
decreased age of onset of the disease (Verghese 2011). Together with other AD blood-based
biomarkers (p217+tau, Aβ42/40 levels and ratio) and other exploratory biomarkers of
neurodegeneration (such as neurofilament light chain (NfL)), APOE genotype may help to explain
interindividual variability in clinical outcomes or define subgroups of dementia patients that may
respond differentially to seltorexant treatment. DNA and biomarker samples may be used to help
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address emerging issues and to enable the development of safer, more effective, and ultimately
individualized therapies.
Biomarkers will be collected for all study participants as per SoA. Genetic and pharmacogenomic
research is optional (a separate ICF will be provided).
4.2.1. 
Study-Specific Ethical Design Considerations
The investigator must assess the capacity of the participant to provide informed consent prior to
the study entry  (at screening) and throughout the course of the trial. This should be done in
accordance with the investigator’s standard clinical practice and judgement. Participants who
progress to more advanced clinical stages of the AD during the study should be assessed for
understanding of potential risks/benefits of participation by the investigator and may continue in
the study at the discretion of the investigator.
The following requirements for obtaining ICF should be followed in this vulnerable participant
population:
 All study participants must have a designated study partner as described in Section 5.1
(inclusion criteria 11 and 12) and Section 5.5. All study partners will be required to sign a
separate ICF.
 The informed consents for participants and study partners should be in accordance with
principles that originated in the Declaration of Helsinki, current ICH and GCP guidelines,
applicable regulatory requirements, and sponsor policy.
 If the participant is deemed capable to understand the risks, benefits, and potential AEs of
the study, and provide their consent voluntarily as assessed by the investigator, written
informed consent must be obtained from the participant prior to the initiation of any trial
related procedures. Potential participants and study partners will be fully informed of the
risks and requirements of the study and, during the study, participants and study partners will
be given any new information that may affect their decision to continue participation. They
will be told that their consent to participate in the study is voluntary and may be withdrawn
at any time with no reason given and without penalty or loss of benefits to which they would
otherwise be entitled.
 If the participant is deemed incapable to fully understand the risks, benefits, and potential
AEs of the study, and provide their consent voluntarily as assessed by the investigator,
written informed consent must be obtained from the participant’s legally acceptable
representative prior to the initiation of any trial related procedures. Additionally, any form
of agreement (eg, verbal or written) to participate in the studyshould also be obtained from
the participant and documented. This should be done in accordance with state and/or local
regulations prior to the initiation of any trial related procedures and properly documented
in the source records.
 In any case, if the participant or study partner does not agree to participate in the study,
then the participant is not eligible.
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 
The participant, the study partnerand/or the legal representative can withdraw theirconsent
at any time throughout the study (see also Section 6.8.2 for further details).
The total blood volume to be collected is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study based upon the standard of the
American Red Cross.
4.3. 
Justification for Dose
The 20 mg seltorexant dose selected for this study was shown to be well-tolerated in Phase 1 and
Phase 2 studies in both healthy volunteers and patients with MDD and/or insomnia disorder,
including the elderly (42847922MDD2002 and 42847922ISM2005).
The proposed dose for this study 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.
 
Clinical efficacy and safety data from completed studies. For MDD, an inverse U-shaped
curve for efficacy was observed with only the 20 mg dose demonstrating consistent
efficacy. For insomnia disorder, 20 mg showed greater improvement than placebo in both
adults and elderly for objective measures of sleep. In insomnia disorder including elderly
patients (42847922ISM2005), seltorexant 20 mg demonstrated greater improvement
compared to zolpidem on LPS  (sleep onset) and wake after sleep onset for the first 6
hours of sleep (sleep maintenance).
 
No dose response in AEs up to 20 mg was seen. Safety as assessed by TEAEs as well as
other measures was similar for the elderly (≥65 years) as in adults (18-64 years) in
42847922ISM2005 (up to85 years) and 42847922MDD2002 (up to 70 years).
 
PK in elderly subjects were comparable to young adults (42847922EDI1014).
 
Elderly dose levels should be similar to those in adults based on previous studies
(42847922EDI1014 and 42847922ISM2005).
4.4. 
End of the Study Definition
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 treatment phase.
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 the 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.
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5. 
STUDYPOPULATION
Approximately 86 participants with probable AD and clinically significant agitation/aggression
will be enrolled in this study according to the inclusion and exclusion criteria specific for this
study. Participants will be enrolled after both the participant (or legal representative) and study
partner read the respective information sheet and sign the informed consent document indicating
that they understand the purpose of and procedures required for the study and are willing to
participate in the study and comply with the study procedures.
Screening for eligible participants should be performed within 28 days before administration of
the study interventionwith an extension of up to 2 weeks of the screening phase allowed as defined
in Section 4.1, Sequence and Duration of Study Phases/Periods.
Refer to Section 5.4, Screen Failures for conditions under which the repeat of any screening
procedures or re-screening is allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. 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:
Age
1. 
55 to 85 years of age, inclusive.
Type of Participant and Disease Characteristic
2. 
Criterion modified per Amendment 1
2.1. Participant has received a diagnosis of probable AD (DSM-5) with the following
characteristics at screening:
 
CDR global score ≥1
 MMSE total score of10 to 24 (inclusive)
3. 
Participant meets the criteria of a syndrome diagnosis of agitation based on International
Psychogeriatric Association (IPA) consensus clinical and research definition of agitation
in cognitive disorders for at least 2 weeks before screening (see Appendix 6 for the
criteria).
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4. 
Participant meets the criteria of NPI-12 A/A domain score ≥ 4 with frequency score ≥ 2
at screening and baseline with no more than 35% of improvement in NPI-12 A/A domain
score from the screening to baseline assessments.
5. 
Participant is 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 at the discretion of
the investigator if he/she judges the abnormalities or deviations from normal not to be
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.
6. 
Participant must be medically stable on the basis of the following: physical examination,
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.
7. 
Participant is considered eligible according to the following COVID-19 screening
criteria:
 Has no history of possible or confirmed COVID-19 infection at screening and
within 14 days prior to screening. Possible or confirmed COVID-19 diagnosis
may be based on:
o Symptomatology –at least 1 of the following main symptoms: cough,
dyspnoea, thoracic pain, acute anosmia or dysgeusia without clear
aetiology OR have at least 2 of the following symptoms: fever, muscle
pain, fatigue, rhinitis, sore throat, headache, anorexia, watery diarrhoea
without clear aetiology, acute mental confusion, acute falls without clear
aetiology OR worsening of chronic respiratory infections (COPD, asthma,
chronic cough…)
o Radiology –suggestive clinical presentation AND compatible thorax CT,
even if laboratory COVID-19 antigen test is negative
o Laboratory test –positive COVID-19 antigen test
o Signs or symptoms suggestive of active COVID-19 upon medical history
and/or physical examination.
o Recent (within 14 days) close contact with a person with possible or
confirmed COVID-19.
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Weight
8. 
Body mass index (BMI) within the range 18-40 kg/m2 (inclusive).
Sex and Contraceptive/Barrier Requirements
9. 
Female participants must be postmenopausal before study entry (amenorrhea for at least
12 months).
10. 
Male participant:
 who is heterosexually active with a woman of childbearing potential must agree
to use a double-barrier (a combination of male condom with either cap,
diaphragm, or sponge with spermicide) method of birth control and his female
partner must use a highly effective method of contraception
 must agree not to donate sperm during the study and for 3 months after receiving
the last dose of study agent
 who is sexually active with a woman who is pregnant must use a condom
 must not plan to father a child while enrolled in this study or within 3 months after
the last dose of study intervention.
Informed Consent
11. 
A participant in the study must have a designated study partner who will accompany the
participant to each study visit. A study partner can be a relative, friend or caretaker
indicated by the participant, who is at least 18 years old, who may or may not live with
the participant, who has at least 8 hours of contact with the participant each week (ie, 4
days a week for at least 2 hours per day), and who is available at each visit. As judged by
the investigator, study partners should have adequate literacy to participate and be judged
to have high likelihood of completing the study with the participant.
12. 
Each participant (or legal representative) and study partner (can be the same person as
legal representative) must sign an ICF indicating that he or she understands the purpose
of and procedures required for the study and are willing to participate in the study.
Each participant (or legal representative) must sign a separate ICF if he or she agrees to
provide optional DNA samples for research (where local regulations permit). Refusal to
give consent for the optional DNA research samples does not exclude a participant from
participation in the study.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
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participating in the study:
Medical Conditions
1. 
Participant fulfils diagnostic criteria for non-Alzheimer’s Dementia: eg, Frontotemporal
Dementia (FTD), Diffuse Lewy Body Dementia (DLBD), and post-stroke dementia,
based on clinical history. (Participants may be included with mixed AD/vascular
dementia).
2. 
Participant has a diagnosed sleep disorder other than insomnia disorder or hypersomnia
such as OSA or periodic limb movement disorder, REM sleep behavior disorder based
on medical history.
3. 
Participant has a neurological, psychiatric or medical condition associated with a long-
term risk of significant cognitive impairment or dementia including but not limited to
pre-manifest Huntington’s disease, multiple sclerosis, Parkinson’s disease, Down
syndrome, or major psychiatric disorders such as history or current diagnosis of
schizophrenia, schizoaffective or bipolar disorder.
4. 
Participants with a history of delirium within 30 days prior to or during screening.
5. 
Participant with a cause of agitation that is not secondary to dementia (such as pain) or
significant history of aggression prior to dementia based on investigator judgment.
6. 
Has a history of narcolepsy or seizures (except childhood seizures).
7. 
Participant has evidence of intracranial pathology which may affect cognition including
but not limited to brain tumours (benign or malignant), aneurysm or arteriovenous
malformations, territorial stroke (excluding smaller watershed strokes), recent
haemorrhage (parenchymal or subdural), or obstructive hydrocephalus. Research
participants with an MRI scan demonstrating markers of small vessel disease (eg, white
matter changes or lacunar infarcts) judged to be clinically insignificant, or microbleeds
are allowed
8. 
Participant 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).
9. 
Participants with clinically significant B12 or folate abnormalities at screening
10. 
Criterion modified per Amendment 1
10.1 Has a recent (last 3 months) history of, or current signs and symptoms of
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 severe renal insufficiency (creatinine clearance [CrCl] <30 mL/min);
 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 stable, and if on glucose-lowering therapy (eg diet,
lifestyle or medication), remaining on a stable regimen for at least 2 months prior to
screening.
11. 
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
12. 
Participant has a clinically significant acute illness within 7 days prior to study
intervention administration
13. 
Participant has any cancer or history of cancer (excluding cutaneous basal or squamous
cell cancer resolved by excision), unless in remission or considered stable on hormone
therapy for at least 6 months before screening.
14. 
Participant 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 medical monitor or
designee) the participant is not eligible.
Note: 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 in order to be eligible for participation.
15. 
Participant has a clinically significant condition which may deem the participant’s
participation in an investigational trial unsafe, eg, symptomatic cardiovascular disease
(including re-vascularisation procedures within the previous year), severe renal or
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hepatic failure, any clinically relevant abnormalities in blood parameters included in
local routine assessments, severe loss of vision, hearing or communicative ability,
conditions preventing co-operation or completing the required assessments in the trial,
as judged by the investigator
16. 
Participant has known allergies, hypersensitivity, or intolerance to seltorexant or its
excipients
17. 
Participant has a history of drug or alcohol use disorder according to Diagnostic and
Statistical Manual of Mental Disorders (latest edition) criteria within 6 months before
screening or positive test result(s) for alcohol and/or drugs of abuse [opiates (including
methadone), cocaine, amphetamines, methamphetamines, cannabinoids, barbiturates,
MDMA] at screening or baseline
18. 
Participant has a current or recent history of homicidal ideation or serious suicidal
ideation within the past 6 months, corresponding to a score of 4 (active suicidal ideation
with some intent to act, without specific plan) or 5 (active suicidal ideation with specific
plan and intent) for ideation on the C-SSRS, or a history of suicidal behavior within the
past year, as validated by the C-SSRS at screening or baseline.
19. 
Has Cushing’s Disease, Addison’s Disease, or other evidence of significant medical
disorders of the HPA axis.
20. 
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)
Prior/Concomitant Therapy
21. 
Participants who are not stable on concomitant medications or take prohibited
medications, as defined in Section 6.8
22. 
Participant received an investigational intervention (including investigational vaccines)
or used an invasive investigational medical device within 60 days (or 5 half-lives,
whichever is longest) before the planned first dose of study intervention or is currently
enrolled in an investigational study
23. 
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 10.7, Appendix 7, for examples of strong inhibitors and
moderate/strong inducers of CYP3A4 or CYP2C9 or dual inhibitors/inducers of
CYP3A4 and CYP2C9.
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24. 
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)at screening.
See Section 10.7, Appendix 7, for examples of moderate CYP3A4 or CYP2C9
inhibitors.
Other Exclusions
25. 
Participant is unable to swallow oral medication without requiring crushing.
26. 
Participant and/or study partner is an employee of the investigator or study site with
direct involvement in the proposed study or other studies under the direction of that
investigator or study site, as well as family members of the employees or the
investigator.
27. 
Participant has had major surgery, (eg, requiring general anesthesia) within 8 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 or within 4 weeks
after the last dose of study intervention administration.
Note: participants with planned surgical procedures to be conducted under local
anesthesia may participate.
28. 
Deleted per Amendment 1
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
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 intervention is given
such that the participant 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
retesting. The required source documentation to support meeting the enrollment criteria is noted
in 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 these lifestyle restrictions during the study:
1. 
Participant drinks, on average, no more than 5 cups of tea/coffee/cocoa/caffeinated cola
per day.
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2. 
Abstain from alcohol 24 hours prior to all scheduled visits. On average, 1 or fewer drinks
of alcohol per day is allowed.
3. 
Avoidance of blood donation during the study and for at least 90 days after the last visit
4. 
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.
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
medical monitor 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 AD cannot be rescreened.
5.5. 
Study Partner/Legal Representative
Each participant must have a study partner in order to be eligible for the trial.
For purposes of this trial, the subject’s study partner is defined as the person who is at least 18
years old, who may or may not live with the participant, who has at least 8 hours of contact with
the participant each week (eg, 4 days a week for at least 2 hours per day), and who is available for
contact with the study site staff at each visit. As judged by the investigator, study partners should
have adequate literacy to participate and be judged to have high likelihood of completing the study
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with the participant.
In a non-institutionalized setting, the subject’s study partner may be the person who lives with or
has a close and regular contact with the study participant. This can be for example, a relative or
friend. In the institutionalized setting, the study partner may be an individual who has sufficient
contact with the participant and has direct observation of the participant’s behavior in order to
participate in the study assessments. In the institutionalized setting it can be a staff member (the
staff member cannot be a member of the investigational study staff) or another individual (eg,
family member, a friend, a hired professional caretaker).
The study partner can be the same person as the legal representative or these can be two
individuals, provided the study partner meets the study requirements for regular contacts and
availability. Every effort should be made that each participant has only one study partner during
the trial. Any deviations from this rule should be discussed with the study sponsor in advance.
Prior to the study, study partners will receive oral and written information about the study and will
sign a Study Partner Informed Consent Form (ICF). Please also refer to Section 6.8.2, Withdrawal
of Consent.
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Intervention(s) Administered
Study intervention administration must be captured in the source documents and the electronic
case report form (eCRF). Studysite personnel will instruct participants and partner on how to store
study intervention for at-home use as indicated for this protocol.
For details on rescue medications, refer to Section 6.8.2, Rescue Medication. For a definition of
study intervention overdose, refer to Section 6.7, Treatment of Overdose.
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 ofthe sponsor. Refer to the
latest version of the Investigator's Brochure 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 1 tablet of 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 or their study partners are required to record the administration of study drug or any
missed doses in participant medication diaries, which will be checked at each scheduled visit. Pill
counts of study drug will be performed at in person 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.
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Information about the missing dose should be recorded in participant medication diaries which
will be checked at each scheduled visit.
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6.2. 
Preparation/Handling/Storage/Accountability
The 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
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 or study partners participating in the study for dosing by participants. 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 at interim visits, 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 treatment
phase. Participants will be randomly assigned based on an algorithm implemented in the
interactive web response system (IWRS) before the study. During the DB treatment phase,
participants will be randomly assigned in a 1:1 ratio to receive 1 of 2 treatments: placebo:
seltorexant 20 mg.
The randomization will be balanced by using randomly permuted blocks and will be stratified by
country  (if applicable), baseline NPI-12 sleep domain  score (<4, ≥4), and community
dwelling/assisted living. 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.
Note: ‘Assisted living’ refers to participants living in a staffed facility vs. ‘Community-dwelling’
refers to participants not living in a staffed facility (whether or not needing assistance with
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activities of daily living).
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 as tablets 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,
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 studydrug 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 by the investigator, 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 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 ofDB Treatment/follow-up visit.
6.4. 
Study Intervention Compliance
The study drug will be self-administered by the participant at their residence during the DB
treatment phase. Dosing and medication diary compliance will be done with oversight and/or
assistance by the study partner.
The number of study drug tablets dispensed for self-administration by participants at their
residence will be recorded and compared with the number returned during postbaseline visits.
Participants or study partners are required to record the administration ofstudy drug or any missed
doses in participant medication diaries, which will be checked at each scheduled postbaseline visit.
Participants with repetitive non-compliance to the study drug in the DB treatment phase will be
withdrawn from the study treatment. See Section 7.1 for reasons for withdrawal. Study
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intervention assigned to the participant who discontinued study intervention and/or withdraws
from the study may not be assigned to another participant.
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. 
Dose Modification
Not applicable.
6.6. 
Continued Access to Study Intervention After the End of the Study
No continued access will be proposed for this study as the long-term safety of seltorexant in this
population is unknown. At the end of their participation in the study, the participants will be
instructed that they should return to their primary physician to determine standard of care, if
applicable.
6.7. 
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 medical monitor 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 medical monitor or designee (determined on a case-by-case
basis). The study team will be blinded to the result.
 
Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
Decisions regarding dose interruptions should be made by the investigator in consultation with the
sponsor’s medical monitor or designee based on the clinical evaluation of the participant.
6.8. 
Prior and Concomitant Therapy
Pre-study medication administered up to 30 days before screening must be recorded at screening.
Concomitant medications will be recorded throughout the study, from signing the ICF until the
follow-up visit. Concomitant medications should also be recorded beyond this time only in
conjunction with new or worsening adverse events, until resolution of the event. All concomitant
medications (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special
diets, exercise regimens) must be recorded in the eCRF. Modification of a pre-existing medication
should not be made for the explicit purpose of entering a participant into the study.
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Treatment of stable medical conditions is allowed provided the participants are on stable
medication (for at least 30 days prior to screening) and should remain on stable medication, if
possible, for the duration of the study. These include but are not limited to:
 
Stable AChE inhibitors and memantine
 
Stable non-sedating antidepressants
 
Stable antihypertensives, stable statins, stable anti-thrombotic agents
 
Stable treatment for diabetes mellitus for at least 2 months prior to screening
 
Stable thyroid hormones for at least 3 months prior to screening
 
Patients who take aducanumab should be on a stable dose/regimen for at least 6 months before
screening.
6.8.1. 
Prohibited Medications
Participants treated with 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 must be
excluded. See Section 10.7, Appendix 7, for examples of strong inhibitors and moderate/strong
inducers of CYP3A4 or CYP2C9 or dual inhibitors/inducers of CYP3A4 and CYP2C9.
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. See Section 10.7, Appendix 7, 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 7
<30 
Participant should not be enrolled in
the study (Screen-failure)
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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
AST/ALT >1.5X ULN and 
Bilirubin >1.5X ULN 
Limitation on concurrent drugs, see
Appendix 7
≥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).
Participant should not be included in
the study (Screen-failure)
St. John’s wort, ephedra, 5-hydroxytryptophan, ashwagandha, Chinese herbal medications known
to affect CYP3A4 or CYP2C9, ginkgo, ginseng, or kava are prohibited from at least 7 days before
Day 1 until the duration of the study.
Monoamine oxidase inhibitors (MAOIs) should be prohibited by Day -28.
The following medications should be discontinued by Day -7:
 
Sedating antidepressants: doxepin, trazadone, mirtazapine, agomelatine, and
trimipramine, amitriptyline
 
Mood stabilizers such as Lithium, or anticonvulsants
 
Benzodiazepines (other than lorazepam as a rescue medication in the protocol defined
doses), buspirone, Z-drugs, other hypnotics, sedating antihistamines including over-the-
counter hypnotics (eg, diphenhydramine, doxylamine, and hydroxyzine), and melatonin.
 
Antipsychotics
 
Suvorexant or other orexin receptor antagonists
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 pre-study sleep medication and/or benzodiazepine may be remediated by tapering the
medication. The investigator should also consider if 21 days after screening 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 the
primary care physician for clinical management and excluded from participation in this study. If
the investigator determines that more time is needed to stop the sleep medication safely, the
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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.
If a prohibited medication is used for any other than BPSD condition, it should be used at a dose
appropriate for the patient population and treated condition, and should be stable for at least 2
months before screening. Inclusion of such patients should be carefully evaluated for potential
additive sedative effects. The sponsor’s medical monitor or designee should be consulted for such
cases before a patient’s enrollment in the study. Sedating antidepressants, ie. doxepin,
trimipramine, amitriptyline, as well as sedating antihistamines including over-the-counter
hypnotics are strictly prohibited.
If new medications or changes to medication are required, that are expected to have an impact on
study endpoints or safety, these should be initiated following completion of the double-blind
treatment phase. If needed to start prior to the End of DB Treatment phase, the initiation of the
new medication should be discussed with the sponsor’s medical monitor or designee.
If the participant received an investigational intervention (including investigational vaccines) or
used an invasive investigational medical device within 60 days (or 5 half-lives whichever is
longest) before the planned first dose of study intervention, or is currently enrolled in an
investigational study, they will be excluded from participating in the study.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
Concomitant therapies must be recorded throughout the study beginning with screening until after
the end of the follow up period. Concomitant therapies should also be recorded beyond the follow
up period only in conjunction with new or worsening AEs or SAEs that occur within 30 days of
the last study intervention. For participants who fail screening, concomitant therapies do not need
to be recorded unless there is an AE.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special
diets, exercise regimens, or other specific categories of interest) different from the study
intervention must be recorded in the eCRF. Recorded information will include a description of the
type of therapy, duration of use, dosing regimen, route of administration, and indication.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
6.8.2. 
Rescue Medication
The study sponsor will not supply the rescue medication. The following rescue medications may
be used, and will be obtained locally:
 Lorazepam or equivalent up to 2 mg/day and no more than 3 days out of every 14 days
(refer to Appendix 8 for benzodiazepine equivalence table)
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Rescue medication should not be used the night before or any time prior to assessments on
scheduled visit days. The date and time of rescue medication administration as well as the name
and dosage regimen of the rescue medication must be recorded in the source records and eCRF.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
A participant's study intervention must be discontinued if:
 
The participant (or legal representative) withdraws consent to receive study intervention
 
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue study intervention
 
Based upon the clinical judgment of the investigator, a participant may be withdrawn for lack
of efficacy  (ie, clinically significant worsening of agitation/aggression or other BPSD
symptoms).
 
Noncompliance with study drug administration defined as missing either 4 or more
consecutive doses of study drug or a total of 8 or more doses during any 4-week period
 
The participant persistently uses a disallowed medication as discussed with the sponsor’s
medical monitor 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 treatment phase
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 6in the SoA) and
a Follow-up visit (Visit 7 in the SoA). Participants who discontinue study drug prior to Day 35 are
encouraged to continue after the Follow-up visit (Visit 7 in the SoA) with additional follow-up
visits every 2 weeks per the SoA until Day 57. If a participant discontinues study medication and
enters the follow-up phase, other concomitant medications, including disallowed medication, may
be started (see Section 6.8.1). Study intervention assigned to the participant who discontinued
study intervention may not be assigned to another participant. Additional participants will not be
entered to replace participants who discontinue the study early.
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 by the participant (or legal representative)
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 
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 DB 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 DB Treatment phase, End of DB 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 or legal representative and study
partner agreed to when signing the consent form apply as local regulations permit.
The participant (or legal representative) and/or study partner may withdraw their consent at any
time during the study. If this is not possible to keep the same study partner for a participant (ie, the
study partner withdraws consent but the participant still wants to participate in the study), a change
of the study partner as well as further participation of the participant in the trial need to be discussed
with the sponsor in advance.
7.2.1. 
Withdrawal From the Use of Research Samples
A participant who withdraws their consent from the study will have the following options
regarding the optional research samples:
 
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
that the samples have been destroyed.
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.
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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 the participant and/or study partner are 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 and/or study partner 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 and/or study partner 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 and/or study partner (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 and/or study partner 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 Schedule of Activities summarizes the frequency and timing of efficacy, PK, PD, biomarker,
pharmacogenomic, and safety measurements applicable to this study.
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 should be administered after food is provided and
participants feel comfortable, without help or time pressure, and under quiet conditions. Further
details are provided in a separate manual provided to the site (see below in Study-Specific
Materials).
Home Health Care and Telehealth Visits
Home health care and telehealth visits may be implemented by or with approval from the sponsor
and per the clinical judgement of the investigator, where feasible and permissible by local policy.
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Participants for whom there is no safety concern (patient does not require in-person medical visit)
may have home health care and telehealth (conducted via phone or video conference) visits as
indicated for the SoA. Additional home or telehealth visits may be conducted instead of in person
visits after discussion with the sponsor.
Telehealth visits (conducted via phone or video conference) may be implemented by or with
approval from the sponsor and per clinical judgement of the investigator for certain circumstances
when warranted where feasible and permissible by local policy, regulations (as applicable) and for
participants for whom there is no safety concern.
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 Schedule of Activities for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manual.
The total blood volume for the study is approximately 64 mL (30 mL for safety, 4 mL for
pharmacokinetics, 6mL for pharmacogenomics, and 30 mL for biomarkers.
For each participant, the maximum amount of blood drawn from each participant in this study will
not exceed 120 mL.
Study-Specific Materials
The investigator will be provided with the following supplies:
 
IB for seltorexant
 
Pharmacy manual/study site investigational product and procedures manual
 
Laboratory manual
 
eCOA Manual and devices
 
Actigraphy manual and devices
 
Brief Psychosocial Therapy. Therapist Manual
 
IVRS/IWRS Manual
 
Annotated eCRFs (embedded eCRF guidelines)
 
Sample ICF
 
Participant medication diaries
 
Participant recruitment materials
 
Off-body touchless sensors supporting materials, if available and applicable
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8.1. 
Efficacy Assessments
Assessments should be completed at approximately the same time on each day that testing occurs,
and by the same rater(s). The same study partner should complete any caregiver ratings. These
procedures should be employed throughout the study to reduce potential variability.
The following sections brieflydescribe the cognitive and functional testing that will be assessed in
the study.
8.1.1. 
Neuropsychiatric Inventory (NPI-12)
The NPI-12 is a measure of psychobehavioral disturbances (Cummings 1994; 1997), assessing
the frequency and severity of disturbances in 12 domains, based on a caregiver interview. For
each domain, there is also an assessment of caregiver burden. Frequency for each domain is rated
on a 4-point scale (from 1=rarelyto 4=veryoften)andseverityon a3-point scale (from 1=mildto
3=severe), withthe score for each domain being the product of the frequency and severity scores,
such that each domain is scored from 1 to 12. The NPI-12 total score is the sum ofthe 12 domain
scores, ranging from 0 (best) to 144 (worst). Caregiver distress, based on the response to the
question “how emotionally distressing do you find this behavior?”, is rated on a 6-point scale
(from 0=not at all to 5=very severely or extremely), with the total score for caregiver distress
ranging from 0 (best) to 60 (worst).
8.1.2. 
Neuropsychiatric Inventory clinician version (NPI-C)
The Neuropsychiatric Inventory-Clinician Rating (NPI-C) (de Medeiros 2010) is an instrument
developed on the basis of original NPI that gives a score based on product of frequency and
severity ratings of 12 symptom domains that can then be summed to a total score. For NPI-C, the
items and domains of the original NPI have been expanded and the rating approach has been
modified to include a clinician rating methodology. The rating methodology of the NPI-C
incorporates the expert clinician’s impressions to the data provided by the patients and caregivers.
The NPI-C can be used to rate the presence of NPS across many domains, as in the NPI-12, as a
stand-alone measure for specific NPS domains (eg, dysphoria, agitation), or a combination of both
(presence of NPS across domains plus particular focus on one or more specific domains). Five
domains will be measured in the study with NPI-C: Delusions, Hallucinations, Agitation,
Aggression, Dysphoria, and will include both caregiver and participant interviews. The NPI-C
ratings for these domains will be done in their entirety (ie –questions asked and rated, with a
corresponding Clinician Impression of Severity score).
An audio recording will be performed for NPI-C scale. The review of the recordings will be
conducted by central reviewers provided by a study selected vendor for quality purposes.
If the NPI-C is done remotely (ie, at Visit 5, Day 29) this interview should be conducted by
videoconference, if possible (with audio-recording).
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8.1.3. 
Sleep Disorder Inventory (SDI)
The Sleep Disorders Inventory (SDI) is based on a caregiver interview and an expanded version
of one item of the NPI-12 (Tractenberg 2003b). It describes the frequency, severity, and caregiver
burden of sleep-disturbed behaviors during a period prior to its administration.
The SDI was created by expanding item 11 of the 12-item NPI. According to the basic
structure of the NPI-12, the respondent is asked a 'screening' question, a general indication of
whether or not symptoms in that particular behavioral area are present. If the screening
question is positive, then speciﬁc sub-questions are asked. The SDI consists of the seven sub-
questions from the NPI-12 sleep disturbance item. Each of the sub-questions was made into a
separate question with frequency, severity, and caregiver distress rated by the caregiver with
respect to the participant. Thus, in contrast to a single rating for frequency and severity for all
sleep disturbance-related behaviors, which would be incorporated into an overall NPI-12
score, the SDI score is derived after the caregiver rates the frequency and severity of each of
the seven separate sleep disturbance symptoms. Caregiver distress ratings are not part of the
SDI total score, but distress is measured.
8.1.4. 
Cohen-Mansfield Agitation Inventory — Community version (CMAI-C)
The CMAI-C is a 37-item scale that measures the ability of a drug to reduce overall frequency of
agitation symptoms, including aggressive behaviors (Cohen-Mansfield 1991). Individual items
are rated by an expert clinician on a scale of 1 to 7 in which a score of 7 represents the most
frequent for each item assessed.
8.1.5. 
Geriatric Depression Scale, informant version (GDSI)
The GDS is a 30- or 15-item self-report assessment used to identify depressive symptomatology
in the elderly. GDSI is a version developed to be completed based on the informant (a study
partner for the purpose of the study) rating of the participant’s symptoms. The GDSI consists of
the same 15 items as the original GDS 15-item self-report version.
8.2. 
Safety Assessments
Adverse events will be reported and followed by the investigator as specified in Section 8.4,
Adverse Events, Serious Adverse Events, and Other Safety Reporting, and Section 10.4,
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution or until a clinically stable condition is reached.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the Schedule of Activities.
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8.2.1. 
Physical Examination
The study investigator, or other authorized and appropriately qualified designee, will perform the
physical examination. Height will be measured at screening only. Body weight will be measured
for each physical exam 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.
8.2.2. 
Neurological Examination
The study investigator, or other authorized and appropriately qualified designee, will perform the
neurological examination. The neurological exams will include assessment of sensation, level of
alertness, ataxia, tremor, and other routine components of a brief neurological examination.
8.2.3. 
Vital Signs
Temperature, pulse/heart rate, and blood pressure will be assessed.
Blood pressure and pulse/heart rate measurements will be assessed in a sitting position with a
completely automated device. Manual techniques will be used only if an automated device is not
available.
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).
8.2.4. 
Electrocardiograms
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.
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.
Please refer to Exclusion criterion 11  for the ECG requirements at screening or Day 1 prior to
randomization.
If the QTcF is prolonged ≥450 msec for males and ≥470 msec for females on the initial ECG at
any time point after randomization, 3 ECGs recorded 4 minutes apart should be performed. If, after
a triplicate ECG, the values stay above the defined thresholds, a consultancy with a cardiologist
should be considered and the investigator or qualified designee will determine if the participant
can continue in the study and if any change in participant management is needed. This review of
the ECG must be documented. Any new clinically relevant finding should be reported as an AE.
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8.2.5. 
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.
8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring
Seltorexant is considered to be a CNS-active medication being developed for MDD with IS and
BPSD in Patients with probable AD. There has been some concern that CNS-active medications
may be associated with an increased risk of suicidal ideation or behavior. Although this study
intervention or other similar treatments in this class have not been shown to be associated with an
increased risk of suicidal thinking or behavior when given to healthy volunteers or patients, the
sponsor considers it important to monitor for such events before or during this clinical study.
Emergence of potential suicidal ideation will be assessed using the C-SSRS clinician version 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(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.
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.
8.2.7. 
Physician Withdrawal Checklist (PWC)
Potential withdrawal effects will be assessed by the PWC-20 according to the SoA.
The 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 (Rickels 2008).
8.3. 
Other Assessments and Procedures
8.3.1. 
Clinical Dementia Rating (CDR)
The CDRis a structured clinician-rated interview that serves as a global clinical staging instrument
thatincludes3 cognitiveand3 functionalratings, including: 1)memory, 2)orientation, 3) judgment
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and problem solving, 4) involvement in community affairs, 5) home and hobbies, and 6) personal
care based on the CDR interview (Morris 1997). The CDR has been used as a global clinical
staging measure in a number of AD trials. The CDR is scored 2 ways yielding a global CDR score
(CDR-GS, derived from an algorithm developed by the Knight Alzheimer Disease Research
Center at Washington University School of Medicine in St. Louis, Missouri, US, and including
categorical scoring of 0, 0.5, 1, 2, and 3), as well as CDR-SB (the continuous sum of 6 domains,
up to a total score of 18, with higher scores representing worse disease state). CDR global score
will be calculated from the CDR Sum of Boxes at screening and used for determination of clinical
severity at screening.
8.3.2. 
Hachinski Ischemic Scale (HIS)
The HIS is a clinical questionnaire collecting information relevant for the differentiation between
the most common dementia types, Dementia of Alzheimer’s Type and vascular dementia.Because
it systematicallyidentifies risk factors for vascular cognitive impairment, it is a relevant screening
instrument for earlier stages ofAD and will be performed at screening.
8.3.3. 
Alzheimer’s Disease Assessment Scale Cognitive subscale 14-item
version (ADAS-Cog-14)
The ADAS-Cog is a rater administered instrument that was designed to assess the severity of
dysfunction in cognition characteristic of persons with AD (Rosen 1984).  The ADAS-Cog-11
consists of 11 tasks measuring the disturbances of memory, language, praxis, attention, and other
cognitive abilities, which are often referred to as the core symptoms of AD.
The modified ADAS-Cog 14-item scale includes all original ADAS-Cog items with the addition
of a number cancellation task, Maze task and a delayed free recall task, for a total of 90 points,
with higher scores indicative of worse cognitive performance.
8.3.4. 
Mini-Mental State Examination (MMSE)
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)
(Creavin 2016; Folstein 1975).
8.3.5. 
Brief Psychosocial Therapy (BPST)
BPST givenin the study was specifically developed for use in clinical trials of Alzheimer’s patients
with behavioral disorders. The therapy is a non-pharmacological intervention that will be used
during the screening period. It is simple to use and involves regular interactions between a
caregiver (study partner) and the participant based on a plan designed specifically for them. The
important aspect of the BPST is to ensure the participants receive quality social interaction that
they find interesting and engaging.
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The BPST entails regular semi-structured interactions between the participant and a designated
caregiver (study partner). The study partner will require training and assistance from site staff in
developing and implementing an individually-designed interaction strategy for the participant
involved. The details regarding the BPST will be described in the respective therapy manual that
will be provided to the sites. All site staff therapists in the study will complete therapist
qualification training prior to commencing work on the study.
There will be approximately four visits between the site staff (therapist) and the study partner
during the screening period (remote and site visits) leading up to baseline and randomization. The
purpose of each visit is summarized below:
 Training Visit: In-person BPST training for the study partner occurs in the clinic at this
first study visit(screening Visit1). This session is specifically designed to help the therapist
and study partner understand each participant and design an individualized plan of
interaction documented in a BPST-AD Treatment Plan. This session will last between 45
and 60 minutes.
 Follow-up Visits: Follow-up remote contacts may occur approximately every 4 to 5 days
after the Training Visitat screening. The study partneris contacted by the site staff therapist
to assess how BPST is progressing, to review the caregiver worksheet completed by the
study partner and to provide the study partner with supportive suggestions for any
concerns. At least one remote follow-up contact should be conducted during the screening
period for all participants’ study partners.
 Baseline Visit: This in-person visit occurs at the clinic at the conclusion of the screening
period (baseline Visit 2), at least two weeks after the Training Visit conducted at screening.
Then BPST intervention is formally closed.
8.3.6. 
Objective Sleep and Physical Activity Parameters (Actigraphy)
Actigraphy is the process of measuring physical movement of an individual over time to assess
the degree of motor activities and will provide an objective measure of sleep prior to treatment.
The actigraphy device is a small, motion biosensor that is worn on the non-dominant wrist to
monitor daily activity and sleep patterns. Participants are asked to wear the device continuously
throughout the screening and DB Treatment phases of the study. Actigraphy recorded movements
can be used to estimate sleep parameters with specialized algorithms. Actigraphy has been
validated for the estimation of nighttime sleep parameters across age groups (Martin 2011) and
psychiatric conditions (Ancoli-Israel 2003, Baandrup 2015). Subjective and objective sleep
assessment may assess different constructs of sleep and may not have a high correlation
(Smith 2018).
Participants will be instructed to wear an actigraphy device on their non-dominant wrist from
screening to End of DB Treatment phase or Early Withdrawal. Participants should wear it during
the day and night except when bathing. If a participant is not able to tolerate wearing the actigraphy
device (either at night or during the day), the participant may continue in the study and the use of
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the actigraphy device may be discontinued. Movements during the day and night will be captured.
Daytime physical activity may be analyzed. The primary purpose of actigraphy in this study is to
have an objective measure of sleep and physical activity parameters to complement the SDI,
CMAI-C, NPI-12 and NPI-C.
The parameters collected will include but are not limited to the following:
 
sleep onset latency
 
total sleep time
 
wake after sleep onset (WASO)
 
sleep efficiency
 
physical activity.
8.3.7. 
Off-body touchless sensors
This procedure will be implemented in the study as an optional assessment and only if available.
The off-body touchless sensors will be used in a subset of participants who agree to use them
during the study. The sensor(s) will be placed in the participants home and used from screening to
end of the study.
The off-body touchless sensor is a radio wave based touchless sensor and machine learning
platform for health analytics. The off-body touchless sensor operates by transmitting and receiving
low power radio signals that reflect off of the surroundings and return back to the device. The
power of these signals is 1,000 times lower than what a typical Wi-Fi device transmits, and existing
research has not shown these power levels to impact health in any way. The transmissions have
been designed to be in compliance with the Federal Communications Commission (FCC)
regulations governing indoor ultra-wideband (UWB) systems (Part 15.517).
The sensor(s) will be installed in the participant bedroom and optionally, in an additional living
area of the participant, to passively collect mobility and sleep metrics from screening to end of the
study. The sleep staging from this touchless sensor has shown good agreement (Cohen’s κ = 0.7)
of electroencephalogram (EEG)-based sleep stages (Zhao 2017). The off-body touchless sensor
provides additional data not available from wrist-worn actigraphy including the predicted sleep
stages. These complementary measures may prove useful in understanding sleep patterns
(Zhao 2017).
The device operates by transmitting and receiving low power radio waves that reflect off nearby
objects, pets and people and return back to the device. Data collected by the off-body touchless
sensor will be encrypted and transmitted via Wi-Fi to a secure vendor’s file server.
The participant will need to wear a small accelerometer (for approximately 14 days during the
screening period). The layout of the room and the side of the bed in which the participant sleeps,
will be entered into the vendor’s companion app by study mobile personnel. This information will
allow the vendor to create an algorithmic filter that recognizes motion patterns from the consented
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individual extracted by the device. These machine learning algorithms run on the collected data to
produce exploratory clinical endpoints (ie, mobility or sleep metrics). No identifiable information
is collected at any point by the vendor as all data is labeled by a randomly generated identifier that
is unique for the duration of the study.
As shown in Figure 2, the radio waves are first combined with information from the participant
worn accelerometer, and configuration information (ie, participant side of bed and bedroom
layout) using a machine learning model that produces a participant specific filter. This filter is
used by the vendor’s platform to remove irrelevant information, and the participant specific
relevant information is then processed by the platform to produce the data specific to the
participant.
Figure 2: 
Schematic of the Machine Learning Platform
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and PQCs, 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 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 will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant's legally acceptable representative) for the duration of the study.
Further details on AEs, SAEs, and PQCs can be found in  Section 10.4, Appendix 4: Adverse
Events, Serious Adverse Events, Product Quality Complaints, and Other Safety Reporting:
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated ICF is obtained until completion of the participant's last study-related
procedure, which may include contact for follow-up of safety.
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Serious Adverse Events
All SAEs, as well as PQCs, 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.
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study intervention, must be reported. The sponsor will evaluate any safety
information that is spontaneously reported by an investigator beyond the time frame specified in
the protocol.
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 made by
facsimile (fax). Telephone reporting should be the exception and the reporter should be asked to
complete the appropriate form(s) first.
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about AE occurrence,
except AESIs. For AESIs investigators are instructed to inquire about the occurrence of such
events during the collection of AEs at each visit.
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or
PQC as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
Adverse events, including pregnancy, will be followed by the investigator as specified in
Section  10.4, Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints,
and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting.
8.4.4. 
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.
8.4.5. 
Pregnancy
All initial reports of pregnancy in partners of male participants must be reported to the sponsor by
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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.
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.
8.4.6. 
Adverse Events of Special Interest
The following AEs are considered to be of special interest in this study:
 
Somnolence (eg, sleepiness, drowsiness)
 
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 10.4.1, Appendix 4:
Adverse Events: Definitions and Classifications), the Serious Adverse Events Form must also be
completed according to the SAE reporting timeline described in Section 8.4.1, ie, within 24 hours
of having become aware of the event, even if all details are not available.
8.5. 
Pharmacokinetics
Plasma samples will be used to evaluate the PK of seltorexant. Plasma collected for PK may
additionally be used to evaluate safety or efficacy aspects that address concerns arising during or
after the study period. Genetic analyses will not be performed on these plasma samples. Participant
confidentiality will be maintained.
8.5.1. 
Evaluations
Blood samples for the determination of plasma concentrations of seltorexant, its M12 metabolite,
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and alpha-1-acid glycoprotein, will be collected from participants per the SoA.
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.
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 treatment 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 sample collection will be accurately recorded by exact dosing date and time by the
participant or his study partner in the participant medication diary. In addition, in participants who
have ongoing AE leading to discontinuation every effort will be made to collect additional PK
sample.
8.5.2. 
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 (AGP) levels will be determined. AGP will be conducted under Good
Clinical Practice (GCP).
8.5.3. 
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.
8.6. 
Genetic and Pharmacogenomic Evaluations
Blood samples will be collected from participants who consent separately to this optional
component of the study (where local regulations permit) to allow for genotyping of the CYP2C9
and CYP3A4 genes, which may influence metabolism of seltorexant. Samples will also be assessed
for APOE genotype.
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8.7. 
Biomarkers
Biomarker blood samples will be collected to explore biomarkers related to AD, including but not
limited to: p217+tau, Aβ42/40 levels and ratio, and neurofilament light chain (NfL).
Biomarker assays 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.
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the
end of the study, it becomes clear that the analysis will not have sufficient scientific value for
biomarker evaluation, or if there are not enough samples or responders to allow for adequate
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy,
completion of biomarker assessments is based on justification and intended utility of the data.
8.8. 
Immunogenicity Assessments
Not applicable.
8.9. 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not
evaluated in this study.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan.
9.1. 
Statistical Hypotheses
This study is designed to show that the treatment effect in improving agitation and aggression (as
measured by change from baseline on Day 43 in NIPC A+A score) of seltorexant 20 mg is superior
to placebo in participants with probable AD with clinically significant agitation/aggression.
If µT is the mean change in NPI-C A+A for seltorexant 20 mg group and µP is the mean change in
NPC A+A for the placebo group, then the hypothesis can be written as follows:
H0: µT – µP ≥0 vs.
H1: µT – µP <0
Superiority in seltorexant 20 mg can be concluded if the one-sided p-value for the testing of the
hypothesis above is less than 0.1 (equivalently, the two-sided p-value for the testing of the
hypothesis above is less than 0.2, with greater improvement in the 20 mg group).
9.2. 
Sample Size Determination
Assuming a treatment difference of 5 points in change from baseline in NPI-C A+A score between
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seltorexant 20 mg and placebo, a standard deviation of 10 (effect size of 0.5), 15% drop-out rate
during the 6-week double-blind phase, 86 participants (randomized in 1:1 ratio to placebo and
seltorexant 20 mg) will need to be enrolled in the double-blind phase, in order to achieve 80%
power to detect treatment difference, at one-sided 0.1 significance level.
9.3. 
Populations for Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Analysis Set 
Description
Screened 
All participants who sign the ICF
Randomized 
All participants who were randomized in the study
Full 
All randomized participants who take at least 1 dose of study intervention
Safety  
All randomized participants who take at least 1 dose of study intervention.
9.4. 
Statistical Analyses
For all efficacy endpoints, descriptive statistics of the actual values and the change from baseline
to each postbaseline time point in the double-blind phase will be presented by intervention group.
The statistical analysis plan will be finalized prior to DBL and it will include a more technical and
detailed description of the statistical analyses described in this section. This section is a summary
of the planned statistical analyses of the most important endpoints including primary endpoint.
9.4.1. 
Primary Endpoint(s)
The analyses of efficacy endpoints will be based on the full analysis set.
The primary efficacy endpoint is the change in NPI-C A+A score from baseline to Day 43.
There are two estimands defined for the primary efficacy endpoint. The primary estimand is
Estimand 1, and the supplementary estimand is Estimand 2.
Estimand 1:
Study Intervention:
 
Experimental: seltorexant
 
Control: placebo
Population: participants with probable AD with clinically significant agitation/aggression, as
reflected by the inclusion/exclusion criteria.
Variable: change in NPI-C A+A from baseline to Day 43.
Summary measure: difference in treatment means between placebo and seltorexant 20 mg.
Intercurrent events and corresponding strategies:
 
Treatment discontinuation of study drug (Hypothetical strategy: as if the intercurrent event
had not occurred)
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 
Switch of treatment (Hypothetical strategy: see above)
 
Allowed rescue medication (Treatment policy strategy: all observed values of the endpoint
are used regardless of whether or not the participant had experienced this intercurrent event)
Estimand 2:
All components are the same as Estimand 1, except for intercurrent events and corresponding
strategies.
Intercurrent events and corresponding strategies:
 
Treatment discontinuation of study drug (Treatment policy strategy: all observed values of the
endpoint are used regardless of whether or not the participant had experienced this intercurrent
event)
 
Switch of treatment (Hypothetical strategy: as if the intercurrent event had not occurred)
 
Allowed rescue medication (Treatment policy strategy: all observed values of the endpoint
are used regardless of whether or not the participant had experienced this intercurrent event)
Main Analysis Under Estimand 1
The comparison between seltorexant 20 mg and placebo will be performed using the appropriate
contrasts in a MMRM with main comparison at Day 43. The MMRM will include stratification
factors (see Section 6.3), time, intervention group (placebo and seltorexant 20 mg) and time-by-
intervention interaction as factors, and baseline NPI-C A+A as a covariate. Difference in least
square means and 2-sided 80% CI will be presented.
Main Analysis Under Estimand 2
The copy reference (CR) multiple imputation (MI) method will be performed. A mixed model
(which will include the same factors and covariates as in the main analysis for Estimand 1) 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.
9.4.2. 
Secondary and Tertiary/Exploratory Endpoint(s)
The analyses for other efficacy endpoints and the analyses for exploratory endpoints (including
cognitive symptoms, actigraphy  and data obtained from the off-body touchless sensors, if
applicable) that are not described in the protocol will be described separately in the SAP. There is
no multiplicity adjustment for other efficacy endpoints.
9.4.3. 
Safety Analyses
All safety analyses will be made on the Safety Analysis Set.
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
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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 treatment-emergent AEs will be included in the
analysis. For each AE, the percentage of participants who experience at least 1 occurrence of the
given event will be summarized by intervention group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, or who experience a severe or
an SAE or an AESI.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and
for observed values and changes from baseline at each scheduled time point. Frequency tabulations
of the laboratory abnormalities will be made. A listing of participants with any markedly abnormal
laboratory results will be provided.
Electrocardiogram
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.
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 intervention group. The percentage of participants with values beyond clinically
important limits will be summarized. Changes in body weight, and BMI will be summarized
descriptively.
Physical and Neurological Examinations
Participants with abnormal findings in physical or neurological examination will be presented in a
data listing.
C-SSRS
Suicide-related thoughts and behaviors based on the C-SSRS will be summarized by intervention
group.
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Withdrawal Effects (PWC-20)
For PWC-20, frequency for individual item score and mean summaries for a total score (based on
8 items) will be provided by intervention group.
9.4.4. 
Other Analyses
Pharmacokinetic Analyses
Concentration-time data will be displayed by visit date, and time for seltorexant and its metabolite
M12. The levels of α1-acid glycoprotein will also be tabulated. In addition, plasma concentrations
of seltorexant, its M12 metabolite, and α1-acid glycoprotein in participants who discontinue study
intervention 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.
Population PK modelling
If feasible, a population PK analysis using a developed population PK model based on 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 total and unbound exposure parameters (eg, AUC) for seltorexant, and metabolite
M12. As part of the population PK modeling, the effect of intrinsic (eg, age, gender, body weight)
and extrinsic factors (eg, concomitant medications) affecting the PK of seltorexant may be
evaluated if needed. The results of the population PK analysis will be reported separately. The α1-
acid glycoprotein levels will be tabulated for each participant by visit date and time and will be
used to estimate the fraction unbound and predict the unbound concentrations and estimate the
individual unbound exposure parameters for seltorexant and major metabolite M12.
A snapshot date for PK samples to be analyzed will be defined, if required. Samples collected
before this date will be analyzed for seltorexant and included in the population PK analysis.
Samples collected after the snapshot date will be analyzed at a later date, and may be included in
a population PK re-analysis when they become available after database lock.
Data will be listed for all participants with available plasma concentrations per intervention group.
Participants will be excluded from the PK analysis if their data do not allow for accurate
assessment of the PK (eg, incomplete administration of the study intervention; missing information
of dosing and sampling times; concentration data not sufficient for PK parameter calculation).
All concentrations below the lowest quantifiable concentration or missing data will be labeled as
such in the concentration database. All participants and samples excluded from the analysis will
be clearly documented in the study report.
Biomarker, Genetic and Pharmacogenomic Analyses
Biomarker endpoints will be summarized, including change from baseline plasma concentrations
of p217+tau, Aβ42/40 levels and ratio, NfL, and other exploratory markers.
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DNA samples will be analyzed for APOE genotype and to allow for the possible evaluation of
genetic factors that may influence the PK, PD, safety, or tolerability of seltorexant and pathways
related to AD.
All biomarker and genetic data obtained during this study may be included in ongoing cross-study
analyses to investigate the relationship between phenotypes and biomarkers, or to help explain
inter-individual variability in clinical outcomes or safety.
Genetic research on enrolled participants may also consist of the analysis of CYP2C9 and
CYP3A4in relation to seltorexant.
Biomarker and genetic analyses are dependent upon the availability of appropriate assays and
clinical response rates. Biomarker and genetic analysis may be deferred or not performed, if during
or at the end of the study, it becomes clear that the analysis will not have sufficient scientific value
for biomarker or genetic evaluation, or if there are not enough samples or responders to allow for
adequate biomarker or genetic evaluation. In the event the study is terminated early or shows poor
clinical efficacy, completion of biomarker or genetic assessments is based on justification and
intended utility of the data. Results may be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
PK and efficacy assessments relationship may be explored, if feasible. The results of this analysis
may be reported separately.
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations and Definitions
Aβ  
Amyloid Beta
AChE 
Acetylcholinesterase
AD  
Alzheimer’s Disease
ADAS-Cog-14 
Alzheimer’s Disease Assessment Scale Cognitive subscale 14-item version
ADR  
Adverse drug reactions
AE  
Adverse event
AESI 
Adverse event of special interest
AGP  
Alpha-1-acid glycoprotein
ALT  
Alanine aminotransferase
APOE 
Apolipoprotein E
AST  
Aspartate transaminase
AUC  
Area Under the Curve
BMI 
Body mass index
BPSD 
Behavioral and Psychological Symptoms of Dementia
BPST  
Brief psychosocial therapy
CDR  
Clinical Dementia Rating
CI 
Confidence interval
CMAI-C 
Cohen-Mansfield Agitation Inventory — Community version
CNS  
Central Nervous System
COA  
Clinical Outcome Assessment (paper or electronic as appropriate for this study)
COPD  
Chronic Obstructive Pulmonary Disease
CPK  
Creatine phosphokinase
CR  
Copy Reference
(e)CRF  
(Electronic)Case Report Form
CrCl 
Creatinine Clearance
CRO  
Contract Research Organization
C-SSRS  
Columbia Suicide Severity Rating Scale
CT  
Computed Tomography
CTM  
Clinical Trial Manager
DAT  
Dementia of Alzheimer’s Type
DB  
Double-Blind
DBL  
Database lock
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders (5th edition)
DLBD  
Diffuse Lewy Body Dementia
ECG  
electrocardiogram
eDC  
electronic data capture
EMA  
European Medicines Agency
EW  
Early Withdrawal
FDA  
Food and Drug Administration
FOIA  
Freedom of Information Act
FSH  
Follicle Stimulating Hormone
FT4 
Free Thyroxine
FTD  
Frontotemporal Dementia
FU 
Follow-up
GAD2 
Glutamic acid decarboxylase 2
GDSI 
Geriatric Depression Scale, informant version
GCP  
Good Clinical Practice
HbA1c 
Hemoglobin A1c
HCP  
Health care professionals
HDRS-6 
6-item Hamilton Depression Rating Scale
HIS  
Hachinski Ischemic Scale
HMA  
Heads of Medicines Agencies
HPA  
Hypothalamic pituitary adrenal axis
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HRT  
Hormonal replacement therapy
IB  
Investigator’s Brochure
ICF  
informed consent form
ICH  
International Council on Harmonisation
ICMJE 
International Committee of Medical Journal Editors
IEC  
Independent Ethics Committee
IMP  
Investigational Medicinal Product
IND  
Investigational New Drug
IPA  
International Psychogeriatric Association
IRB  
Institutional Review Board
IS  
Insomnia symptoms
IWRS  
Interactive web response system
LC-MS/MS  
Liquid chromatography/mass spectrometry/mass spectrometry
LDH  
Lactic acid dehydrogenase
LPS  
Latency to persistent sleep
LTM  
Local Trial Managers
MADRS-6 
6-item Montgomery-Åsberg Depression Rating Scale
MAOI 
Monoamine oxidase inhibitor
MDD  
Major depressive disorder
MDDIS  
Major depressive disorder with insomnia symptoms
MDMA  
Methylenedioxymethamphetamine
MedDRA  
Medical Dictionary for Regulatory Activities
MI 
Multiple imputation
MMRM  
Mixed model repeated measures
MMSE 
Mini-Mental State Examination
MRI 
Magnetic Resonance Imaging
NfL 
NIMP  
Neurofilament Light Chain
Non-Investigational Medicinal Product
NOAEL 
No Observed Adverse Effect Level
NPI-12 
Neuropsychiatric Inventory
NPI-C 
Neuropsychiatric Inventory clinician version
NPI-C A+A  
Neuropsychiatric Inventory clinician version, sum of agitation and aggression domain scores
NPI-C D+H 
Neuropsychiatric Inventory clinician version, sum of delusion and hallucination domain scores
NPS  
Neuropsychiatric symptoms
OSA  
Obstructive Sleep Apnea
OX2R  
Orexin-2 receptor
PCC  
Protocol clarification communication
PD 
Pharmacodynamic(s)
PK 
Pharmacokinetic(s)
PQC  
Product Quality Complaint
PRO  
Patient-reported outcome(s)(paper or electronic as appropriate for this study)
PWC  
Physician Withdrawal Checklist
QTcF  
QT Interval Corrected Using Fridericia's Formula
REM  
Rapid Eye Movement
SAE 
Serious adverse event
SDI 
Sleep Disorder Inventory
SoA  
Schedule of Activities
SOL 
Sleep onset latency
SUSAR  
Suspected unexpected serious adverse reaction
TEAEs 
Treatment Emergent Adverse Events
TSH  
Thyroid-stimulating hormone
TST  
Total sleep time
ULN  
Upper Limit of Normal
VS  
Vital signs
WASO  
Wake After Sleep Onset
WASO-6 
Wake After Sleep Onset over the first 6 hours
WBC  
White Blood Cell
WHO  
World Health Organization
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Other 
Screening Tests 
 
Urine Drug Screen [opiates (including methadone), cocaine, amphetamines,
methamphetamines, cannabinoids, cannabidiol, barbiturates, MDMA]
 
Alcohol breath test
 
Lipid panel:
o Total cholesterol
o Triglycerides
o Low-density lipoprotein cholesterol
o High-density lipoprotein cholesterol
 
Hemoglobin A1c [HbA1c]
 
Thyroid-stimulating hormone [TSH]. For participants with a history of thyroid
disease and for participants who, regardless of thyroid history have TSH value
out of range, a free thyroxine [FT4] test will be conducted
 
Plasma concentrations of seltorexant, its M12 metabolite, and alpha-1-acid
glycoprotein [AGP].
 
Additional drug and alcohol tests may be conducted as needed per the
investigator’s judgment. In case of a positive result, one retest is allowed.
Furthermore, ifthe test results contradict to the data obtained from the patient and
caregiver, clinical judgement should be applied.
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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
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 Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification
communication (PCC) may be prepared. The PCC Document will be communicated to the
Investigational Site, Site Monitors, Local Trial Managers (LTMs), Clinical Trial Managers
(CTMs), and/or Contract Research Organizations (CROs) who will ensure that the PCC
explanations are followed by the investigators.
The PCC Document may be shared by the sites with Independent Ethics Committees/Institutional
Review Boards (IECs/IRBs) per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the
PCC Document must be included in any future protocol amendments.
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.
In situations where a departure from the protocol is unavoidable during the study, 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
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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 intervention
to the study site:
 
Protocol and amendment(s), if any, signed and dated by the principal investigator
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICFs, 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 sub-investigators
 
Documentation of sub-investigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
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 
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 ICFs (and any other written materials to be provided to the participants
and/or legal representatives and study partners)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants or study partners
 
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 ICFs, 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 ICFs and any other written materials to be provided to participants and/or legal
representatives and study partners
 
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 IB and amendments/addenda
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 
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
intervention
 
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
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  4.2.1, Study-Specific Ethical Design
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.3.2. 
Financial Disclosure
Investigators and sub-investigators 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 study and
for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
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10.3.3. 
Informed Consent Process
Each participant (or a legally acceptable representative) and their study partner must give written
consent according to local requirements after the nature of the study has been fully explained. The
ICF(s) must be signed before performance of any study-related activity. The ICF(s) that is/are used
must be approved by both the sponsor and by the reviewing IEC/IRB and be in a language that the
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 (or their legally acceptable representatives) and their study
partners the aims, methods, reasonably anticipated benefits, and potential hazards of the study, and
any discomfort participation in the study may entail. Participants and their partners 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 for the treatment of his or her disease. Participants will be told that
alternative treatments are available if they refuse to take part and that such refusal will not
prejudice future treatment. Finally, they will be told that the investigator will maintain a 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.
The participant (or legally acceptable representative) and their study partner 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 either the
participant's or his or her legally acceptable representative's, as well as study partner’s personally
dated signatures. After having obtained the consent, a copy of the ICF must be given to the
participant and their partner. In case when the participant’s legally acceptable representative signs
the ICF, any form of agreement (eg, verbal or written) to participate in the study should also be
obtained from the participant and documented. This should be done in accordance with state and/or
local regulations prior to the initiation of any trial related procedures and properly documented in
the source records. In any case, if the participant does not agree to participate in the study, then
the participant is not eligible.
Participants who are rescreened and their study partners are required to sign a new ICF.
Participants will be asked for consent to provide optional samples for research (where local
regulations permit). After informed consent for the study is appropriately obtained, the participant
(or his or her legally acceptable representative)will be asked to sign and personally date a separate
ICF indicating agreement for the participant to participate in the optional 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.
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
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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 (or his or her legally acceptable representative)
and their study partner 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
conditions of the study, and the applicable laws and regulations.
Exploratory DNA, PD, 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.
10.3.4. 
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 BPSD,
to understand differential intervention responders, and to develop tests/assays related to
seltorexant and BPSD. 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).
10.3.5. 
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 exploratory biomarker
research data, generated as a result of this study, are considered confidential and remain the sole
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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 exploratory biomarker analyses performed after the Clinical Study Report
has been issued will be reported in a separate report and will not require a revision of the Clinical
Study Report.
Study 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 sub-study approaches, secondary results generally should not
be published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 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
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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 the study in
order to ensure the statistical analyses are relevant.
10.3.6. 
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
study site personnel before the study, periodic monitoring visits by the sponsor, and direct
transmission of clinical data from central laboratory, ECG, eCOA, actigraphy, and IWRS vendors
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 as part of the annotated eCRFs.
The sponsor may review the eCRF for accuracy and completeness during on-site monitoring visits
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or
designee, as appropriate. After upload of the data into the study database they will be verified for
accuracy and consistency with the data sources.
10.3.7. 
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All protocol-required data relating to the study must be recorded in the eCRF. All eCRF
entries, corrections, and alterations must be made by the investigator or authorized study site
personnel. The investigator must verify that all data entries in the eCRF are accurate and correct.
The study data will be entered directly or transcribed by study site personnel from the source
documents onto an electronic eCRF. Study-specific data will be transmitted in a secure manner to
the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
the eCRF in English. The eCRF must be completed during or 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, scale information or other questionnaires) will be completed
by the same individual who made the initial baseline determinations whenever possible.
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If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed after
the initial entry into the eCRF, this can be done in either of the following ways:
 Investigator and study site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and study
site personnel.
10.3.8. 
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; intervention
receipt/dispensing/return records; study intervention administration information; and date of study
completion and reason for early discontinuation of study intervention  or withdrawal from the
study, if applicable. This includes eSource data captured directly in the eDC system.
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 another equivalent document). Site-specific source data collection methods will be captured in
the source data blueprint and monitored accordingly.
Any data recorded directly into the eCRF as the first recording of protocol-mandated data will be
considered source data.
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, including eSource, or
 Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant or study partner interview or other protocol required assessment (eg,
physical examination, laboratory assessment) and documented in the source documents.
An eSource 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. Protocol-required data is electronically
extracted for use by the sponsor. If eSource is utilized, references made to the eCRF in the protocol
include the eSource system but information collected through eSource may not be limited to that
found in the eCRF. eSource includes both source collected in a site’s own electronic health record,
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which will be transcribed into the eDC as soon as possible, and eSource captured directly in the
eDC.
10.3.9. 
Monitoring
The sponsor will use a combination of monitoring techniques: central, remote, or on-site
monitoring to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the
monitor will compare data entered into the eCRF with the source documents (eg,
hospital/clinic/physician’s office medical records); a sample may be reviewed. The nature and
location of all source documents will be identified to ensure that all sources of original data
required to complete the eCRF are known to the sponsor and study site personnel and are 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.
10.3.10. 
On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. 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.
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10.3.11. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs
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
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.
10.3.12. 
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/Site 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
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 Inadequate recruitment of participants by the investigator
 Discontinuation of further study intervention development
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10.4. Appendix 4: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.4.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have
a causal relationship with the intervention. 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 on
Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section  8.4.1, Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events Information, for time of last AE recording).
Serious Adverse Event
A 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
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between the study intervention and the event (eg, death from anaphylaxis), the event must be
reported as a serious and unexpected suspected adverse reaction even if it is a component of the
study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An 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 concomitant medication allowed for
treatment of the studied condition (eg, non-sedative antidepressants, AChE inhibitors, memantine)
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.
10.4.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is determined by the Investigator. The following
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.4.3. 
Severity Criteria
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation.
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
10.4.4. 
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional studythat may require
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expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study intervention
 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention
 
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal 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 intervention 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.
10.4.5. 
Procedures
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, 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 the
participant's discontinuation from the study, must be followed until any of the following occurs:
 
The event resolves
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 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study intervention 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)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the 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 intervention period.
The cause of death of a participant in a study within 30 days of the last dose of study intervention,
whether or not the event is expected or associated with the study intervention, is considered an
SAE.
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form, which
must be completed and signed by a physician from the study site, and transmitted in a secure
manner to the sponsor within 24 hours. The initial and follow-up reports of an SAE should be
made by facsimile (fax). Telephone reporting should be the exception and the reporter should be
asked to complete the appropriate form(s) first.
10.4.6. 
Product Quality Complaint Handling
Definition
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, reliability, or performance of a distributed product, including its labeling, drug delivery
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product.
In addition, it includes any technical complaints, defined as any complaint that indicates a potential
quality issue during manufacturing, packaging, release testing, stability monitoring, dose
preparation, storage or distribution of the product or the drug delivery system.
Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after
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being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues, PQC, or questions regarding the study 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
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Only women who are postmenopausal are allowed to enter the study (amenorrhea for at least 12
months).
Male participants who are heterosexually active with a woman of childbearing potential must use
a double-barrier (a combination of male condom with either cap, diaphragm, or sponge with
spermicide) method of birth control and not to donate sperm during the study and for 3 months
after receiving the last dose of study agent, and his female partner must use a highly effective
method of contraception.
Male participants who is sexually active with a woman who is pregnant must use a condom.
Participant must not plan to father a child while enrolled in this study or within 3 months after the
last dose of study intervention.
Pregnancy information will be collected and reported as noted in Section 8.4.5, Pregnancy and
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: 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
Female participants must be postmenopausal to participate in the study. A postmenopausal
state is defined as no menses for 12 months without an alternative medical cause. A high
follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the postmenopausal range
may be used to confirm a postmenopausal state in women not using hormonal contraception
or hormonal replacement therapy (HRT), however in the absence of 12 months of amenorrhea,
a single FSH measurement is insufficient.
 
permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, or bilateral salpingectomy, or bilateral
oophorectomy.
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
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be consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDYINCLUDE:
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)
 Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)
 Azoospermic partner (vasectomized or due to medical cause)
(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 74days.)
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 intervention.
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 intervention, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study intervention.
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: International Psychogeriatric Association (IPA) consensus
clinical and research definition of agitation in cognitive disorders
1. The patient meets criteria for a cognitive impairment or dementia syndrome (eg, AD, FTD,
DLB, vascular dementia, other dementias, a pre-dementia cognitive impairment syndrome
such as mild cognitive impairment or other cognitive disorder).
2. The patient exhibits at least one of the following behaviors that are associated with observed
or inferred evidence of emotional distress (eg, rapid changes in mood, irritability, outbursts).
The behavior has been persistent or frequently recurrent for a minimum of two weeks and
represents a change from the patient’s usual behavior.
a) Excessive motor activity (examples include: pacing, rocking, gesturing, pointing fingers,
restlessness, performing repetitious mannerisms).
b) Verbal aggression (eg, yelling, speaking in an excessively loud voice, using profanity,
screaming, shouting).
c) Physical aggression (eg, grabbing, shoving, pushing, resisting, hitting others, kicking
objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing
things, and destroying property).
3. Behaviors are severe enough to produce excess disability, which in the clinician’s opinion is
beyond that due to the cognitive impairment and including at least one of the following:
a) Significant impairment in interpersonal relationships.
b) Significant impairment in other aspects of social functioning.
c) Significant impairment in ability to perform or participate in daily living activities.
4. While co-morbid conditions may be present, the agitation is not attributable solely to another
psychiatric disorder, suboptimal care conditions, medical condition, or the physiological
effects of a substance.
Reference: Cummings 2015
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10.7. Appendix 7: 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
verapamil
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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 (eg, 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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10.8. Appendix 8: Benzodiazepine Equivalence Table
Benzodiazepines
Approximately Equivalent
Oral dosages (mg)
Alprazolam
(Xanax, Xanor, Tafil)
0.5
Bromazepam
(Lexotan, Lexomil)
5-6
Chlordiazepoxide
(Librium)
25
Clobazam
(Frisium)
20
Clonazepam
(Klonopin, Rivotril)
0.5
Clorazepate
(Tranxene)
15
Diazepam
(Valium)
10
Estazolam
(ProSom, Nuctalon)
1-2
Flunitrazepam
(Rohypnol)
1
Flurazepam
(Dalmane)
15-30
Halazepam
(Paxipam)
20
Ketazolam
(Anxon)
15-30
Loprazolam
(Dormonoct)
1-2
Lorazepam
(Ativan, Temesta, Tavor)
1
Lormetazepam
(Noctamid)
1-2
Medazepam
(Nobrium)
10
Nitrazepam
(Mogadon)
10
Nordazepam
(Nordaz, Calmday)
10
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Oxazepam
(Serax, Serenid, 
Serepax, Seresta)
20
Prazepam
(Centrax, Lysanxia)
10-20
Quazepam (Doral) 
20
Temazepam
(Restoril, Normison, 
Euhypnos)
20
Triazolam
(Halcion)
0.5
The Resource Site for Involuntary Benzodiazepine Tranquiliser Addiction, Withdrawal & Recovery.
Source: Benzodiazepine Equivalence Table.
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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 ofpower 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 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 (or legally acceptable representative) and study partner 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 local regulations, the informed consent
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form can be mailed to the potential participant and study partner 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 (or legally acceptable representative) and study partner can sign the
consent at home and mail it to the study site, if allowed by local regulations. Alternatively, the PI
or designee can visit the participant and study partner at home or residence to present the study
and obtain the informed consent form signatures. If the participant (or legally acceptable
representative) orstudy partner 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 (or legally acceptable representative’s) and study partner’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 (and legally
acceptable representative, if applicable) and study partner.
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, and alcohol breath tests.
Paper diaries: Paper-based versions will be either mailed/couriered or otherwise delivered to the
home and administered according to the instructions of the site staff or qualified designee. 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 diaries.
Observer-reported and clinician-reported interviews: Observer-reported and clinician-reported
interviews 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 NPI-C primary endpoint assessment is
to be administered in person; if the NPI-C is done remotely (eg, at Visit 5, Day 29) this interview
should be conducted by videoconference if possible (with audio-recording) The MMSE scale can
only be administered in person (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 Visitsand 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 DB Treatment/Early Withdrawal in the
double-blind phase visits should be prioritized.
At a minimum, the NPI-C, NPI-12, SDI, CMAI-C, 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, neurological and physical examinations. If the participant
has completed or withdrawn from the treatment phase, the final medical assessments of the End of
DB 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
High-level details of Amendment 1 are provided on Page 2.
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11. 
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: electronic signature appended at the end of the protocol 
Date: 
8 April 2023
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT05307692


Signature
User 
Date 
Reason
 
08-Apr-2023
08:57:45
(GMT)
Document Approval
PPD
NCT05307692

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: November 16, 2023
1
Janssen Research & Development
Statistical Analysis Plan
A Multicenter, Randomized, Placebo-Controlled, Double-Blind Study to Investigate the
Safety, Tolerability, and Clinical Efficacy of Seltorexant (JNJ-42847922) on Behavioral
and Psychological Symptoms of Dementia in Patients with Probable Alzheimer’s Disease
Protocol 42847922ALZ2001; Phase 2a
JNJ-42847922 (seltorexant)
Status:
Approved
Date:
November 16, 2023
Prepared by:
Janssen Research & Development, LLC
Document No.:   EDMS-RIM-700114; 3.0
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.
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Statistical Analysis Plan 42847922ALZ2001
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................................2
VERSION HISTORY ..................................................................................................................................................4
1.
INTRODUCTION...............................................................................................................................................5
1.1.
Objectives and Endpoints............................................................................................................................5
1.2.
Study Design .................................................................................................................................................7
2.
STATISTICAL HYPOTHESES.......................................................................................................................8
3.
SAMPLE SIZE DETERMINATION ................................................................................................................8
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS ..............................................................................8
5.
STATISTICAL ANALYSES ............................................................................................................................8
5.1.
General Considerations...............................................................................................................................8
5.1.1.
Visit Windows ............................................................................................................................................8
5.1.2.
Analysis Phases..................................................................................................................................... 10
5.1.3.
Imputation of Efficacy............................................................................................................................ 11
5.2.
Participant Dispositions ............................................................................................................................ 11
5.3.
Primary Endpoint(s) Analysis................................................................................................................... 11
5.3.1.
Definition ................................................................................................................................................. 11
5.3.2.
Estimand 1 .............................................................................................................................................. 12
5.3.2.1.
Analysis Methods ............................................................................................................................... 13
5.3.2.1.1.
Primary Analysis ............................................................................................................................. 13
5.3.3.
Estimand 2 .............................................................................................................................................. 13
5.3.3.1.
Analysis Methods ............................................................................................................................... 14
5.3.3.1.1.
Primary Analysis ............................................................................................................................. 14
5.4.
Secondary Endpoint(s) Analysis ............................................................................................................. 15
5.4.1.
Secondary Efficacy Endpoint(s)........................................................................................................... 15
5.4.1.1.
Cohen-Mansfield Agitation Inventory – Community Version (CMAI-C)...................................... 15
5.4.1.1.1.
Definition .......................................................................................................................................... 15
5.4.1.1.2.
Analysis Methods............................................................................................................................ 15
5.4.1.2.
Sleep Disorder Inventory (SDI) ........................................................................................................ 15
5.4.1.2.1.
Definition .......................................................................................................................................... 15
5.4.1.2.2.
Analysis Methods............................................................................................................................ 16
5.5.
Exploratory Endpoint(s) Analysis ............................................................................................................ 16
5.5.1.
Variables Derived from NPI-12 ............................................................................................................ 16
5.5.1.1.
Definition.............................................................................................................................................. 16
5.5.1.2.
Analysis................................................................................................................................................ 17
5.5.2.
Variables Derived from NPI-C.............................................................................................................. 17
5.5.2.1.
Definition.............................................................................................................................................. 17
5.5.2.2.
Analysis................................................................................................................................................ 17
5.5.3.
SDI Caregiver Distress Score..................................................................................................... 18
5.5.3.1.
Definition.............................................................................................................................................. 18
5.5.3.2.
Analysis................................................................................................................................................ 18
5.5.4.
Patient Withdrawal Checklist (20 items; PWC-20)............................................................................ 18
5.5.4.1.
Definition.............................................................................................................................................. 18
5.5.4.2.
Analysis................................................................................................................................................ 18
5.5.5.
Short-term rebound effects on behavioral and psychological symptoms of dementia (BPSD)      
as well as withdrawal symptoms ................................................................................................18
5.5.5.1.
Definition.............................................................................................................................................. 18
5.5.5.2.
Analysis................................................................................................................................................ 18
5.5.6.
CMAI-C Factor Scores .......................................................................................................................... 19
5.5.6.1.
Definition.............................................................................................................................................. 19
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Statistical Analysis Plan 42847922ALZ2001
5.5.6.2.
Analysis................................................................................................................................................ 19
5.5.7.
Geriatric Depression Scale, Informant Version (GDSI).................................................................... 19
5.5.7.1.
Definition.............................................................................................................................................. 19
5.5.7.2.
Analysis................................................................................................................................................ 19
5.5.8.
The association between treatment effect of seltorexant in sleep and treatment effect in 
agitation/aggression .............................................................................................................................. 20
5.5.8.1.
Analysis................................................................................................................................................ 20
5.5.9.
Cognitive Symptoms.............................................................................................................................. 20
5.5.9.1.
Definition.............................................................................................................................................. 20
5.5.9.2.
Analysis................................................................................................................................................ 21
5.5.10.
Subgroup Analyses................................................................................................................................ 21
5.6.
Safety Analyses ......................................................................................................................................... 21
5.6.1.
Extent of Exposure ................................................................................................................................ 22
5.6.1.1.
Intervention Compliance.................................................................................................................... 22
5.6.2.
Adverse Events ...................................................................................................................................... 22
5.6.3.
Additional Safety Assessments ........................................................................................................... 23
5.6.3.1.
Clinical Laboratory Tests................................................................................................................... 23
5.6.3.2.
Vital Signs and Physical Examination Findings ............................................................................. 24
5.6.3.3.
Electrocardiogram .............................................................................................................................. 25
5.6.3.4.
Other Safety Parameters................................................................................................................... 26
5.6.3.4.1.
Columbia Suicide Severity Rating Scale (C-SSRS) .................................................................. 26
5.7.
Other Analyses........................................................................................................................................... 27
5.7.1.
Pharmacokinetics................................................................................................................................... 27
5.7.2.
Actigraphy................................................................................................................................... 27
5.7.2.1
   Analysis ................................................................................................................................... 27
5.7.3.
Biomarkers.............................................................................................................................................. 28
5.7.4.
Definition of Subgroups......................................................................................................................... 28
6.
SUPPORTING DOCUMENTATION ........................................................................................................... 29
6.1.
Appendix 1 List of Abbreviations............................................................................................................. 29
6.2.
Appendix 2 Changes to Protocol-Planned Analyses............................................................................ 31
6.3.
Appendix 3 Demographics and Baseline Characteristics.................................................................... 32
6.4.
Appendix 4 Protocol Deviations............................................................................................................... 33
6.5.
Appendix 5 Prior and Concomitant Medications................................................................................... 34
6.6.
Appendix 6 Adverse Events of Special Interest .................................................................................... 35
6.7.
Appendix 7 Medications of Special Interest........................................................................................... 36
6.8.
Appendix 8 Criteria for Treatment-emergent Markedly Abnormal Laboratory Values..................... 37
6.9.
Appendix 9 Analyses for Assessing and Mitigating the Impact of COVID-19 on Study       
Outcome...................................................................................................................................................... 39
7.
REFERENCES................................................................................................................................... 40
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CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Statistical Analysis Plan 42847922ALZ2001
VERSION HISTORY
Table   – SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1.0
08/15/22
2.0
09/07/2023
1.1: Updated CDR cutoff for 
population from 2 to 1
5.1.1: Updated Visit Window for 
MMSE
5.3.1: Clarified the data usage 
rules regarding ICE strategies for 
the estimands
5.3.2, 5.3.3: Clarified rescue 
medication ICE
5.3.2, 5.5.7, 5.5.10: Removed 
community dwelling/assisted 
living status as factors from 
MMRM/ANCOVA models
5.3.2, 5.5.7, 6.3: Changed 
primary models to use per-eDC 
values of stratification factors, 
rather than per-IWRS values
5.3.2.1.1: Added that in the case 
that a structured covariance 
matrix needs to be used, a robust 
sandwich variance estimator will 
be used.
5.3.4: Section added to describe 
sensitivity analyses related to use 
of per-eDC vs per-IWRS values 
of stratification factors
5.4.1.2.2, 5.5.5.2, 5.5.8.1: 
Clarified that both SDI summary 
scores should be used.
Change is consistent with 
protocol amendment
Added baseline and Day 43 
windows to be consistent with 
schedule of activities for MMSE 
and windows for other 
parameters
Updated rules to remain 
consistent with other studies in 
the program
Existing wording did not specify 
how to handle rescue medication 
occurring after treatment 
discontinuation
Insufficient numbers of 
participants were stratified to 
each of the levels to include as a 
factor in models
Significant mis-stratification 
based on these stratification 
factors was observed. Study 
team agreed that per-eDC values 
should be used for primary 
analysis
Change to remain consistent 
with health authority feedback
for other studies in the program
Given that primary analysis was 
changed to use per-eDC values, 
a sensitivity analysis based on 
per-IWRS values was desired
Two different SDI summary 
scores exist. Both are of interest. 
Existing wording did not specify 
that both should be included
NCT05307692


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: November 16, 2023
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Statistical Analysis Plan 42847922ALZ2001
5.5.1.2: Remove Change from 
Baseline in NPI-12 Caregiver 
Distress Score MMRM analysis
5.5.5.2: Specified the exact NPI-
C analyses to be performed for 
rebound analysis
5.6.3.1: Added Shift in 
Metabolic Lab value table
5.6.3.1, 5.6.3.3: Clarified that 
only DB Lab and ECG values 
may be TE.
5.7.2.1: Actigraphy section 
updated to specify mobility 
parameters to be analyzed, and 
to specify analyses performed to 
explore correlations
5.7.4: Added Baseline NPI-12 
Sleep Doman Score, Age Group 
II, and BMI to listing of 
Subgroups
6.1: Added eCOA abbreviation 
to abbreviation table
6.3: Removed Prior Medications 
of Special Interest from Baseline 
Disease Characteristics table. 
Added baseline CDR score.
6.8: Updated several markedly 
abnormal thresholds for 
hematology variables to be 
expressed in Fraction of 1, rather 
than %. Updated lab test names. 
Updated Vitamin B12 limits to 
be expressed in correct units.
Team agreed that means and 
mean changes in Caregiver 
Distress over time were 
sufficient for exploration of this 
endpoint
Specified sub-totals are of more 
interest for this study than total 
score
To assist in clinical 
understanding of treatment
Clarifying that post-
discontinuation of treatment labs 
would not be considered TE
After seeing the parameters 
included in actigraphy data, the 
team agreed upon exact 
parameters to analyze, and 
analyses to perform
Updated subgroups of interest 
based on team consensus
For clarification
Prior Medications of Special 
Interest to be included in a 
separate output. Baseline CDR
added to observe impact of 
protocol amendment
Updates made to align table with 
structure of received data
3.0
11/14/2023
5.4.1.1.1
5.6.3.1
Clarified the calculation of 
CMAI-C total score
Team decision to produce shift 
in lab value table for all 
chemistry labs. Added categories 
for metabolic lab shifts
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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analyses for study 42847922ALZ2001.
1.1.
Objectives and Endpoints
For the following objectives and endpoints, probable AD with clinically significant 
agitation/aggression is defined as: Diagnostic and Statistical Manual of Mental Disorders-5th Edition
(DSM-5) diagnosis of probable Alzheimer’s Disease (AD) and criteria of a syndrome diagnosis of 
agitation based on International Psychogeriatric Association (IPA) consensus clinical and research 
definition of agitation in cognitive disorders, have an MMSE total score from 10 to 24 (inclusive), 
and a Clinical Dementia Rating (CDR) of ≥1. Additionally, patients will be characterized by the 
presence of clinically significant agitation/aggression defined as NPI-12 agitation/aggression (A/A) 
domain score ≥4 with NPI frequency score ≥2 at entry and baseline with no more than 35% of 
improvement allowed in NPI-12 A/A score during the screening period.
Double-blind Treatment Phase
Objectives
Endpoints
Efficacy
Primary

To investigate the effect of seltorexant 
versus placebo on the sum of agitation and 
aggression domain scores (A+A) of the 
Neuropsychiatric Inventory - Clinician 
rating (NPI-C) in participants
with 
probable AD with clinically significant
agitation/aggression.

Change from baseline to Day 43 on NPI-
C A+A scores.
Secondary –Efficacy
To investigate the effect of seltorexant versus placebo on the following in participants with
probable AD with clinically significant agitation/aggression:

Cohen-Mansfield Agitation Inventory 
community version (CMAI-C) total score

Change from baseline to Day 43 on the 
total CMAI-C score.

Sleep symptoms as assessed by the Sleep 
Disorder Inventory (SDI).

Change from baseline to Day 43 on SDI 
total score.
Secondary –Pharmacokinetics

To investigate the plasma 
pharmacokinetics (PK) of seltorexant and 
its M12 metabolite in participants with 
probable AD with clinically significant 
agitation/aggression.

Plasma concentrations of seltorexant and 
its M12 metabolite at Day 15 and Day 43.
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Objectives
Endpoints
Exploratory –Digital
To investigate the effect of seltorexant versus placebo on the following in participants with
probable AD with clinically significant agitation/aggression:

Sleep and activity metrics using an 
actigraphy device.

Change from baseline on sleep and 
activity metrics.

Sleep and mobility using an off-body 
touchless sensor in a subset of 
participants, (if feasible and available)

Change from baseline on sleep and 
mobility measurements.
Exploratory –Biomarkers

To investigate the effect of seltorexant 
versus placebo in participants with 
probable AD with clinically significant 
agitation/aggression on blood biomarkers 
including but not limited to:
o
biomarkers of AD, eg, p217+tau, Aβ1-
42/40 levels and ratio, NfL, and other
exploratory biomarkers

Change from baseline in levels of blood 
biomarkers of AD
Other Exploratory
To investigate the effect of seltorexant versus placebo on the following in participants with
probable AD with clinically significant agitation/aggression:

Variables derived from the NPI-12/NPI-C 
rating:
o
The sum of the NPI-C delusion and
hallucination domain scores (NPI-C
D+H)
o
Individual NPI-C domain scores for
agitation, aggression, dysphoria,
delusions, and hallucinations
o
NPI-12 total score
o
NPI-12 Caregiver Distress total score
o
All NPI-12 individual item scores

Change from baseline over time on the 
specified NPI-12/NPI-C variables.

SDI Caregiver Distress score

Change from baseline over time in SDI 
caregiver distress

Short-term rebound effects on behavioral 
and psychological symptoms of dementia 
(BPSD) as well as withdrawal symptoms

Change in Physician Withdrawal
Checklist (PWC-20) from End of DB 
Treatment/EW to first follow up visit.

Change in NPI-12, NPI-C and SDI scores 
from End of DB Treatment/EW to first 
follow up visit.

CMAI-C factor scores

Change from baseline over time on 
CMAI-C factor scores.

Depressive symptoms as assessed by the 
Geriatric Depression Scale, Informant 
version (GDSI).

Change from baseline on GDSI Total 
score at Day 43.
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Objectives
Endpoints

The association between treatment effect
of seltorexant in sleep and treatment effect 
in agitation/aggression

Correlation between change in NPI-C 
A+A and change in SDI total score, and 
mediation effect on change in NPI-C 
A+A through change in SDI total score

Cognitive symptoms

Change from baseline to Day 43 on 
Alzheimer’s Disease Assessment Scale 
Cognitive subscale 14-item version
(ADAS-Cog-14) composite cognitive 
score and from screening to Day 43 on 
the Mini-Mental State Examination
(MMSE) total score.
Safety
To investigate the effect of seltorexant versus placebo on the following in participants with
probable AD with clinically significant agitation/aggression:

Safety and tolerability of seltorexant

Change from baseline in Vital signs, 
Clinical Labs (chemistry, hematology, 
urinalysis), ECG, C-SSRS, and 
Treatment Emergent Adverse Events
(TEAEs) including AEs of special
interest (AESI).
Statistical hypotheses pertaining to the primary endpoint are described in Section 2.
Descriptive analysis of pharmacokinetic data is described in section 5.7.1. Details about further
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 to assess the
efficacy and safety of seltorexant 20mg in participants aged 55 to 85 years, inclusive, with probable 
AD with clinically significant agitation/aggression.
This study will consist of 3 phases: a screening phase (up to 28 days), a double-blind treatment
phase (43 days), and a post-treatment follow-up phase (14 days after DB treatment phase).
Approximately 86 participants with probable AD and clinically significant agitation/aggression 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 stratified by baseline NPI-12 sleep domain score (<4, ≥4) 
and community dwelling/assisted living.
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 57.
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Participants will take their assigned study intervention at home, once daily at bedtime during DB 
treatment phase.
2.
STATISTICAL HYPOTHESES
This study is designed to show that the treatment effect in improving agitation and aggression (as 
measured by change from baseline on Day 43 in NPI-C A+A score) of seltorexant 20 mg is superior 
to placebo in participants with probable AD with clinically significant agitation/aggression.
If µT is the mean change in NPI-C A+A total score for seltorexant group and µP is the mean change 
in NPI-C A+A 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 0.20.
3.
SAMPLE SIZE DETERMINATION
Assuming a treatment difference of 5 points in change from baseline in NPI-C A+A score between 
seltorexant 20 mg and placebo, a standard deviation of 10 (effect size of 0.5), and a 15% drop-out 
rate during the 6-week double-blind phase, 86 participants (randomized in 1:1 ratio to placebo and 
seltorexant 20 mg) will need to be enrolled in the double-blind phase, in order to achieve 80% power 
to detect treatment difference, at one-sided 0.1 significance level.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Analysis Sets
Description
All Enrolled
All participants who sign the ICF
All Randomized
All participants who were randomized in the study.
Full
All randomized participants who take at least 1 dose of 
study intervention
Follow-up
All randomized participants who provide data in the 
follow-up visit(s).
Safety
All randomized participants who take at least 1 dose of 
study intervention
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
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analyses, but they can be used for determination of clinically important endpoints. If 2 actual 
visits are equidistant from the target day within a visit window, the later visit is used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point except for the endpoint. Listed below
(Table 1) are the 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)*
NPI-12
SDI
C-SSRS
SCR
1
Screening
<1
DB
2
Baseline (DB)
<=1
1
4
Day 15
2 to 22
15
5
Day 29
23 to 36
29
6
Day 43
37 to End of DB
43
DB final visit
Endpoint (DB)
2 to End of DB
FU (DB)
7
Day 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 57 EW
49 to End of FU
57
NPI-C
DB
2
Baseline (DB)
<=1
1
4
Day 15
2 to 22
15
5
Day 29
23 to 36
29
6
Day 43
37 to End of DB
43
DB final 
Endpoint (DB)
2 to End of DB
FU (DB)
7
Day 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 57 EW
49 to End of FU
57
CMAI-C
ADAS-Cog-14
DB
2
Baseline (DB)
<=1
1
4
Day 15
2 to 29
15
6
Day 43
30 to End of DB
43
DB final
Endpoint (DB)
2 to End of DB
GDSI
DB
2
Baseline (DB)
<=1
1
6
Day 43
2 to End of DB
43
DB final visit
Endpoint (DB)
2 to End of DB
MMSE
SCR
1
Screening
<1
DB
2
Baseline (DB)
<=1
6
Day 43
2 to End of DB
43
DB final visit
Endpoint (DB)
2 to End of DB
Weight
Labs
SCR
1
Screening
<1
DB
2
Baseline (DB)
<=1
1
DB final visit
Endpoint (DB)
2 to End of DB
Vital Signs
SCR
1
Screening
<1
DB
2
Baseline (DB)
<=1
1
4
Day 15
2 to 29
15
6
Day 43
30 to End of DB
43
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DB final visit
Endpoint (DB)
2 to End of DB
Parameter
Analysis Phase
Scheduled 
Visit Number
Time Interval (label 
on output)
Time Interval 
(Day)*
Target Time 
Point (Day)*
FU (DB)
7
Day 57
End of DB + 1 
to End of FU
10
Day 15 EW
2 to 29
15
Day 43 EW
30 to 48
43
Day 57 EW
49 to End of FU
57
12-lead ECG
SCR
1
Screening
<1
DB
2
Baseline (DB)
<=1
1
6
Day 43
2 to End of DB
43
DB final visit
Endpoint (DB)
2 to End of DB
PWC-20
DB
DB final visit
Endpoint (DB)
2 to End of DB
43
FU (DB)
7
Day 57
End of DB + 1 
to End of FU
10
Actigraphy
SCR
Screening
<1
DB
Baseline (DB)
-7 to -1
Week 1
1 to 7
Week 2
8 to 14
Week 3
15 to 21
Week 4
22 to 28
Week 5
29 to 35
Week 6
36 to End of DB
* 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.
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 studyintervention. 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 study disposition date.
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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
Copy Reference
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, full 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 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 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 studyintervention

Participants who were unblinded during the studyperiod

Participants who were randomized yet did not receive studyintervention.
Additional analyses of disposition data for assessing and mitigating the impact of COVID-19 on 
study outcome are presented in Section 6.9.
5.3.
Primary Endpoint(s) Analysis
The primary analysis will be based on the full analysis set using the NPI-C A+A score.
5.3.1.
Definition
The primary efficacy endpoint is the change in NPI-C A+A score from baseline (DB) to Day 43.
The Neuropsychiatric Inventory-Clinician Rating (NPI-C) (de Medeiros 2010) is an instrument that
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expands upon the items and 12 symptom domains of the original NPI. The modified rating 
methodology of the NPI-C incorporates the expert clinician’s impressions to the data provided by the 
patients and caregivers. For each domain, the domain score will be calculated as the sum of clinician 
severity ratings (from 0=does not occur to 3=severe) for each item. NPI-C A+A score is the sum of 
the domain scores from the Agitation and Aggression domains at a given time point, and ranges from 
0 to 63. Higher scores represent a more serious condition.
Negative changes in NPI-C A+A represent improvement.
Two estimands are defined for the primary endpoint: The primary estimand is Estimand 1, and
the supplementary estimand is Estimand 2.
The sections below describe the primary analyses performed for each primary and supplementary 
estimand. For treatment policy strategy, data collected after participants experienced intercurrent 
events will be included in analyses; for hypothetical strategy, data collected after participants 
experienced an intercurrent event of treatment switch will not be included in analyses. Otherwise, 
data observed up to and including DB disposition day will be included.
5.3.2.
Estimand 1
Estimand 1 will be the primary estimand.  The analysis will be performed on the full analysis set.
Primary Trial Objective: To evaluate the efficacy of seltorexant 20 mg compared with placebo in 
improving agitation/aggression symptoms in participants with probable AD with clinically 
significant agitation/aggression.
Estimand Scientific Question of Interest: What is the benefit in improving agitation/aggression 
symptoms from seltorexant 20 mg versus placebo in adults and elderly participants with probable AD 
with clinically significant agitation/aggression based on the change from baseline in NPI-C A+A
score if the participants take study intervention as directed?
Estimand 1 is defined by the following 5 components:
Study Intervention:
Experimental: Seltorexant dose of 20 mg
Control: Placebo
Population: Participants with probable AD with clinically signification agitation/aggression, as reflected 
by the inclusion/exclusion criteria.
Variable: Change in NPI-C A+A total score from baseline to Day 43
Summary Measure: Difference in intervention means
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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.
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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 NPI-C A+A total score by intervention group. Under the treatment policy 
strategy, data from participants who discontinued the 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.
5.3.4.
Sensitivity Analysis Related to Mis-stratifications
Sensitivity analyses to evaluate the impact of using per-eDC values of stratification factors rather than 
per-IWRS values on the primary endpoint will be performed. The analyses described in sections 5.3.2 
and 5.3.3 will be performed using the per-IWRS values of the NPI Sleep domain score category
instead of the per-eDC values. Difference in least square means and 2-sided 80% CI will be presented.
5.4.
Secondary Endpoint(s) Analysis
5.4.1.
Secondary Efficacy Endpoint(s)
Similar to the primary endpoint, the primary analysis of the secondary efficacy endpoints will be based 
on the full analysis set.
5.4.1.1.
Cohen-Mansfield Agitation Inventory —Community Version (CMAI-C)
5.4.1.1.1.
Definition
The first secondary endpoint is the change in CMAI-C from baseline(DB) to Day 43.
The CMAI-C is a 37-item scale that measures the ability of a drug to reduce overall frequency of
agitation symptoms, including aggressive behaviors (Cohen-Mansfield 1991). Individual items
are rated by an expert clinician on a scale of 1 to 7 in which a score of 7 represents the most
frequent for each item assessed. CMAI-C total score is the sum of the first 36 individual item 
responses.
Negative changes in CMAI-C total score indicate improvement.
5.4.1.1.2.
Analysis Methods
The change from baseline in CMAI-C total score will be analyzed using the same MMRM model as 
described for the NPI-C A+A score, with baseline CMAI-C total score as the covariate. Comparison 
between seltorexant and placebo at Day 43 will be performed using the appropriate contrast. 
Difference in least square means and 2-sided 80% CI will be presented.
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point will be presented for CMAI-C total score by intervention group.
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Least squares mean changes from baseline(DB) (+/- SE) will be presented graphically over time.
5.4.1.2.
Sleep Disorder Inventory (SDI)
5.4.1.2.1.
Definition
The Sleep Disorders Inventory (SDI) is based on a caregiver interview and an expanded version
of one item of the NPI-12 (Tractenberg 2003). It describes the frequency, severity, and caregiver
burden of sleep-disturbed behaviors during a period prior to its administration.
The SDI was created by expanding item 11 of the 12-item NPI. According to the basic structure of 
the NPI-12, the respondent is asked a 'screening' question, a general indication of whether or not 
symptoms in that particular behavioral area are present. If the screening question is positive, then 
specific sub-questions are asked. The SDI consists of the seven sub-questions from the NPI-12 sleep 
disturbance item. Each of the sub-questions was made into a separate question with frequency, 
severity, and caregiver distress rated by the caregiver with respect to the participant. 
Thus, in contrast to a single rating for frequency and severity for all sleep disturbance-related 
behaviors, which would be incorporated into an overall NPI-12 score, the SDI score is derived after 
the caregiver rates the frequency and severity of each of the seven separate sleep disturbance 
symptoms. The SDI Average Total score is calculated by multiplying the average frequency score 
across all items by the average severity score across all items. The SDI Summed Product score is the 
calculated by summing the product of frequency and severity scores for each item.
5.4.1.2.2.
Analysis Methods
The change from baseline in SDI average total score and SDI summed product score will be analyzed 
using the same MMRM model as described for the NPI-C A+A score, with baseline SDI Average 
Total score and baseline SDI Summed Product score, respectively, as the covariate. Comparison 
between seltorexant and placebo at Day 43 will be performed using the appropriate contrast. 
Difference in least square means and 2-sided 80% CI will be presented.
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point will be presented for SDI average total score and SDI summed product score by intervention
group.
Least squares mean changes from baseline(DB) (+/- SE) will be presented graphically over time.
5.5.
Exploratory Endpoint(s) Analysis
Exploratory analyses will be performed for the endpoints described in the sections below for the full 
analysis set.
5.5.1.
Variables Derived from NPI-12
5.5.1.1.
Definition
The NPI-12 is a measure of psychobehavioral disturbances (Cummings 1994; 1997), assessing the
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frequency and severity of disturbances in 12 domains, based on a caregiver interview. An answer of 
“No” on the domain screening question indicates that the patient does not exhibit symptoms in the
domain and will result in a domain score of 0. Otherwise, frequency of each domain is rated on a 4-
point scale (from 1=rarely to 4=very often) and severity on a 3-point scale (from 1=mild to 3=severe), 
with the score for each domain being the product of the frequency and severity scores, such that each 
domain is scored from 1 to 12. The NPI-12 total score is the sum of all individual NPI-12 domain 
scores.
For each domain, there is also an assessment of caregiver burden. Caregiver distress, based on the 
response to the question “how emotionally distressing do you find this behavior?”, is rated on a 6-
point scale (from 0 = not at all to 5 = very severely or extremely), with the total score for caregiver 
distress ranging from 0 (best) to 60 (worst).
The following variables derived from the NPI-12 will be analyzed:

NPI-12 total score

NPI-12 Caregiver Distress total score

All NPI-12 individual item scores
5.5.1.2.
Analysis
The change from baseline in NPI-12 total score will be analyzed using the same MMRM model as 
described for the NPI-C A+A score, with baseline NPI-12 total score as the covariate. Comparison 
between seltorexant and placebo at Day 43 will be performed using the appropriate contrast. 
Difference in least square means and 2-sided 80% CI will be presented.
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point will be presented for NPI-12 total score by intervention group. 
Least squares mean changes from baseline(DB) (+/- SE) will be presented graphically over time.
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point will be presented for NPI-12 Caregiver Distress total score by intervention group. 
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point will be presented for each NPI-12 individual score by intervention group. 
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5.5.2.
Variables Derived from NPI-C
5.5.2.1.
Definition
The following variables derived from the NPI-C will be analyzed:

The sum of the NPI-C delusion and hallucination domain scores (NPI-C D+H)

Individual NPI-C domain scores for agitation, aggression, dysphoria, delusions, and 
hallucinations
5.5.2.2.
Analysis
The change from baseline in NPI-C D+H score will be analyzed using the same MMRM model as
described for the NPI-C A+A score, with baseline NPI-C D+H score as the covariate. Comparison 
between seltorexant and placebo at Day 43 will be performed using the appropriate contrast. 
Difference in least square means and 2-sided 80% CI will be presented.
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point will be presented for NPI-C D+H total score by intervention group. 
Least squares mean changes from baseline(DB) (+/- SE) will be presented graphically over time.
The change from baseline in the specified individual NPI-C domain scores will be analyzed using 
the same MMRM model as described for the NPI-C A+A score, with the corresponding baseline 
NPI-C domain score as the covariate.
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point will be presented for the specified individual NPI-C domain scores by intervention group.
5.5.3.
SDI Caregiver Distress Score
5.5.3.1.
Definition
Caregiver distress is collected for each item in the SDI, as defined in Section 5.4.1.2.1. The total 
caregiver distress score is the sum of the distress score for each item.
5.5.3.2.
Analysis
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point will be presented for the SDI Caregiver Distress score by intervention group.
5.5.4.
Patient Withdrawal Checklist (20 items; PWC-20)
5.5.4.1.
Definition
The PWC-20 is a reliable and sensitive instrument for the assessment of discontinuation symptoms 
(Rickels K, Garcia-Espana R, Mandos LA, Case GW. Physician Withdrawal Checklist (PWC-20). J
Clin Psychopharmacol.2008;28(4):447-451.). The PWC-20 is a simple and accurate method used to 
assess potential withdrawal symptoms following cessation of studyintervention.
5.5.4.2.
Analysis
The proportion of participants with withdrawal symptoms at the end of DB phase and follow-up visits 
will be presented by intervention group.
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In addition, symptoms at follow-up will be compared to the end of therapy visit for double-blind 
phase 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.
5.5.5.
Short-term rebound effects on behavioral and psychological symptoms of 
dementia (BPSD) as well as withdrawal symptoms
5.5.5.1.
Definition
The NPI-12, NPI-C and SDI will be used to monitor changes in symptoms between withdrawal and 
the first follow up visit.
5.5.5.2.
Analysis
The baseline(FU) is defined as the value at the end of DB phase for participants who have entered 
the follow-up phase.
Descriptive statistics of the actual values and the change from baseline (FU) to the first follow up 
visit will be presented for the NPI-12 total score, NPI-C A+A score, NPI-C D+H score, NPI-C 
Dysphoria score, SDI average total score, and SDI summed product score by intervention group.
5.5.6.
CMAI-C Factor Scores
5.5.6.1.
Definition
CMAI-C factors are derived from the original CMAI-C scale. Each item is classified as a physically 
nonaggressive behavior (PNAB), physically aggressive behavior (PAGB), verbally nonaggressive 
behavior (VNAB), or verbally aggressive behavior (VAGB). The CMAI-C factor score for each 
factor is calculated by summing the individual scores for each item within the factor.

Physically nonaggressive behaviors (PNAB): General restlessness, repetitious
mannerisms, pacing, trying to get to a different place, handling things inappropriately, hiding, and
inappropriate dressing or undressing; scale items 14, 15, 16, 17, 18, 19, 21, 22

Physically aggressive behaviors (PAGB): Hitting, pushing, scratching, grabbing things,
and grabbing people (kicking, biting); scale items 10, 13, 20, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 
35

Verbally nonaggressive behaviors (VNAB): Negativism, doesn’t like anything, constant
requests for attention, verbal bossiness, complaining or whining, relevant interruptions, irrelevant
interruptions, and repeating sentences; scale items 1, 2, 3, 6, 7, 8, 11

Verbally aggressive behaviors (VAGB): Screaming, cursing, temper outbursts, and
making strange noises; scale items 4, 5, 9, 12, 23
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5.5.6.2.
Analysis
Descriptive statistics of the actual values and the change from baseline(DB) to each post-baseline time 
point will be presented for each CMAI-C factor by intervention group.
5.5.7.
Geriatric Depression Scale, Informant Version (GDSI)
5.5.7.1.
Definition
The GDSI is a 30- or 15-item self-report assessment used to identify depressive symptomatology in 
the elderly. GDSI is a version developed to be completed based on the informant (a study partner for 
the purpose of the study) rating of the participant’s symptoms. The GDSI consists of the same 15 
items as the original GDS 15-item self-report version.
5.5.7.2.
Analysis
Descriptive statistics of the patient-reported GDSI total score at baseline(DB) and endpoint (DB), as 
well as the change from baseline to Endpoint (DB), will be presented by intervention group.
An ANCOVA model will be used to test the difference of change from baseline at endpoint(DB) in 
GDSI total score between seltorexant and placebo. The model will include intervention and baseline 
NPI Sleep domain score category (per eDC) as factors, and baseline(DB) GDSI total score value as 
a covariate. Difference of least square means and 2-sided 80% CI will be presented.
5.5.8.
The association between treatment effect of seltorexant in sleep and 
treatment effect in agitation/aggression
5.5.8.1.
Analysis
Correlations between change in NPI-C A+A score and change in SDI average total score and between 
change in NPI-C A+A score and change in SDI summed product score over time will be explored; 
Pearson and Spearman correlation coefficients will be calculated. Scatter plot of change in scores of 
the 2 assessment scales over time will be presented for each intervention group.
A mediation analysis will be performed to examine the mediating role of improvement in sleep 
assessed by change from baseline in SDI score on change from baseline in NPI-C A+A score 
provided that both endpoints demonstrate a statistically significant difference between seltorexant
and placebo. This analysis will assess the extent to which change in NPI-C A+A score may be 
mediated by or independent of change in SDI score based on observed data (i.e., data collected at 
each time point without carrying forward previous values) at Day 43. The analysis will consider both 
change in NPI-C A+A score and change in SDI score as continuous variables.

Simulation-based Counterfactual Approach: this analysis introduced by Imai et. al obtains the 
natural direct effect and natural indirect effect using numerical simulations. The approach 
uses parametric bootstrapping to construct the point estimate and its uncertainty estimates for 
direct effect and indirect effect from the bootstrap sampling distribution. For each 
bootstrapped sample, change from baseline in NPI-C A+A score and change from baseline in 
SDI score will be analyzed. The ANCOVA analysis of change in NPI-C A+A score from 
baseline will include factors for treatment (placebo and seltorexant dose groups), change 
from baseline (Day 1, predose) in SDI score, treatment-by-change from baseline in SDI score 
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interaction if the interaction is significant, and baseline NPI-C A+A score as a covariate. The 
ANCOVA analysis of change in SDI score will include factors for treatment (placebo and 
seltorexant dose groups), and baseline NPI-C A+A score as a covariate. Estimate of the 
controlled direct effect will be obtained by plugging in the estimated coefficient values and 
the mean level of change in SDI score into the analytic expressions. 
5.5.9.
Cognitive Symptoms
5.5.9.1.
Definition
The Alzheimer’s Disease Assessment Scale Cognitive subscale 14-item version (ADAS-Cog-14) is 
a rater administered instrument that was designed to assess the severity of dysfunction in cognition 
characteristic of persons with AD (Rosen 1984). The ADAS-Cog-11 consists of 11 tasks measuring 
the disturbances of memory, language, praxis, attention, and other cognitive abilities, which are often 
referred to as the core symptoms of AD.
The modified ADAS-Cog 14-item scale includes all original ADAS-Cog items with the addition of 
a number cancellation task, Maze task and a delayed free recall task, for a total of 90 points, with 
higher scores indicative of worse cognitive performance.
The Mini-Mental State Examination (MMSE) 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) 
(Creavin 2016; Folstein 1975).
5.5.9.2.
Analysis
The change from baseline in ADAS-Cog-14 total score will be analyzed using the same MMRM 
model as described for the NPI-C A+A score, with baseline ADAS-Cog-14 total score as the 
covariate. Comparison between seltorexant and placebo at Day 43 will be performed using the 
appropriate contrast. Difference in least square means and 2-sided 80% CI will be presented.
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point will be presented for ADAS-Cog-14 total score by intervention group. 
Least squares mean changes from baseline(DB) (+/- SE) will be presented graphically over time.
The change from baseline in MMSE total score will be analyzed using the same ANCOVA model as 
described for the GDSI score, with baseline MMSE total score as the covariate. Comparison between 
seltorexant and placebo at Day 43 will be performed using the appropriate contrast. Difference in 
least square means and 2-sided 80% CI will be presented.
Descriptive statistics of the actual values and the change from baseline(DB) to each postbaseline time 
point will be presented for MMSE total score by intervention group.
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5.5.10.
Subgroup Analyses
For the subgroups listed in Section 5.7.4, subgroup analyses using MMRM will be performed for the 
change in NPI-C A+A total score at Day 43. The fixed terms in the model will be intervention group,
baseline NPI-12 sleep domain score category (<4, ≥4) per eDC, time, subgroup, time-by-intervention 
interaction, intervention-by-subgroup interaction, and time-by-intervention-by-subgroup interaction
as factors, and baseline(DB) NPI-C A+A total score as a covariate. Point estimate of the treatment
difference and 2-sided 80% CI will be estimated using appropriate contrasts. 
The analysis results (difference of LS means and 80% CI) of the different subgroups will be displayed 
in a forest plot.
Additionally, descriptive statistics of the actual values and the change from baseline(DB) to each 
postbaseline time point will be presented for NPIC A+A total score by intervention group and 
subgroup.
Similar subgroup analyses will be performed for the change in CMAI-C score. The results will be 
displayed in a forest plot.
The analyses will be performed for the Full analysis set.
5.5.11.
Change in Care Settings
A listing of participants who have changed their care settings (community dwelling or assisted living) 
during the DB phase will be provided for the Full analysis set. 
5.6.
Safety Analyses
All safety analyses will be based on safetyanalysis set.
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 (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, 9-21 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. 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).
The analysis will be performed on the safety analysis set.
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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.
Compliance will be calculated for the study intervention as:
Compliance (%) = (number of days where the expected number of tablets were taken)/(days expected 
to be dosed (includes days where the study intervention was not taken)) x 100
The analysis will be performed on the safety analysis set.
5.6.2.
Adverse Events
The verbatim terms used in the CRF byinvestigators to identifyadverse 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 planned 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

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.
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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.
Shift in chemisty lab values from baseline to maximum post-baseline value will be summarized for 
the double-blind phase and displayed by study intervention group. Shift in Metabolic Lab values
specifically from baseline to maximum post-baseline value will be summarized for the double-blind 
phase and displayed by study intervention group based on the following categories.
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 to high)

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/very high)

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 to low)
LDL Cholesterol  

from < 100mg/dL to ≥160 mg/dL (normal to high)
Clinical laboratory test values in the double-blind phase will be considered “treatment-emergent 
markedly abnormal” (TEMA) using the criteria defined by the sponsor listed in Section 6.8.

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.
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
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, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center
for Biologics Evaluation and Research (CBER). [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 the criteria or are missing will be eligible for these analyses.
A listing of participants with treatment emergent 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.
5.6.3.2.
Vital Signs
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 for the double-blind phase. 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. 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 or High).

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
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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.
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.
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Postbaseline abnormalities will be compared with their corresponding average baseline result:

Treatment-emergent will be concluded if the postbaseline value in the double-blind phase 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 in the double-blind phase 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.
A listing of treatment emergent 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 K, Oquendo 
MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide Assessment (C-
CASA): classification of suicidal events in the FDA’s pediatric suicidal risk analysis of 
antidepressants. Am J Psychiatry. 2007;164:1035-1043.). 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
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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.
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.
5.7.
Other Analyses
5.7.1.
Pharmacokinetics
PK analyses will be addressed in a separate plan.
5.7.2.
Actigraphy
Objective sleep parameters are measured using Actigraphy.
The device, Phillips Actiwatch Spectrum, is a wristwatch actigraphy system that provides accurate 
and objective activity, sleep, wake, and light-exposure data. Subjects will wear the device 
continuously during the screening and double-blind phases. Data will be downloaded and transmitted 
electronically to a study data file during study visits. 
5.7.2.1.
Analysis
The following parameters will be used for the analysis:
Parameter
Description
Total sleep time (min)
Number of scored sleep epochs, in minutes.
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Parameter
Description
Number of wake bouts
A wake bout is an epoch or continuous epochs scored as 
awake
Sleep efficiency (%)
Scored total sleep time divided by total time in bed minus 
total invalid time, multiplied by 100.
Sleep onset latency (min)
Time between the start of a given rest interval and the 
following Sleep Start Time, in minutes.
Wake after sleep onset 
(min)
Number of epochs of the given sleep Interval scored as 
WAKE by the actigraphy software.
24 hour mean motor 
activity (counts/min)
The average of all valid physical activity counts for all 
epochs in a 24 hour period divided by the epoch
length in minutes.
Daytime mean motor 
activity (counts/min)
The average of all valid physical activity counts for all 
epochs scored as ACTIVE divided by the epoch
length in minutes.
Notes: An epoch is 30 to 60 seconds.
The continuously collected data will be grouped into weekly intervals in the double-blind phase. 
Descriptive statistics of the mean weekly data (calculated based on non-missing daily data) and the 
change from baseline to each postbaseline time point in the double-blind phase will be presented by 
intervention group for the parameters listed in the table.
The change from baseline(DB) in each of the parameters will be analyzed using the same MMRM 
model as described for the primary endpoint with the respective baseline(DB) value as the covariate.
The correlation between actigraphy parameters and the primary efficacy endpoint, SDI summary 
scores, and CMAI-C scores will be explored. Pearson and Spearman correlation coefficients will be 
calculated. Scatter plot of change in scores of the 2 assessment scales over time will be presented for 
each intervention group.
5.7.3.
Biomarkers and Off-Body Sensor Data
Analysis of biomarker data will be discussed in a separate SAP. Analysis of off-body sensor data will 
be included in a separate plan.
5.7.4.
Definition of Subgroups
Subgroup analyses of the primary endpoint will be performed for the full analysis set for the 
following subgroups:
Subgroup
Definition
Sex
Male 
Female 
Other
Age Group
Adult (<65 years) 
Elderly (≥ 65 years)
Age Group II
<65 years
65-<75 years
≥75 years
BMI
underweight (<18.5 kg/m2)
normal (18.5-<25 kg/m2)
overweight (25-<30 kg/m2)
obese (≥30 kg/m2)
Baseline NPI-12 sleep 
domain score (per eDC)
<4
≥4
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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AD
Alzheimer’s Disease
ADAS-Cog-14
Alzheimer’s Disease Assessment Scale Cognitive subscale 14-item version
AE
adverse event
AESI
adverse event(s) of special interest
ALT/SGPT
alanine aminotransferase
ANCOVA
analysis of covariance
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic class
BMI
body mass index
BPSD
Behavioral and Psychological Symptoms of Dementia
C-SSRS
Columbia Suicide Severity Rating Scale
CDR
Clinical Depression Rating
CI
confidence interval
CIR
copy increment from reference
CMAI-C
Cohen-Mansfield Agitation Inventory community version
CR
copy reference
CRF
case report form
CV
coefficient of variation
DB
double-blind
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
electrocardiogram
eCOA
Electronic clinical outcome assessment
eDC
Electronic data capture
EW
Early Withdrawal
GDSI
Geriatric Depression Scale, Informant version
IPA
International Psychogeriatric Association
IQ
interquartile
IS
insomnia symptoms
IWRS
interactive web response system
LS
least squares
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
MMRM
mixed model for repeated measures
MMSE
Mini-Mental State Exam
MNAR
missing not at random
NPI-12
Neuropsychiatric Inventory – 12 item
NPI-12 A/A
Neuropsychiatric Inventory – 12 item Agitation/Aggression Domain
NPI-C
Neuropsychiatric Inventory – Clinician Rating
NPI-C A+A
Neuropsychiatric Inventory – Clinician Rating Agitation + Aggression Domains
NPI-C D+H
Neuropsychiatric Inventory – Clinician Rating Delusion + Hallucination Domains
PK
pharmacokinetic(s)
PWC-20
Physician Withdrawal Checklist-20
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SDI
Sleep Disorder Inventory
SE
standard error
SNRI
selective norepinephrine reuptake inhibitors
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SSRI
selective serotonin reuptake inhibitors
TE
Treatment Emergent
TEAE
Treatment Emergent Adverse Event
TEMA
Treatment Emergent Markedly Abnormal
ULN
Upper limit normal
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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 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 full analysis set.
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 (55-64 years, 65-74 years, and ≥75 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)
aIf 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 full analysis set.
Table 8: Baseline Disease Characteristics
Continuous Variables
Summary Type
Baseline NPI-C A+A score
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Baseline NPI-12 total score
Baseline NPI-12 A/A domain score
Baseline NPI-12 sleep domain score per eCOA
Baseline CMAI-C total score
Baseline MMSE
Categorical Variables
Family history of diagnosed Alzheimer’s disease or other cause of 
dementia
Frequency distribution with the 
number and percentage of participants 
in each category.
Baseline NPI-12 sleep domain score category per eDC (<4, ≥4)
Community dwelling/assisted living per eDC
Baseline MMSE category (10 to 20, 21 to 24)
Baseline CDR score (1, 2-3)
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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 Section 6.9.
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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 ATC level 4 terms
and base preferred term for the double-blind and follow-up phases for safetyand 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. 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 medications of special interest will be summarized by ATC level 2 and ATC 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
Somnolence
Somnolence
Cataplexy
Cataplexy
Sleep paralysis
Sleep paralysis
Complex, sleep-related 
behaviors/parasomnias
Confusional arousal
Somnambulism
Sleep terror
Bruxism
Sleep sex
Sleep-related eating 
disorder
Sleep behaviour disorder
Catathrenia
Fall
Fall
Motor vehicle accident
Motor vehicle 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
AChE inhibitors and memantine
Aducanumab
Non-Pharmacological Therapy
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6.8.
Appendix 8 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
High-density lipoprotein cholesterol (HDL)
mg/dL
35
N/A
High-density lipoprotein cholesterol (HDL)
mmol/L
0.905
N/A
Lactic acid dehydrogenase (LDH)
U/L
N/A
500
Low-density lipoprotein cholesterol (LDL)
mg/dL
N/A
160
Low-density lipoprotein cholesterol (LDL)
mmol/L
N/A
4.1376
Phosphate
mg/dL
2.0
6.0
Phosphate
mmol/L
0.6458
1.9374
Potassium
mmol/L
3.0
5.8
Sodium
mEq/L
125
155
Sodium
mmol/L
125
155
Total protein
g/L
50
N/A
Total protein
g/dL
5
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
%
28
50
- male
%
24
55
Hemoglobin
g/dL
8
19
Hemoglobin
g/L
80
190
Hemoglobin A1c
%
4
8
Neutrophils/Leukocytes
Fraction of 1
0.3
0.9
Monocytes/Leukocytes
Fraction of 1
N/A
0.2
Eosinophils/Leukocytes
Fraction of 1
N/A
0.1
Basophils/Leukocytes
Fraction of 1
N/A
0.06
Lymphocytes/Leukocytes
Fraction of 1
0.1
0.6
MCV
fL
40
140
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MCH
pg
22
38
Reticulocytes/Erythrocytes
Fraction of 1
0.005
0.028
Platelet count
109/L; giga/L
100
600
Red blood cell (RBC) count - female
1012/L; tera/L
3.0
N/A
- male
1012/L; tera/L
3.0
N/A
White blood cell (WBC) count
109/L; giga/L
2.5
15.0
Urinalysis
Urine pH
N/A
8.5
Urine specific gravity
< 1.001
> 1.035
Other
Folate
ng/mL
4
4.8
B12
pmol/L
111
812
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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6.9.
Appendix 9 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 discontinuations and study discontinuations including 
reasons due to COVID-19 will be presented.
2.
Protocol deviations related to COVID-19 including missing visits and remote visits due to 
COVID will be summarized; corresponding listing will be provided.
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7.
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10.1046/j.0962-1105.2003.00374.x. PMID: 14633245; PMCID: PMC4418643.
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