A Phase III Randomized, Placebo-Controlled Clinical Trial to Study the Safety and Efficacy of Suvorexant (MK-4305) for the Treatment of Insomnia in Subjects With Alzheimer's Disease
Phase: PHASE3
Conditions: Sleep Initiation and Maintenance Disorders, Alzheimer Disease
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02750306  
Document Date: 
02-Jun-2017
A Phase III Randomized, Placebo-Controlled Clinical Trial to Study 
the Safety and Efficacy of Suvorexant (MK-4305) for the Treatment 
of Insomnia in Subjects with Alzheimer’s Disease

Product:  MK-4305 
1
Protocol/Amendment No.: 061-01 
MK-4305-061-01 Final Protocol
2-Jun-2017
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase III Randomized, Placebo-Controlled Clinical Trial to Study the Safety and Efficacy 
of Suvorexant (MK-4305) for the Treatment of Insomnia in Subjects with Alzheimer’s 
Disease
IND NUMBER:  US 101,874
EudraCT NUMBER:  2015-003154-40 
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 13
1.0
TRIAL SUMMARY.................................................................................................. 18
2.0
TRIAL DESIGN........................................................................................................ 18
Trial Design ........................................................................................................... 18
2.1
Trial Diagram........................................................................................................ 19
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 20
Primary Objective(s) & Hypothesis(es) .............................................................. 20
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 20
3.2
Exploratory Objectives......................................................................................... 20
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 21
Background ........................................................................................................... 21
4.1
Pharmaceutical and Therapeutic Background .................................................... 21
4.1.1
Rationale................................................................................................................ 23
4.2
Rationale for the Trial and Selected Subject Population .................................... 23
4.2.1
Rationale for Dose Selection/Regimen............................................................... 23
4.2.2
4.2.2.1
Rationale for the Use of Placebo ................................................................. 24
4.2.2.2
Starting Dose for This Trial ......................................................................... 24
4.2.2.3
Maximum Dose/Exposure for This Trial..................................................... 24
Rationale for Endpoints ...................................................................................... 24
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 24
4.2.3.2
Safety Endpoints .......................................................................................... 25
4.2.3.3
Exploratory Endpoints ................................................................................. 25
4.2.3.4
Pharmacokinetic Endpoints ......................................................................... 26
 
 
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4.2.3.5
Pharmacodynamic Endpoints....................................................................... 26
4.2.3.6
Planned Exploratory Biomarker Research................................................... 26
4.2.3.7
Future Biomedical Research........................................................................ 26
Benefit/Risk ........................................................................................................... 27
4.3
5.0
METHODOLOGY ................................................................................................... 27
Entry Criteria........................................................................................................ 27
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 27
5.1.1
Subject Inclusion Criteria.................................................................................... 27
5.1.2
Subject Exclusion Criteria .................................................................................. 30
5.1.3
Trial Treatment(s) ................................................................................................ 37
5.2
Dose Selection/Modification .............................................................................. 38
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 38
5.2.1.2
Dose Modification/Titration ........................................................................ 38
Timing of Dose Administration .......................................................................... 38
5.2.2
Trial Blinding/Masking....................................................................................... 39
5.2.3
Randomization ...................................................................................................... 39
5.3
Stratification.......................................................................................................... 39
5.4
Concomitant Medications/Vaccinations (Allowed)............................................ 39
5.5
Rescue Medications & Supportive Care............................................................. 41
5.6
Diet/Activity/Other Considerations..................................................................... 42
5.7
Diet...................................................................................................................... 42
5.7.1
Use of Alcohol, Caffeine, and Tobacco.............................................................. 42
5.7.2
Activity ............................................................................................................... 43
5.7.3
Subject Withdrawal/Discontinuation Criteria................................................... 43
5.8
Subject Replacement Strategy............................................................................. 45
5.9
 
 
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Beginning and End of the Trial ........................................................................... 45
5.10
Clinical Criteria for Early Trial Termination ................................................... 45
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 46
7.0
TRIAL PROCEDURES ........................................................................................... 49
Trial Procedures ................................................................................................... 49
7.1
Administrative Procedures.................................................................................. 49
7.1.1
7.1.1.1
Informed Consent......................................................................................... 49
7.1.1.1.1
General Informed Consent.................................................................... 49
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 50
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 50
7.1.1.3
Subject Identification Card .......................................................................... 50
7.1.1.4
Medical History ........................................................................................... 50
7.1.1.5
Prior and Concomitant Medications Review ............................................... 50
7.1.1.5.1
Prior Medications.................................................................................. 50
7.1.1.5.2
Concomitant Medications..................................................................... 51
7.1.1.6
Assignment of Screening Number............................................................... 51
7.1.1.7
Assignment of Treatment/Randomization Number ..................................... 51
7.1.1.8
Trial Compliance (Medication).................................................................... 51
7.1.1.9
Interactive Voice Response System/Integrated Web Response System ...... 53
7.1.1.10 Trial Medication Dispensing........................................................................ 53
7.1.1.11 E-diary and Activity/Sleep Watch Training and Monitoring ...................... 53
Clinical Procedures/Assessments........................................................................ 54
7.1.2
7.1.2.1
Physical Assessments/Examinations ........................................................... 54
7.1.2.1.1
Physical Examination/Neurological Examination (PE/Neuro Exam) .. 54
 
 
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7.1.2.1.2
Lead Electrocardiogram........................................................................ 54
7.1.2.1.3
Vital Signs............................................................................................. 54
7.1.2.1.4
Body Height/Weight ............................................................................. 55
7.1.2.2
Clinical and Neurobehavioral Assessments................................................. 55
7.1.2.2.1
The National Institute on Aging – Alzheimer’s Association (NIA-
AA) ....................................................................................................... 55
7.1.2.2.2
The Diagnostic and Statistical Manual of Mental Disorders, 5 th
Edition (DSM-5)................................................................................... 55
7.1.2.2.3
Mini-Mental State Examination (MMSE) ............................................ 55
7.1.2.2.4
Modified Hachinski Ischemia Scale (MHIS)........................................ 56
7.1.2.2.5
Insomnia Diagnostic Interview (IDI).................................................... 56
7.1.2.2.6
Sleep History (SHX)............................................................................. 56
7.1.2.2.7
Geriatric Depression Scale (GDS)........................................................ 56
7.1.2.2.8
Neuropsychiatric Inventory (NPI) ........................................................ 56
7.1.2.2.9
Clinical Global Impressions – Severity, for Insomnia (CGI-S)............ 57
7.1.2.2.10 Columbia-Suicide Severity Rating Scale (C-SSRS)............................. 57
7.1.2.2.11 Digit Symbol (DS) ................................................................................ 58
7.1.2.2.12 Single-Item Sleep Quality Scale-Caregiver (SSQC) ............................ 58
7.1.2.2.13 Modified Cataplexy Questionnaire (MCQ) .......................................... 58
7.1.2.2.14 Polysomnography (PSG) ...................................................................... 59
PSG Definitions and Scoring ....................................................... 59
7.1.2.2.14.1
PSG Measurements ...................................................................... 59
7.1.2.2.14.2
Alcohol Breathalyzer.................................................................... 60
7.1.2.2.14.3
7.1.2.2.15 Electronic Diary (e-diary)..................................................................... 60
Morning Sleep Diary.................................................................... 61
7.1.2.2.15.1
 
 
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Sleep Quality Rating (SQR)......................................................... 61
7.1.2.2.15.2
Sleep Disorders Inventory for Dementia (SDI)............................ 61
7.1.2.2.15.3
7.1.2.2.16 Activity/Sleep Watch............................................................................ 61
7.1.2.2.17 Adverse Experience Monitoring........................................................... 62
Laboratory Procedures/Assessments .................................................................. 62
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry, Urinalysis, 
and Other) .................................................................................................... 62
7.1.3.1.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)............................................................................................. 62
7.1.3.1.2
Urine Drug Screen ................................................................................ 64
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 64
7.1.3.2.1
Blood Collection for Plasma MK-4305................................................ 64
7.1.3.3
Planned Genetic Analysis Sample Collection.............................................. 64
7.1.3.4
Future Biomedical Research Sample Collection ......................................... 64
Other Procedures................................................................................................. 65
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 65
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 65
7.1.4.2
Blinding/Unblinding .................................................................................... 65
7.1.4.3
Domiciling ................................................................................................... 66
7.1.4.4
Calibration of Critical Equipment................................................................ 66
Visit Requirements.............................................................................................. 66
7.1.5
7.1.5.1
Screening...................................................................................................... 67
7.1.5.1.1
Visit 1 Screening................................................................................... 67
7.1.5.1.2
Visit 2 Screening PSG and Visit 3 Baseline PSG................................. 68
7.1.5.2
Treatment Period – Visits 4 through 6......................................................... 70
 
 
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7.1.5.3
Procedures for Subjects Who Discontinue Treatment But Continue in 
the Trial........................................................................................................ 71
7.1.5.4
Post-Treatment Follow-up ........................................................................... 72
Assessing and Recording Adverse Events .......................................................... 72
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 73
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 73
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 74
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 74
7.2.3.2
Events of Clinical Interest............................................................................ 75
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting ............ 76
Evaluating Adverse Events ................................................................................. 76
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 79
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 79
7.3
Scientific Advisory Committee........................................................................... 79
7.3.1
Clinical Adjudication Committee ....................................................................... 79
7.3.2
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 79
Statistical Analysis Plan Summary ..................................................................... 80
8.1
Responsibility for Analyses/In-House Blinding ................................................. 81
8.2
Hypotheses............................................................................................................. 81
8.3
Analysis Endpoints ............................................................................................... 82
8.4
Efficacy and Ancillary Endpoints....................................................................... 82
8.4.1
Safety Endpoints ................................................................................................. 82
8.4.2
Derivations of Efficacy Endpoints...................................................................... 84
8.4.3
Derivations of Safety Endpoints ......................................................................... 84
8.4.4
 
 
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Analysis Populations............................................................................................. 84
8.5
Efficacy Analysis Populations ............................................................................ 84
8.5.1
Safety Analysis Population ................................................................................. 85
8.5.2
Statistical Methods................................................................................................ 85
8.6
Statistical Methods for Efficacy Analysis........................................................... 86
8.6.1
Statistical Methods for Safety Analysis .............................................................. 86
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 88
8.6.3
8.6.3.1
Demographic and Baseline Characteristics ................................................. 88
Interim Analysis.................................................................................................... 89
8.7
Multiplicity ............................................................................................................ 89
8.8
Sample Size and Power Calculations .................................................................. 89
8.9
Subgroup Analyses ............................................................................................... 91
8.10
Compliance (Medication Adherence).................................................................. 92
8.11
Extent of Exposure................................................................................................ 93
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 93
Investigational Product ........................................................................................ 93
9.1
Packaging and Labeling Information ................................................................. 93
9.2
Clinical Supplies Disclosure................................................................................. 94
9.3
Storage and Handling Requirements.................................................................. 94
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 94
9.5
Standard Policies................................................................................................... 94
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 95
Confidentiality....................................................................................................... 95
10.1
Confidentiality of Data ....................................................................................... 95
10.1.1
 
 
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Confidentiality of Subject Records ..................................................................... 95
10.1.2
Confidentiality of Investigator Information........................................................ 95
10.1.3
Confidentiality of IRB/IEC Information............................................................. 96
10.1.4
Compliance with Financial Disclosure Requirements....................................... 96
10.2
Compliance with Law, Audit and Debarment ................................................... 96
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 98
10.4
Quality Management System............................................................................... 99
10.5
Data Management................................................................................................. 99
10.6
Publications ........................................................................................................... 99
10.7
11.0
LIST OF REFERENCES....................................................................................... 100
12.0
APPENDICES......................................................................................................... 104
Merck Code of Conduct for Clinical Trials...................................................... 104
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research............................................................................................................... 106
Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs 
& 
12.3
Investigational Site Staff .................................................................................... 110
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.4
by Sample Types ................................................................................................. 119
List of Abbreviations and Definition of Terms ................................................ 120
12.5
Calculating Body Mass Index (BMI) ................................................................ 123
12.6
List of Caffeine Products and Caffeine Content .............................................. 124
12.7
DSM-5 Criteria for Major or Mild Neurocognitive Disorder Due to 
12.8
Alzheimer's Disease ............................................................................................ 125
National Institute on Aging-Alzheimer’s Association (NIA-AA) diagnostic 
12.9
guidelines for Alzheimer's disease..................................................................... 126
DSM-5 Criteria for Insomnia Disorder ............................................................ 129
12.10
General Neurological Exam............................................................................... 130
12.11
 
 
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Algorithm for Assessing Out-of-Range Laboratory Values ........................... 134
12.12
Predefined Limits Of Change Criteria ............................................................. 135
12.13
Mapping Between the 11 Categories of Suicidal Ideation and Behavior, 
12.14
the C-SSRS, and CDR for Programming Standard Tables............................ 137
13.0
SIGNATURES......................................................................................................... 138
Sponsor's Representative ................................................................................... 138
13.1
Investigator.......................................................................................................... 138
13.2
 
 
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LIST OF TABLES
   
Table 1
Prohibited Medications that Require a Washout Period Prior to Visit 2 
(Non-inclusive List). .............................................................................................. 35
Table 2
Trial Treatments...................................................................................................... 37
Table 3
Allowed Medications, Supplements, and Other Substances (non-inclusive 
list).......................................................................................................................... 40
Table 4
Discontinuation Scenarios ..................................................................................... 44
Table 5
Laboratory Tests ..................................................................................................... 63
Table 6
Evaluating Adverse Events..................................................................................... 77
Table 7
Analysis Strategy for Key Efficacy Variables........................................................ 86
Table 8
Analysis Strategy for Safety Parameters ................................................................ 88
Table 9
Power (%) for Comparing the Primary Efficacy Endpoint (TST at Week 4) 
Between 
the 
Suvorexant 
and 
Placebo 
Treatment 
Groups 
with 
approximately 130 Subjects Randomized to Each Treatment Group .................... 90
Table 10 Power (%) for Comparing the Primary Endpoint (TST at Week 4) and the 
Secondary Endpoint (WASO at Week 4) Between Treatment Groups 
According to the Multiplicity Testing Strategy...................................................... 91
Table 11 Product Descriptions .............................................................................................. 93
 
 
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LIST OF FIGURES
          
Figure 1
Trial Design Diagram ......................................................................................... 19
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
Multiple, including 1.0, 5.1.2, 
5.1.3, 5.4, 5.5, and others as 
detailed below.
Multiple, including Trial 
Summary, Subject Inclusion 
Criteria, Subject Exclusion 
Criteria, Stratification, 
Concomitant Medications 
Allowed, and others as detailed 
below. 
Multiple changes detailed in 
table below. 
To facilitate recruitment and 
modify barriers to enrollment 
via modifying Exclusion 
Criterion #33, increased
flexibility for trial partners, site 
logistics, and generalizability 
of the population to reflect 
older adults with insomnia and 
Alzheimer’s disease.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0
Trial Summary
Expected trial duration increased to 
24 months.
Recruitment is taking longer 
than originally anticipated.
2.1
Trial Design
Added sentence describing 
circumstances for increasing 
suvorexant dose from 10 mg to 20 mg 
nightly. 
Clarification to Section 2.1
4.2.2.2.
Starting Dose for This Trial
Added language on dose timing.
Clarification
5.1.2
Subject Inclusion Criteria, #4
Clarified language on insomnia 
diagnosis.
Clarification
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.1.2 and 7.1.5
Subject Inclusion Criteria, 
#10
Added bullet point and language 
regarding trial partner (TP) 
qualifications.
To exclude TPs with
dementia, and to remove 
requirement for TPs to attend 
PSG visits.
5.1.3
Subject Exclusion Criteria, 
#1
Added language regarding subject 
living quarters.
To clarify that subjects 
residing in assisted living 
facilities may be eligible.
5.1.3
Subject Exclusion Criteria, 
#16
Added language that recently 
controlled or treated medical 
conditions may be considered for re-
screening. 
To allow trial re-screen for 
subjects who left for medical 
reasons and are stabilized, as 
appropriate.
5.1.3, 7.1.3.3.1, and 12.4
Subject Exclusion Criteria, 
#19, 
Laboratory 
Procedures/Assessments, 
Table 5, and 
Approximate Blood/Tissue 
Volumes Drawn/Collected 
by Trial Visit and by Sample 
Types
Added language regarding Vitamin 
B12 and folic acid deficiency
Clarified that subjects may be eligible 
once B12, folate, or thyroid 
abnormalities are treated. 
Methylmalonic acid and homocysteine 
tests added to “Other” column.
Blood volumes added for 
supplemental laboratory tests 
(methylmalonic acid and 
homocysteine)
To allow for supplementary 
methylmalonic acid and 
homocysteine serum testing 
to identify subjects who have 
true B12 or folate deficiency 
rather than only low B12 or 
folate levels.
5.1.3
Subject Exclusion Criteria, 
#28
Added language on subject 
participation in other trials
Clarification that subjects 
participating in observational 
studies without an 
intervention may be eligible.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.1.3, 6.0, and 7.1.5.1.2
Subject Exclusion Criteria, 
#33
Trial Flow Chart, footnote 
dd, and
Visit 2 Screening PSG and 
Visit 3 Baseline PSG
Age categories deleted, upper 
threshold for Apnea Hypopnea Index 
(AHI) score and number of periodic 
leg movements with arousal /hour 
(PLMA) increased to 30.
Added language to allow subjects who 
screen failed due to exclusion criterion 
#33 to be re-screened if eligible based 
on the amended criteria. 
AHI severity increases with 
age and AD severity. 
Increasing the AHI threshold 
will facilitate enrollment and 
evaluate the safety and 
efficacy of suvorexant in 
subjects with AHI of 26 to 
30, which is a substantial 
proportion of subjects with 
AD and insomnia. Subgroup 
analysis based on AHI has 
been added to evaluate 
potential treatment effect for
subjects with higher versus 
lower AHI values.
5.4
Stratification
Revised to state that approximately 
30% of randomized subjects will be in 
the moderate AD stratum (MMSE 
score 12 to 20 at screening)
To allow some flexibility for 
moderate AD stratum.
5.5
Concomitant 
Medications 
Allowed
Table 3: revised to specify that 
quetiapine is allowed if used to treat 
neuropsychiatric behavior issues and 
not used to treat insomnia
To allow for the use of 
quetiapine to treat 
neuropsychiatric symptoms.
6.0
Trial Flow Chart, footnote e
Added language to note that screening 
visit window applies to several 
situations.
Clarification
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
6.0 and 7.1.5.2 
Trial Flow Chart, footnote w, 
and Treatment Period –
Visits 4 through 6
Time to collect PK samples expanded 
to 11 hour post-dose.
Assist with site logistics 
6.0 and 7.1.5.2
Trial Flow Chart, footnote 
cc, and Treatment Period –
Visits 4 through 6
Timing and location for V6 
assessments specified 
Clarification as  provided in a 
Protocol Clarification Letter
(PCL dated 4-August-2016)
7.1.1.5.1
Prior Medications
Changed following sentence as shown
(new text underlined): 
“These earlier discussions will allow 
subjects to discuss discontinuation of 
prohibited medications with their 
primary care physician once consented
prior to Visit 2.”
Clarification
7.1.1.8
Trial Compliance 
(Medication)
Clarifications to computation for 
medication compliance and the 
applicable period for assessing Events 
of Clinical Interest (ECI) of potential 
study medication misuse.
Clarification
7.1.2.2.10
Columbia Suicide Severity 
Rating Scale (C-SSRS)
Clarifications to instances of suicidal 
ideation or suicidal behavior that 
should be reported as Events of 
Clinical Interest (ECI).
Clarification to align with 
ECI guidance for events of 
suicidal ideation and 
behavior for the trial.
7.1.5.1.1
Visit 1 Screening
Added language regarding positive 
urine drug screen (UDS) at Visit 1.
Clarification
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
8.10
Subgroup Analyses
AHI categories added as a subgroup 
analysis
To evaluate the treatment 
effect, and possible 
differences, for the two AHI 
categories (<15, 15 to 30).
Global
Multiple sections
Global minor spelling, punctuation, 
grammar, style and wording changes
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Safety and Efficacy of suvorexant (MK-4305) for the treatment of
insomnia in AD subjects
Trial Phase
Phase 3
Clinical Indication
Treatment of insomnia
Trial Type
Interventional
Type of control
Placebo
Route of administration
Oral
Trial Blinding
Double-blind
Treatment Groups
1)
Placebo
2)
Suvorexant 10 mg (dose may be increased to suvorexant 20 
mg)
Number of trial subjects
Approximately 260 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 24
months from the time the first subject signs the informed consent 
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for approximately 9 weeks
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact. After a screening/run-in period of 
approximately 3 weeks, each subject will receive assigned treatment 
for approximately 4 weeks. After the end of the 4-week treatment
period, each subject will receive a follow-up phone contact at
approximately 14 days post-treatment to assess for post-treatment 
adverse events (AEs).
A list of abbreviations used in this document can be found in Appendix 12.5.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind trial of 
suvorexant (MK-4305) for the treatment of insomnia in subjects with Alzheimer’s disease 
(AD). This trial will be conducted in conformance with Good Clinical Practices.
The overall study is composed of a 3-week screening period (including a 2-week single-blind 
placebo run-in), a 4-week double-blind treatment period, and a 14-day post-treatment
telephone contact (occurring after the subject’s last dose of trial medication). In total, there 
Randomization Ratio
1:1
 
 
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will be 6 clinic visits, 3 of which will be overnight polysomnography (PSG) visits (2 in the 
screening period and 1 at the end of the double-blind treatment period).
To qualify for randomization, subjects are required to meet diagnostic criteria for both AD 
and insomnia and have a qualified trial partner, in addition to other trial entry criteria. After 
the subject has been randomized to suvorexant 10 mg or matching placebo, subjects will take 
1 tablet nightly. After 2 weeks of double-blind treatment, the subject’s dose may be escalated 
from suvorexant 10 mg (or matching placebo) to suvorexant 20 mg (or matching placebo) if 
Clinical Global Impression - Severity, for Insomnia (CGI-S) >3 and acceptable subject 
tolerability based on investigator assessment.
An electronic diary (e-diary) to record sleep data (entered by the trial partner) and an 
activity/sleep watch (eg, watch-like device worn by the subject) will be used in this trial.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
2.2
The trial design is depicted in Figure 1.
Figure 1
Trial Design Diagram
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
Objectives:
(1)
To evaluate the efficacy of suvorexant compared with placebo in improving 
insomnia, as measured by change from baseline in PSG-derived total sleep time 
(TST), at Week 4.
(2)
To evaluate the safety and tolerability of suvorexant for up to 4 weeks of treatment.
Hypothesis:
(1)
Suvorexant is superior to placebo in improving insomnia as measured by change from 
baseline in PSG-derived TST, at Week 4.
Secondary Objective(s) & Hypothesis(es)
3.2
Objective:
(1)
To evaluate the efficacy of suvorexant compared with placebo in improving insomnia 
as measured by change from baseline in PSG-derived wakefulness after persistent 
sleep onset (WASO), at Week 4.
Hypothesis:
(1)
Suvorexant is superior to placebo in improving insomnia as measured by change from 
baseline in PSG-derived WASO, at Week 4.
Exploratory Objectives
3.3
Objectives:
(1)
To evaluate other PSG parameters (eg, sleep efficiency [SE], latency to onset of 
persistent sleep [LPS]), and treatment response based on achieving a pre-specified 
clinically meaningful improvement in TST.
(2)
To characterize sleep/wake activity using an activity/sleep watch.
(3)
To evaluate the subject’s sleep as reported by the trial partner and by subjective 
clinical assessment.
(4)
To evaluate the subject’s cognition and neuropsychiatric behavior.
(5)
To evaluate the trial partner’s sleep and levels of distress associated with the subject’s 
sleep behaviors.
 
 
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(6)
To explore the relationship between Apolipoprotein E4 (APOE4) genotype status and 
AD diagnosis and their association with insomnia and/or clinical data collected in this 
study.
(7)
To explore the relationship between genetic variation and response to the treatment(s) 
administered. Variation across the human genome will be analyzed for association 
with clinical data collected in this study.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB) and/or approved labeling for detailed background 
information on MK-4305.
Pharmaceutical and Therapeutic Background
4.1.1
Sleep disturbance and insomnia are common in AD, affecting up to 45% of individuals [1].
Patients and caregivers report symptoms attributable to nighttime sleep fragmentation and 
nighttime awakenings, early morning awakenings, increased time to fall asleep, decreased 
deep sleep, and increased daytime napping due to insufficient nighttime sleep [2]. Broader
consequences of insomnia in AD span a wide range of potential morbidity, including
physical disability, respiratory symptoms, hypertension, cardiac insufficiency, and decreased 
immune function [2]. Furthermore, insomnia can be associated with accentuation of
depression and poor cognitive and psychological functioning [2]. Together, over time these 
physical and mental impairments can significantly impair capacity for daily self-care, leading 
to an increased need for and cost of healthcare. Additionally, nighttime awakenings and 
associated wandering can endanger AD patients and cause significant stress for family 
members and caregivers, often culminating in nursing home placement [2].
The underlying causes for insomnia in AD are not fully understood, but are likely 
heterogeneous in origin. In terms of neuroanatomical hypotheses, sleep disturbances in AD 
have been postulated to result from progressive deterioration and decrease in the number of 
neurons in the suprachiasmatic nucleus, with resultant fluctuations in neurohormones critical 
for the homeostatic maintenance of circadian rhythm [3]. Other findings suggest a role for
neurodegenerative loss of hypothalamic hypocretin/orexin neurons, contributing to disturbed 
sleep-wake patterns [4]. Progression of AD itself may also cause dysregulation of the orexin
system, leading to increased orexinergic output and promotion of inappropriate nighttime 
wakefulness in AD patients.
Important intersections between sleep, cognition, amyloid beta (A), and orexin signaling
exist. For instance, it is well established that sleep is essential for sleep-dependent learning 
and memory consolidation [5]. Sleep has been shown to promote increased Aclearance [6].
In a clinical study of cognitively intact, pre-symptomatic individuals deemed at-risk for AD, 
lower sleep quality was correlated with increasing amyloid deposition, as assessed by 
cerebrospinal fluid (CSF) A42 levels, suggesting a potential linkage between sleep and
 
 
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development of AD [7]. More recently, cognitive decline, tau and Alevels were shown to 
correlate with sleep disturbance and increased CSF orexin levels in AD patients, but not in 
age-matched cognitively intact controls [8]. These clinical findings are intriguing, 
particularly in light of a report that showed sleep-deprivation-related increases in Alevels 
and plaque formation in rodents were reduced by modulation of orexin signaling, using both 
genetic and pharmacological (via orexin receptor antagonist – [ORA]) approaches [9].
Options for effective pharmacological treatment of insomnia in AD are limited. Evidence for 
efficacy in randomized controlled trials of melatonin and the melatonin receptor agonist,
ramelteon, has been inconsistent. For example, melatonin failed to achieve primary endpoints
in 3 of 4 randomized controlled trials, as did ramelteon in its only trial in AD patients. 
Additionally, melatonin was observed to have a deleterious effect on mood in one of the 
studies [10],[11],[12],[13]. Second-generation antipsychotics have shown some improvement 
in insomnia, likely due to their sedating effects, but these medications are primarily used to 
target other neuropsychiatric and behavioral concerns associated with AD. Importantly, 
however, these agents also carry risk for significant adverse effects, including increased risk 
of metabolic abnormalities and sudden death [14]. Two sedating antidepressants, mirtazapine 
and trazodone, were also found to have inconsistent efficacy in 2 non-randomized studies 
[15],[16]. Furthermore, trazodone is associated with significant side effects, including 
daytime somnolence, orthostatic hypotension, dizziness, and priapism [17],[18],[19] and 
tolerance appears to develop in non-depressed subjects [20].
Potential for worsening of cognitive impairment is a concern encountered in treating sleep 
problems in AD subjects. In one study of medications commonly prescribed to AD subjects, 
it was found that the rate of deterioration was faster in those taking antipsychotic drugs and 
those taking sedatives than those not taking any of these drugs (OR 2.74 [95% CI 1.17, 6.41]
and 2.77 [1.14, 6.73], respectively) [21]. Additionally, benzodiazepines and other sedatives, 
especially in combination with antipsychotic medications, have been observed to increase the 
rate of cognitive and functional decline in AD patients and falls in the elderly [22], [23]. The 
potential for next-day, negative cognitive effects in the elderly is cited in the zolpidem label. 
Collectively these data, along with the limited and inconsistent evidence of efficacy and 
safety in the randomized controlled trial setting, support that informed and effective 
treatment of insomnia in AD remains a significant challenge.
Suvorexant is a first-in-class ORA that enables sleep to occur via selective antagonism of the 
orexin receptors OX1R and OX2R. Suvorexant has previously been demonstrated to be 
efficacious and generally well-tolerated for the treatment of elderly and non-elderly adults 
with insomnia (references noted in Section 4.2.2). Suvorexant is currently approved and 
marketed for the treatment of insomnia in 2 countries: the United States and Japan. Via its 
novel ORA mechanism of action, suvorexant offers a potentially differentiating alternative 
treatment relative to currently available sleep agents. Moreover, its unique profile may 
overcome limitations of existing agents to address important unmet medical need in this 
growing patient population.
 
 
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Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
Transient and selective night-time antagonism of the orexin pathway may help stabilize and 
improve sleep-wake patterns in AD patients, by dampening orexin-mediated inappropriate 
wakefulness during the sleep cycle. Trials to evaluate sleep in Alzheimer’s patients have 
typically focused on subjective endpoints. Although actigraphy has been used as a surrogate 
to provide objective sleep estimates, only a few appropriately powered polysomnography 
studies have been published to objectively characterize sleep in AD patients with insomnia.
While the peer-reviewed literature characterizing insomnia in AD is growing, interpretation 
of this information is difficult given lack of uniformity in the diagnostic criteria used to 
identify patients across the various studies. In one published PSG trial of mild to moderate 
AD patients (N=35), the mean total sleep time at baseline was ~5 hours (298 minutes) 
indicating that global sleep deficits are substantial in this population [24]. 
In prior Phase 3 trials [25], suvorexant 20 mg (in non-elderly) and 15 mg (in elderly)
improved total sleep time (TST) and sleep maintenance throughout the entire night 
(particularly during the 2nd and 3rd thirds of the night when wake-after-sleep-onset (WASO) 
is most prominent), with significant improvements compared to placebo in PSG-assessed 
TST of 44.8 minutes on Night 1 and 34.7 minutes at Month 1, as well as significant placebo-
subtracted reductions in PSG-assessed WASO by 34.6 minutes on Night 1 and 25.4 minutes 
at Month 1 in the pooled efficacy data. Significant improvements versus placebo in TST of 
48.4 minutes on Night 1 and 32.7 minutes at Month 1, as well as significant reductions 
versus placebo in WASO by 39.3 minutes on Night 1 and 26.9 minutes at Month 1 were
observed in elderly subjects. 
Given the demonstrated effectiveness of suvorexant, and the lack of available proven 
treatments for insomnia in AD, this study aims to examine the safety and efficacy of 
suvorexant to improve sleep in individuals with AD. The core treatment period in this 
parallel group, placebo-controlled study will assess suvorexant effects over a duration of 
4 weeks, consistent with the primary 4 week efficacy assessment in the Phase 3 pivotal trials. 
Rationale for Dose Selection/Regimen
4.2.2
The clinical safety and efficacy of the 10 and 20 mg doses of suvorexant for this study are 
supported by data from 4 Phase 2/3 insomnia studies: a Phase 2b insomnia trial evaluated
suvorexant doses of 10 mg up to 80 mg [26]; two Phase 3 insomnia trials evaluated doses of 
15 mg and 30 mg (in elderly) and 20 mg and 40 mg (in non-elderly) [25]; and a Phase 3
insomnia trial evaluated suvorexant 30 mg (in elderly) and 40 mg (in non-elderly) over one 
year [27]. Given overlapping PK and efficacy/safety profiles of the 15 mg and 20 mg doses 
in Phase 3, only the 20 mg dose will be included as an additional dose option in this study. 
The dose titration regimen for the current study is consistent with the dosing and 
administration specified in the U.S. label. Subjects will initiate double-blind treatment with 
either 10 mg dose of suvorexant or placebo; then at Visit 5, the dose may be increased to 
 
 
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20 mg at the discretion of the investigator based on the subject’s response to trial medication. 
The decision to increase the dose will based on insufficient efficacy (based on a Clinical 
Global Impressions of Insomnia Severity assessment [CGI-S]) and acceptable tolerability, as 
reported by the subject and/or trial partner. Additional guidance regarding the investigator’s 
decision to dose escalate at Visit 5 is provided in Section 5.2.1.2.
4.2.2.1
Rationale for the Use of Placebo
Because insufficient Class I evidence exists to support the efficacy and safety of any 
available potential active comparator sleep medication for use in AD patients (see 
Section 4.1.1), this study will be placebo controlled. Placebo groups are commonly used in 
insomnia trials and are required for approval of insomnia medications. Similarities in 
drop-out rates observed across treatment groups in placebo-controlled trials in insomnia are 
supportive of the concept that subjects randomized to placebo in these trials are not exposed 
to harm, nor is the condition of insomnia sufficiently debilitating to require provision of 
rescue medication. In addition, given the subjective nature of several key clinical endpoints, 
inclusion of a placebo group in this trial will be important in demonstrating the safety, 
tolerability, and efficacy of suvorexant in AD patients. Inclusion of a placebo control group 
also provides an anchor between the new data collected in this study and the precedent 
observed in prior placebo-controlled insomnia clinical trials and will facilitate comparison of 
adverse event rates on suvorexant to rates on placebo.
4.2.2.2
Starting Dose for This Trial
The starting dose of suvorexant in this trial is 10 mg (1 tablet) per day, taken nightly.
4.2.2.3
Maximum Dose/Exposure for This Trial
Based on investigator assessment of the CGI-S score and subject tolerability at Visit 5 (see 
Section 5.2.1.2 for more details), the dose of suvorexant may be increased to a maximum 
dose of 20 mg per day, taken nightly. Therefore, the maximum exposure in this trial will be 
10 mg for approximately 14 days, followed by 10 or 20 mg for approximately 14 additional 
days.
Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
Until recently, validated instruments to measure sleep disturbances in AD patients were 
limited and so a variety of subjective report instruments have been used in the past. Studies 
to characterize sleep disturbances in AD have revealed that 50-82.3% of caregivers report
patient awakenings during the night and 36-63% of caregivers report patients waking up too 
early [28], [29]. A quarter of caregivers reported that subjects took more than 30 minutes to 
fall asleep [29]. Another study reported that approximately 40% of a subject’s time in bed is 
spent awake. Furthermore, the mean percent awake time in bed and mean number of
nighttime awakenings increased with severity of AD [30]. 
 
 
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Given the uncertain accuracy of subjective caregiver assessment of sleep in subjects with 
AD, polysomnography (PSG), the gold standard objective assessment of sleep has been 
selected for this study. A prior PSG study characterizing sleep in AD subjects with nocturnal 
agitation, found that mean total sleep time (TST) was 338.3 minutes, mean sleep latency to 
first epoch of sleep was 43.2 minutes, mean total wake time was 151.6 minutes, and mean 
sleep efficiency was 66.6% [31]. Among the numerous potential sleep assessments PSG 
provides, TST has been selected as the primary endpoint measure for this study, in part 
because TST reflects the most comprehensive global sleep assessment. Additionally, the 
standardized effect size (ie, difference between treatment groups divided by the standard 
deviation [SD]), is higher for TST than for any other PSG endpoint, indicating good endpoint 
stability, and thus allows for the smallest number of subjects to demonstrate a treatment 
difference between groups. The robust suvorexant treatment response observed in Phase 3
studies, as assessed by PSG (see Section 4.2.1), further supports the selection of TST as the
primary efficacy endpoint measure in this study.
Lastly, in light of suvorexant’s 
demonstrated ability to help patients with insomnia stay asleep throughout the night, the 
measure of PSG-derived wake after persistent sleep onset (WASO), the gold standard 
objective assessment for sleep maintenance, will be a key secondary endpoint. 
In addition to these and other objective PSG-derived sleep measurements, subjective sleep 
assessments and data from an activity/sleep watch will also be collected and evaluated as 
exploratory measures in this study.
4.2.3.2
Safety Endpoints
The safety and tolerability of suvorexant will be continuously assessed throughout the trial 
via Adverse Event reporting, and vital signs will be assessed at every trial visit. In addition, 
safety laboratory evaluations will be drawn, electrocardiograms (ECGs) will be conducted,
and physical and neurological examinations will be performed during the trial. The 
Columbia-Suicide Severity Rating Scale (C-SSRS) will be conducted at every visit to 
prospectively assess for the emergence of suicidal ideation and behavior. 
Protocol-specific ECIs (see Section 7.2.3.2) will be monitored as well. A supplemental 
document will be provided that contains a list of specific terms and guidance for additional 
information to be collected and reported. Additionally, pre-specified ECIs will be reviewed 
by an external clinical adjudication committee (CAC) (see Section 7.3.2).
4.2.3.3
Exploratory Endpoints
Measures of cognition and neuropsychiatric behavior are diminished in patients with AD;
therefore, assessments to evaluate these features will be collected and evaluated as 
exploratory measures in this trial. Other exploratory measures will include subjective sleep
measures (collected via e-diary), objective measures of sleep-wake (measured by an
activity/sleep watch), and assessment of titration. The list of exploratory endpoints will be 
detailed in the supplemental Statistical Analysis Plan (sSAP).
 
 
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4.2.3.4
Pharmacokinetic Endpoints
Plasma samples will be collected for evaluation of pharmacokinetic (PK) properties of MK-
4305, and may be used to characterize the plasma concentration of MK-4305. Additionally, 
this data may be compared to that reported historically or used in population pharmacokinetic 
(PK) and/or pharmacodynamic (PD) model development and analysis. Plasma samples will 
be collected at specific visits as indicated in the Trial Flow Chart (Section 6.0). 
The final decision as to which plasma samples will be assayed will be made by the Sponsor's 
Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism (PPDM) and 
the Clinical Monitor.
Information regarding the collection and shipping of plasma samples will be provided in the 
administrative binder.
4.2.3.5
Pharmacodynamic Endpoints
Aside from efficacy and safety endpoints, there are no specific pharmacodynamics endpoints 
that will be collected in the current trial.
4.2.3.6
Planned Exploratory Biomarker Research
Planned Genetic Analysis
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
In addition to studying variation across the human genome, APOE4 will specifically be 
investigated since the presence of the APOE4 genotype predicts an increased chance of 
developing AD. Evolving literature additionally suggests the potential for association 
between AD and insomnia, thereby implicating the APOE4 genotype. The relationship, if 
any, between the APOE4 genotype and response to symptomatic treatment of insomnia in 
AD has not been established. For these reasons, the potential relationship of APOE4 
genotype to insomnia and response to treatment in AD subjects may be analyzed as an 
exploratory objective.
4.2.3.7
Future Biomedical Research
The Sponsor may conduct Future Biomedical Research on DNA specimens collected for 
future biomedical research during this clinical trial.
Such research is for biomarker testing to address emergent questions not described elsewhere in 
the protocol (as part of the main trial) and will only be conducted on specimens from 
 
 
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appropriately consented subjects. The objective of collecting specimens for Future Biomedical 
Research is to explore and identify biomarkers that inform the scientific understanding of 
diseases and/or their therapeutic treatments. The overarching goal is to use such information to 
develop safer, more effective drugs/vaccines, and/or to ensure that subjects receive the correct 
dose of the correct drug/vaccine at the correct time. The details of this Future Biomedical 
Research sub-trial are presented in Appendix 12.2 - Collection and Management of Specimens 
for Future Biomedical Research. Additional informational material for institutional review 
boards/ethics committees (IRBs/ERCs) and investigational site staff is provided in 
Appendix 12.3.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male and female subjects aged 50 to 90 years (inclusive) with insomnia and Alzheimer’s 
disease will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
Visit 1: Screening Inclusion
1. Be between 50 to 90 years of age (inclusive) on the day of signing informed consent. 
2. Meet the criteria for a diagnosis of probable Alzheimer’s disease based on either a) 
the National Institute on Aging – Alzheimer’s Association (NIA-AA) criteria
(Appendix 12.9), or b) the Diagnostic and Statistical Manual of Mental Disorders, 5th
Edition, (DSM-5) criteria for AD (Appendix 12.8).
(Note: information on 
documentation to support diagnosis of AD can be found in Section 7.1.5.1.1.)
3. Have a Mini Mental State Examination (MMSE) score ≥12 and ≤26 at Screening.
4. Have sleep complaints that meet DSM-5 criteria for the diagnosis of insomnia (eg, 
difficulty initiating or maintaining sleep, and/or early morning awakenings with 
inability to return to sleep for at least 3 nights per week for ≥the past 3 months prior 
 
 
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to Visit 1, despite adequate opportunity for sleep) based on the investigator’s 
judgment and by the subject’s sleep history, as assessed by the sleep items on the
Insomnia Diagnostic Interview and Sleep History assessments. (Note: information on 
documentation to support diagnosis of insomnia can be found in Section 7.1.5.1.1.)
5. Be willing to stay overnight at a sleep laboratory and stay in bed for at least 8 hours 
for PSG testing.
6. Have a regular bedtime between 8 PM (20:00) and 1 AM (01:00) and is willing to 
maintain it for the duration of the trial.
7. Be able and willing to wear an activity/sleep watch on the wrist throughout the day 
and night. Additional details are provided in Section 7.1.2.2.16. 
8. Each subject (or legal representative) must sign the informed consent form, in 
accordance with local requirements, after the scope and nature of the investigation 
have been explained to them, and before Screening assessments. The subject may also 
provide consent for Future Biomedical Research. However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
9. Based on the investigator's judgment (with legal representative input, as applicable), 
the subject should:

Be able to speak, read, and understand the language of the trial staff and the 
informed consent form;

Possess the ability to respond verbally to questions, follow instructions, and 
complete study assessments;

Be able to adhere to dose and visit schedules.
10. Have a reliable and competent trial partner (eg, spouse, family member, or other 
caregiver) who meets the following requirements and trial obligations (see 
Section 7.1.5.1 for source documentation information):

Signs their own informed consent, after the trial has been explained to them, 
and before Screening assessments.

Is not diagnosed with dementia.

Resides with the subject overnight (see Section 7.1.5 for more details) and has 
a close relationship with the subject (defined as daily face-to-face contact, at 
least 15 waking hours a week for at least 3 months prior to Visit 1).

Accompanies the subject to and from trial visits and willing to stay overnight 
at the sleep laboratory, if needed, for the 3 PSG visits (See Section 7.1.5 for 
 
 
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more details regarding flexibility for alternate caregivers to accompany the 
subject on clinic visits and overnight PSG visits).

Assumes responsibility for trial medication procedures (eg, witnessing and/or 
helping to administer trial medication, assessing compliance), for completion
of the sleep e-diary each morning, and oversight of the activity/sleep watch
worn throughout the trial.

Answers questions regarding the trial partner’s sleep quality and trial partner’s 
distress related to the subject’s behaviors.
11. Have results of clinical laboratory tests (complete blood count [CBC], blood 
chemistries, thyroid function tests, and urinalysis) within normal limits or clinically 
acceptable to the investigator at Screening.
12. Have results of a physical examination (PE), including neurological exam, vital signs, 
and ECG (Bazett’s correction) within normal limits (based on the population under 
study, ie Alzheimer’s disease and insomnia) or clinically acceptable based on
investigator judgment at Screening.
13. If female, not be of childbearing potential as indicated by one of the following:

Has reached natural menopause, defined as years of age with either:
i. ≥12 months of spontaneous amenorrhea 
or
ii. ≥6 months of spontaneous amenorrhea with serum follicle stimulating 
hormone (FSH) levels >40 IU/L as determined by the central laboratory

Has had a hysterectomy;

Has had bilateral tubal ligation; or

Has had a bilateral oophorectomy (with or without a hysterectomy) and greater 
than 6 weeks have passed since the surgery
14. Be willing to provide a blood sample for APOE genotyping.
Visit 2: Screening PSG Inclusion
Note: Continue to fulfill relevant Inclusion Criteria at Visit 1.
15. Have a TST ≤6.5 hours as determined by the Visit 2 Screening PSG confirmed by the 
central PSG rating vendor. 
 
 
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Visit 3: Baseline PSG Inclusion
Note: Continue to fulfill relevant Inclusion Criteria at Visit 1.
16. Have a mean TST <6 hours on the combined Screening (Visit 2) and Baseline 
(Visit 3) PSGs, where neither night is >6.5 hours as confirmed by the central PSG 
rating vendor.
Visit 4: Randomization Inclusion
Note: Continue to fulfill relevant Inclusion Criteria at Visit 1.
17. Have a trial partner who is ≥70% compliant with completing the e-diary during the 
Run-in Period (eg, the last 10 available days of e-diary data from Visit 4). 
18. Have >75% trial medication compliance rate for trial medication taken from Visit 2 to 
Visit 4. This should be assessed with a standard pill count (ie, number of pills taken 
divided by (/) number of nights from Visit 2 (inclusive) to the day prior to Visit 4).
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Resides in a nursing home (or similar institutional facility). Note: assisted-living 
facilities are not excluded if full-time nursing care is not required.
2. Has a Modified Hachinski Ischemia Scale (MHIS) Score >4 at Screening (ie, 
evidence of vascular dementia).
3. Has a known history of recent (or past) stroke that in the investigator's opinion 
confounds the diagnosis of either AD or insomnia.
4. Has evidence of a clinically relevant neurological disorder other than the disease 
being studied (ie, probable AD) at Screening, including but not limited to: vascular 
dementia, parkinsonism, frontotemporal dementia, Huntington's disease, amyotrophic 
lateral sclerosis, multiple sclerosis, progressive supranuclear palsy, neurosyphilis, 
dementia with Lewy bodies, other types of dementia, mental retardation, hypoxic 
cerebral damage, cognitive impairment due to other disorders, or history of head 
trauma with loss of consciousness that either led to persistent cognitive deficits or in 
the opinion of the investigator  confounds the diagnosis of either AD or insomnia.
5. Has a history of seizures or epilepsy within the last 5 years before Screening.
 
 
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6. Has a history or diagnosis of any of the following conditions, in the opinion of the 
investigator:

Narcolepsy

Cataplexy (familial or idiopathic)

Circadian Rhythm Sleep Disorder

Parasomnia including nightmare disorder, sleep terror disorder, sleepwalking 
disorder

REM behavior disorder

Significant degree of sleep-related Breathing Disorder (ie, AHI >30, and/or use of 
Continuous Positive Airway Pressure (CPAP) or Bilevel Positive Airway Pressure 
(BIPAP))

Periodic Limb Movement Disorder

Restless Legs Syndrome

Primary Hypersomnia

Excessive Daytime Sleepiness (EDS) characterized by uncharacteristic chronic 
and persistent sleepiness throughout the day
7. Has a clinically significant movement disorder, such as akinesia, that would affect the
activity/sleep watch differentiation of sleep and wakefulness.
8. In the opinion of the investigator, has difficulty sleeping primarily due to a 
confounding medical condition. Note:  “Medical Conditions” may include chronic 
pain syndromes, chronic migraine, cardiac disease, nocturia (>3 times/night), asthma, 
gastroesophageal reflux disease (GERD), or hot flashes.
9. Has evidence of a current episode of major depression based on investigator's 
judgment. A score of 5 or more on the 15-item Geriatric Depression Scale (GDS)
requires an assessment by an appropriate health care professional (a psychiatrist or 
other trained mental health professional, such as a licensed psychologist, social 
worker or mental health nurse practitioner or comparable professional qualification in 
countries outside the United States) to evaluate for the presence of major depression. 
Subjects with a score of 5 or more who are not diagnosed with major depression 
following such an assessment may be included in the trial. Major depression in 
remission is not exclusionary.
10. Has any of the following based on clinician interview and DSM-5 criteria: 

Lifetime history of bipolar disorder, a primary
psychotic disorder, or 
posttraumatic stress disorder; or,

A psychiatric condition requiring treatment with a prohibited medication; or,

Other psychiatric condition that, in the investigator’s opinion, would interfere 
with the subject’s ability to participate in the study. 
 
 
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11. Is at imminent risk of self-harm, based on clinical interview and responses on the 
Columbia-Suicide Severity Rating Scale (C-SSRS), or of harm to others in the 
opinion of the investigator. Subjects must be excluded if they report suicidal ideation 
with intent, with or without a plan or method (eg, positive responses to items 4 or 5 in 
assessment of suicidal ideation on the C-SSRS) in the past 2 months or suicidal 
behavior in the past 6 months.
12. Has a history of alcoholism or drug dependency/abuse within the last 5 years of
Screening.
13. Has a recent history (within the 6 months prior to Screening) of regular consumption 
(3 or more days per week) of either:

More than 2 alcoholic beverages per day or alcohol consumption within 3 
hours prior to bedtime

More than >600 mg caffeine a day (eg, 4 standard 8-ounce cups of brewed 
coffee, See Appendix 12.7 for a list of caffeinated products) or consumes
caffeine after 4pm (16:00)
14. Consumes the equivalent of >15 cigarettes a day and the investigator confirms that 
the subject’s insomnia is in part the result of tobacco consumption (eg, subjects 
unable to refrain from smoking during the night, subjects who interrupt sleep to 
smoke or use tobacco products, or subjects who require a cigarette within 30 minutes 
of waking in the morning).
15. Has a history of excessive daytime napping (defined as more than 3 hours a day for 
more than 3 days of the week based on trial partner estimates, on average for the past 
4 weeks).
16. Has a recent or ongoing, uncontrolled, clinically significant medical condition or 
major surgery where participation in the trial would pose a significant medical risk to 
the subject within 3 months of Screening, such as:

Conditions including but not limited to diabetes, hypertension, Human 
Immunodeficiency Virus (HIV) or other relevant infections, thyroid or endocrine 
disease, Chronic Obstructive Pulmonary Disease (COPD), delirium, congestive 
heart failure, angina, cardiac or gastrointestinal disease, or renal disease requiring 
dialysis.
Note: Controlled co-morbid conditions (including diabetes, hypertension, heart 
disease, etc.) are not exclusionary if stable within 3 months of the Screening Visit. 
All concomitant medications, supplements, or other substances must be kept as 
stable as medically possible during the trial. Urinary tract infections at Screening 
are not exclusionary if adequately treated (as documented by repeat urinalysis) 
prior to Visit 2.
 
 
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
Major surgery including not limited to abdominal, thoracic, cardiac or orthopedic 
surgery, or any procedure requiring general anesthesia
Subjects with recently controlled or treated medical conditions may be considered for 
re-screening on a case-by-case basis after consultation with the Sponsor. 
17. Has confirmed abnormal pre-randomization laboratory values per the guidance below 
or other clinically significant, unexplained laboratory abnormality in the opinion of 
the investigator:

Alanine transaminase (SGPT or ALT) ≥3 x the upper limit of normal (≥3 x 
ULN)

Aspartate transaminase (SGOT or AST) ≥3 x ULN

Total bilirubin ≥1.5 x ULN
Should a liver function test (LFT) be abnormal (ALT/AST >ULN but <3x ULN,
T-BIL >ULN but <1.5x ULN) at Screening but not meet the specified criteria, the 
investigator should attempt to characterize at entry the reason(s) for the elevation 
(eg, alcohol abuse, metabolic syndrome with fatty liver, etc.). Subjects with 
suspected Gilbert’s Syndrome who have isolated T-BILI ≥1.5x ULN may enter 
the 
trial 
upon 
genetic 
confirmation 
(eg, 
uridine 
diphosphate 
glucuronosyltransferase 1A1 [UGT1A] assessment).
See Appendix 12.12 for an algorithm for assessing out-of-range laboratory values.
18. Has an estimated creatinine clearance of less than 30 mL/min:

For Males:  Creatinine Clearance    =    (140 – Age[yr]) x Weight (kg)
   serum creatinine (mg/dL) x 72

For Females:  Creatinine Clearance =    0.85 x (140 – Age[yr]) x Weight (kg)
         serum creatinine (mg/dL) x 72
19. Has one of the following:

Vitamin B12 or folate deficiency at Visit 1 that is confirmed by serum 
homocysteine or methylmalonic acid levels (supplemental testing as needed for 
abnormal B12 and folate at Visit 1), as determined by central laboratory normal 
values;

Clinically significant untreated B12 or folate deficiency 1 month prior to Visit 1;

Abnormal thyroid function tests at Visit 1, as determined by central laboratory 
normal values, or clinically significant untreated thyroid disease 1 month prior to 
Visit 1.
 
 
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Note: Subjects are eligible for re-screening, after consultation with the Sponsor, once
B12 deficiency, folate deficiency, or thyroid disease treatment has been stable for at 
least 1 month.
20. Has a history of hepatitis or liver disease that, in the opinion of the investigator, has 
been active within the 6 months prior to Visit 1.
21. Has a positive Visit 1 urine drug screen (eg, positive for benzodiazepines, 
cannabinoids, cocaine, etc.). Note:  The screen may be repeated at investigator's 
discretion and as warranted by medical history and concomitant medications. A 
repeat drug screen must be negative prior to randomization.
22. Has a known allergy or hypersensitivity to suvorexant or to any of the formulation 
components (refer to Investigator’ Brochure [Section 3.4] for the pharmaceutical 
formulation). 
23. Has a history of hypersensitivity or idiosyncratic reaction to more than 3 chemical 
classes of drugs, including prescriptions and over-the-counter medications.
24. Has donated blood products or has had phlebotomy of >300 mL within 8 weeks of 
signing informed consent, or intends to donate or receive blood products during 
participation in the study.
25. Has a history of malignancy occurring within the 5 years immediately before 
Screening, except for a subject who has been adequately treated for: 

Basal cell or squamous cell skin cancer;

In situ cervical cancer;

Localized prostate carcinoma; 

Who has undergone potentially curative therapy with no evidence of recurrence 
for ≥3 year post-therapy, and who is deemed at low risk for recurrence by her/his 
treating physician.
26. Is pregnant, is attempting to become pregnant, or is nursing children.
27. Has a Body Mass Index (BMI) >40 kg/m2. BMI is calculated by taking the subject’s 
weight in kg and dividing by the subject’s height in meters, squared (see Appendix 
12.6).
28. Is currently participating or has participated in a study with an investigational 
compound or device within 30 days of signing informed consent. Note: participation 
in observational studies without an intervention may be allowed after consultation 
with the Sponsor. 
29. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
 
 
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30. Is taking, or plans to take, one or more of the following medications (non-inclusive), 
shown in Table 1 within the specified washout period prior to Visit 2 (unless 
specified by a note below) and throughout the course of the trial (a detailed list of the 
prohibited medications is provided in Section 5.5).
Table 1
Prohibited Medications that Require a Washout Period Prior to Visit 2 (Non-
inclusive List).
Prohibited Medications, Supplements, and 
Other Substances
Washout Period prior to Visit 2*
Investigational compounds
4 weeks or 5 t½ lives 
Moderate or Strong CYP3A4 Inhibitors 
eg, atazanavir, clarithromycin, indinavir, itraconazole, 
ketoconazole, nefazodone, refinavir, ritonavir, saquinavir, 
telithromycin, and voriconazole
2 weeks or 5 t½ lives 
Strong CYP3A4 Inducers
eg, barbiturates, carbamazepine, efavirenz, modafinil, 
nevirapine, phenytoin, pioglitazone, primidone, rifabutin, 
rifampin, rifapentin, St. John's Wort (hypericum), and 
systemic glucocorticoids 
Exception: inhaled corticosteroids are permitted)
2 weeks or 5 t½ lives
Antihistamines (sedating)
eg, chlorpheniramine, clemastine, cyproheptadine, 
diphenhydramine, hydroxyzine, thiothixene, trifluoperazine
2 weeks
Hypnotics
eg, acetaminophen and diphenhydramine (Tylenol™ PM), 
diphenhydramine (Nytol™), doxylamine (Unisom™), 
eszopiclone, zaleplon, zolpidem, zopiclone
2 weeks or 5 t½ lives for intermittent use: 
defined as use of <4 times/week
4 weeks or 5 t½ lives for chronic use: defined 
as use of ≥4 times/week
Anxiolytics (benzodiazepines, non-benzodiazepines)
eg, chlordiazepoxide, clonazepam, diazepam, flurazepam, 
lorazepam, meprobamate, triazolam, 
2 weeks or 5 t½ lives for intermittent use: 
defined as use of <4 times/week
4 weeks or 5 t½ lives for chronic use: defined 
as use of ≥4 times/week
Anticonvulsants and Mood Stabilizers
eg, carbamazepine, lamotrigine, levetiracetam, lithium, 
phenytoin, valproic acid
Exception:
Use 
of 
gabapentin 
or 
pregabalin 
for 
neuropathic pain is acceptable.
4 weeks or 5 t½  lives
Anti-Parkinsonian
eg, amantadine, bromocriptine, I-deprenyl/selegiline, 
L-dopamine, pergolide, pramipexole, ropinirole
4 weeks or 5 t½ lives
Other CNS depressants
eg, MAOI, trazodone, or tricyclic antidepressants used for 
sleep complaints are excluded.
2 weeks
Stimulants / Diet Pills
eg, amphetamine, atomoxetine, methylphenidate, 
modafinil,  
2 weeks
Supplements with possible psychotropic effects
eg, kava-kava, melatonin, S-Adenosyl methionine 
[SAMe], St. John’s Wort, tryptophan, and  valerian
2 weeks
*
Interval notes minimum washout period. Washout should occur for 5 half-lives or the minimum specified 
period (2 or 4 weeks), whichever is longer to systemically eliminate the compound.
 
 
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Visit 2: Screening PSG Exclusion:
Note: Meets any relevant Visit 1 Exclusion criteria. Additionally, meets any of the following 
Exclusion criteria based upon Visit 2 tests/results:
31. Has a positive urine drug screen test, as confirmed by central laboratory vendor at 
Visit 2. Note: See details in Section 7.1.3.1.2.
32. Has a positive alcohol breath test as analyzed by a breathalyzer machine at Visit 2. 
Note: The test may be repeated at investigator's discretion (eg, recent use of 
mouthwash) and as warranted by medical history. A repeat test must be negative prior 
to the PSG. Note: See details in Section 7.1.3.1.3.
33. Has an underlying pathology of sleep, identified and confirmed by the central PSG 
rating vendor, during the Visit 2 Screening PSG as follows:

An Apnea Hypopnea Index of >30; 

>30 periodic leg movements associated with an arousal per hour of sleep 
(PLMAs);

Evidence of an exclusionary sleep disorder as detailed in Exclusion Criteria 6 
(eg, REM behavior disorder, parasomnia, etc.).
Note: Subjects who initially screen failed based on this exclusion criterion (AHI 
and/or PLMA) may be considered for re-screening. If the Visit 2 Screening PSG 
would be eligible based on the amended criteria (ie, AHI <30 and PLMA <30 as 
confirmed by Central PSG vendor), subjects may be re-screened after consultation 
with the Sponsor. Details regarding the schedule of re-screening assessments will be 
provided in a Sponsor Communication Form. 
Visit 3: Baseline PSG Exclusion:
Note: Meets any relevant Visit 1 Exclusion criteria. Additionally, meets any of the following 
Exclusion criteria based upon Visit 3 tests/results.
34. PSG reveals evidence of any exclusionary sleep disorder(s) as listed in Exclusion 
Criteria 6 (eg, REM behavior disorder, parasomnia, etc.) at Visit 3.
35. Has a positive urine drug screen at Visit 3. See Note in Exclusion 31.
36. Has a positive alcohol breath test at Visit 3. See Note in Exclusion 32.
Visit 4: Randomization Exclusion:
Note: Meets any relevant Visit 1 Exclusion criteria.
 
 
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Trial Treatment(s)
5.2
The treatments to be used in this trial are outlined below in Table 2.
Table 2
Trial Treatments
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/T
reatment 
Period
Use
Single-Blind Placebo Run-in Period
Placebo 
(to match  suvorexant
10 mg)
0 mg tablet
1 tablet 
every night
Oral
Nightly for 
2 weeks
Placebo
Double-Blind Treatment Period
Suvorexant 10 mg
10 mg tablet
1 tablet 
every night
Oral
Nightly for 
4 weeks
Investigational
Placebo 
(to match  suvorexant 
10 mg)
0 mg tablet
1 tablet 
every night 
Oral
Nightly for 
4 weeks
Placebo
*Options for dose escalation (per investigator’s discretion) – beginning at Visit 5
Suvorexant 20 mg*
20 mg tablet
1 tablet 
every night 
Oral
Nightly for 
2 weeks
Investigational
Placebo (to match 
suvorexant 20 mg) *
0 mg tablet
1 tablet 
every night
Oral
Nightly for 
2 weeks
Placebo
*At Visit 5, the dose of suvorexant may be increased to 20 mg (or matching placebo). See Section 5.2.1.2.
The first dose of trial medication for the single-blind placebo Run-in Period will begin the 
night of Visit 2; dosing will continue until the subject returns for randomization at Visit 4.
The first dose of trial medication for the randomized double-blind Treatment Period will
begin the night of Visit 4. Subjects will remain on the specified trial medication that they are 
randomized to (suvorexant or matching placebo) throughout the trial, with their last dose on 
the night of Visit 6. At Visit 5, the investigator may increase the subject’s trial medication 
dose for the remaining 2 weeks. Please see Section 5.2.1.2 for more information.
To maintain blinding with respect to the treatment period (ie, Run-in, Treatment), subjects 
will not be informed when transitioning between the treatment periods.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
 
 
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Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
5.2.1.2
Dose Modification/Titration
At Visit 5, the dose of trial medication may be increased from 1 tablet of 10 mg suvorexant 
(or 10 mg matching placebo) to 1 tablet of 20 mg suvorexant (or 20 mg matching placebo). 
The decision to increase the dose will be made by the investigator, and is to be based on the 
following 2 criteria: 1) CGI-S score ≥3, and 2) acceptable tolerability. This dose adjustment 
will be performed in a double-blind manner, with maintenance of the original treatment 
assignment (eg, subjects assigned to placebo treatment will continue to receive placebo to 
match the 20 mg suvorexant dose). The modified dose will be taken for the remainder of the 
trial, barring emergence of tolerability issues.
If the subject (or trial partner on behalf of the subject) reports a tolerability issue after the 
dose titration step at Visit 5, the site investigator will determine the subject’s treatment plan 
and next steps (ie, continue current 20 mg dose of suvorexant, down-titrate to the original
10 mg dose of suvorexant, or discontinue trial medication). A clinic visit may be required for 
further evaluation.
All trial medication assignments/adjustments will be completed using the IVRS/IWRS 
system. 
Timing of Dose Administration
5.2.2
For at-home dosing, subjects are to be instructed (and reminded) to take their trial medication
within 30 minutes prior to bedtime. The trial partner is responsible for providing and 
witnessing daily dosing of trial medication to the subject, and may assist in administration of 
trial medication if needed. During PSG visits in the sleep lab, trial medication will be 
administered within 30 minutes before bedtime (Lights Off), and dosing will be witnessed by 
study personnel.
Each morning, the trial partner will record the dosing time from the previous night, in the e-
diary, along with the responses to other e-diary questions.
If a subject happens to miss their evening dose, they should resume taking their medication 
the following night. The subject should not take an additional dose (ie, the morning following 
the missed dose) to ‘make up’ the missed dose. Missed doses should be reported to the site.
It is important that subjects have taken trial medication for at least 3 days prior to a PSG visit 
(with the exception of Visit 2); therefore, in the event trial medication is interrupted on nights 
leading up to the end-of-treatment PSG visit (ie, Visit 6), the visit should be rescheduled.
 
 
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Trial Blinding/Masking
5.2.3
A double-blind/masking technique will be used.  All doses of suvorexant and their respective 
matching placebo for the 4-week double-blind Treatment Period will be packaged identically
so that blind/masking is maintained. The subject, the investigator and Sponsor personnel or 
delegate(s) who are involved in the treatment or clinical evaluation of the subjects are 
unaware of the group assignments.
Additionally, a single-blind/masking technique will be used for the Run-in Period. See 
Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a subject 
during the trial, should such action be warranted.
Randomization
5.3
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 1:1 ratio to either suvorexant or placebo. 
Stratification
5.4
Treatment allocation/randomization will be stratified by the IVRS/IWRS system according to 
the following factors:

Alzheimer’s disease severity category, mild versus moderate, as defined by 
MMSE score ranges at Visit 1 Screening: 12 to 20 (moderate), 21 to 26 (mild). 
Approximately 30% of the randomized subjects will be assigned to the moderate 
AD stratum.
Concomitant Medications/Vaccinations (Allowed)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy requires the mutual agreement of the investigator, the Sponsor and 
the subject.
Table 3 displays the list of concomitant medications that are allowed during the trial. While 
the list is not inclusive of all medications within a given category, the investigator should use 
his/her medical judgment when a subject presents with a medication not on the list that falls 
within a relevant category. When medically possible, the dose of a concomitant medication 
should be kept stable throughout the entire trial.
It is strongly encouraged, but not required, that the dose of allowed medications, 
supplements, and other substances for chronic conditions be stable for at least one month 
 
 
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prior to screening and remain stable during the trial. This is particularly important for 
medications that can impact cognition (eg, pregabalin and gabapentin). Exception: 
acetylcholinesterase inhibitors and memantine are allowed during the trial, but the dose must 
be stable for at least one month prior to Visit 1, and should not be changed during the trial 
unless medically necessary to ensure subject safety. 
If necessary, the medications, supplements, and other substances in Table 3 can be initiated 
during the trial if medically indicated. Note that the use of any concomitant medication must 
relate to the documented medical history, prophylaxis, or an adverse event of the subject. 
In the event that a subject requires an extended washout period (ie, greater than 2 weeks) for 
a prohibited medication(s) or other therapy, an abbreviated Visit 1 may be performed (see 
Section 7.1.5.1.1). After the subject has completed the proper washout based on , the subject 
will return to complete the remaining Visit 1 procedures/assessments. Once the subject has 
fully completed Visit 1 and eligibility has been confirmed, the subject may proceed to Visit 2 
per protocol.
Concomitant medications should be collected during the post-treatment follow-up phone call 
in the event an AE is reported.
Table 3
Allowed Medications, Supplements, and Other Substances (non-inclusive list)
Medication Category
Examples*/ Notes
(*specific medications listed are examples of class compounds and are not 
limited to those listed)
AD medications
eg, donepezil, galantamine, memantine, rivastigmine
Note: Subject must be on a stable dose for at least 1 month prior to 
Screening Visit.
Antidepressants
eg, SSRI and SNRI medications, including bupropion, citalopram, 
escitalopram, fluoxetine, mirtazapine, paroxetine, sertraline, venlafaxine
Antihistamines:
Non-sedating
Note:  Non-sedating antihistamines are not to be taken more than twice a 
week.  
Note: Montelukast sodium (SINGULAIR™) and inhaled corticosteroids 
may be used more than twice weekly as needed for allergic symptoms
Antipsychotics
eg, aripiprazole, asenapine, olanzapine, risperidone, ziprasidone
Note: quetiapine is allowed if used on an as needed basis for 
daytime control of neuropsychiatric symptoms, but quetiapine is 
prohibited if used for sleep. Subjects should avoid taking 
quetiapine for at least 3 hours before going to bed throughout the 
duration of the study, and refrain from using quetiapine, for at 
least 24 hours before, and during, PSG visits. 
 
 
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Medication Category
Examples*/ Notes
(*specific medications listed are examples of class compounds and are not 
limited to those listed)
Centrally acting analgesics
eg, codeine, hydromorphone, morphine, oxycodone, propoxyphene, and its 
variations, & combination products that contain a narcotic.
May be taken as needed for pain relief (with the documented approval of 
the Merck clinical monitor), but use may not exceed 3 consecutive days or 
>4 days per any week.
Note:  Use of narcotics for pain relief should be avoided if there are 
effective alternative therapies such as non-steroidal anti-inflammatory 
agents. Sponsor must be notified of any use exceeding 3 consecutive days 
or >4 days per any week.
Muscle relaxants (centrally acting with 
psychotropic effects) 
eg, methocarbamol 
Note:  Use of centrally acting muscle relaxants should be avoided if there 
are effective alternative therapies such as non-steroidal anti-inflammatory 
agents.  Sponsor must be notified of any use exceeding 3 consecutive days 
or >4 days per any week.
Over-the-Counter (OTC), combination 
products containing caffeine for pain 
relief 
eg, acetaminophen, aspirin, and caffeine (EXCEDRIN™), and aspirin and 
caffeine (ANACIN™)
Note: 2 tablets are equivalent to a caffeinated beverage and should be 
counted as such toward the maximum 600 mg caffeine per day (eg, 4 
standard 8-ounce cups of brewed coffee). As with any caffeinated 
beverages, patients should be advised to refrain from using these 
medications after 4 PM. These medications should not be taken on 
days/nights when PSGs are conducted.
Pseudoephedrine
Note:  May only be used before 2 PM, and no more than twice a week. 
Dosage is limited to 30 mg of active ingredient in each tablet. Extended 
release formulations are prohibited. These medications should not be taken 
on days/nights when PSGs are conducted.
Suvorexant is a substrate of CYP3A4 and should not be co-administrated with strong to 
moderate CYP3A4 inhibitors (see ). Suvorexant is a weak inhibitor of CYP3A and the 
intestinal 
P-glycoprotein 
(P-gp) 
transporter 
following 
consecutive, 
multiple-dose 
administration. For most drugs metabolized by CYP3A4, suvorexant is not expected to 
increase plasma levels of other medications to a clinically significant degree. Concomitant 
administration of suvorexant with digoxin slightly increased digoxin levels due to inhibition 
of intestinal P-gp. Subjects may continue on digoxin with digoxin level monitoring during 
the study, consistent with general clinical practice. No clinically significant pharmacokinetic 
interactions were observed following co-administration of suvorexant with warfarin. The 
investigator should use his/her clinical judgment to determine if any concomitant 
medications (not specifically prohibited) should be discontinued, or alternatively, if careful 
clinical monitoring is sufficient.
Rescue Medications & Supportive Care
5.6
No rescue or supportive medications are specified to be used in this trial.
 
 
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Diet/Activity/Other Considerations
5.7
The following are recommendations/guidance for subjects; monitoring is not required.
Diet
5.7.1
Subjects should maintain their usual diet throughout the duration of the trial.
Use of Alcohol, Caffeine, and Tobacco
5.7.2
The site should advise subjects/trial partner that alcohol should NOT be consumed in 
combination with suvorexant because of potential additive effects.
The site should advise subjects to limit their alcohol intake as follows:

Do NOT consume alcohol in combination with suvorexant

Limit consumption to no more than 2 drinks a day and avoid alcohol at least 3 hours 
before going to bed throughout the duration of the study. 
o
One drink is defined as a 12-ounce bottle/can of beer (~14 grams alcohol) or a 
4-ounce glass of wine (~12 grams alcohol) or 1 ounce of liquor (80 proof or 
40 % alcohol, ~ 9 grams alcohol).

Refrain from consuming any alcohol for at least 24 hours prior to and during PSG 
visits. 
Note that subjects will be asked to take an alcohol breath test at PSG visits; if a subject 
tests positive on the alcohol breath test, that visit should be rescheduled as soon as 
possible. See Section 7.1.3.1.3 for more details.
The site should advise subjects to limit their caffeine consumption as follows:

Limit their daily caffeine consumption to ≤600 mg caffeine, and avoid caffeine after 
4 PM (16:00) throughout the duration of the trial. (See Appendix 12.7 for additional 
guidance on caffeine products and content.) 

Refrain from consuming any caffeine after 1 PM (13:00) on the day of PSG visits. In 
addition, caffeinated products should not be consumed until after completion of all 
morning procedures at the PSG visit.
The site should advise subjects to limit their tobacco use as follows: 

Refrain from the equivalent of >15 cigarettes a day during the trial, and

Refrain from smoking during the night, interrupting their sleep to smoke, or smoking
within 30 minutes of waking in the morning
 
 
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The day before a PSG visit, it is recommended that sites call the subject/trial partner to 
remind them of alcohol and caffeine limitations. It is also recommended that the site staff 
inquire about alcohol, caffeine, and tobacco consumption when a subject/trial partner returns 
for a visit, and record any information regarding this consumption in the subject’s source 
documentation.
Activity
5.7.3
Subjects should not drive, operate hazardous machinery, or do other dangerous activities, 
after taking trial medication, until they feel fully awake. 
Subjects who are provided non-trial treatments, such as day-care, may continue these 
throughout the trial. The frequency should not change unless medically indicated. 
During the study, every effort should be made by the subject to maintain a habit of going to 
bed at their regular bedtime. The regular bedtime for subjects should be between 8:00 PM 
(20:00) and 1:00 AM (01:00). "Bedtime" is defined as the time when the subject 
intends/attempts to fall asleep for the night (eg, lying down or reclining with eyes closed with 
intention of getting a full night of sleep). The subject should sleep in a conducive 
environment (ie, a darkened room, a relatively quiet room, a room free from distractions). 
Throughout the study, and in particular on the nights just prior to a PSG visit, trial partners 
should ensure that subjects have adequate opportunity for sleep (ie, at no time during the trial 
should the time allotted for sleep be shortened). If for some reason, the subject’s opportunity 
for sleep the night prior to a PSG visit is inadequate or disrupted due to extenuating 
circumstances (eg, traveling, illness), then it is recommended that the subject’s PSG visit be 
rescheduled in a timely manner, preferably within 1-3 days of the originally scheduled visit.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
Table 4 provides reasons why a subject must be discontinued from treatment but may 
continue to be monitored in the trial, as well as reasons why a subject must be discontinued 
from treatment and the trial.
 
 
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Table 4
Discontinuation Scenarios
Reason for Discontinuation Scenario
Action
The subject or legal representative (such as a parent 
or legal guardian) withdraws consent.
Discontinuation from Treatment and Trial
The subject’s treatment assignment has been 
unblinded by the investigator, Merck subsidiary or 
through the emergency unblinding call center.
Discontinuation from Treatment, but Continue in 
Trial
The subject has a medical condition or personal 
circumstance which, in the opinion of the investigator 
and/or Sponsor, places the subject at unnecessary risk 
through continued participation in the trial or does not 
allow the subject to adhere to the requirements of the 
protocol.
Discontinuation from Treatment and Trial
The subject’s trial partner is no longer willing 
(withdraws consent) or able to participate in the trial 
or is not compliant with trial-related procedures, and 
a suitable replacement trial partner cannot be 
identified within a reasonable period of time.
Discontinuation from Treatment and Trial
The subject is no longer able to participate in the trial 
or is not compliant with trial-related procedures.
Discontinuation from Treatment and Trial
The subject has an elevated ALT, AST, or T-BIL 
meeting any one of the following criteria:

ALT or AST ≥8x ULN;

ALT or AST ≥5x ULN for more than 
2 weeks;

ALT or AST ≥3x ULN and T-BIL ≥2x ULN 
at the same visit;

ALT or AST ≥3x ULN with the appearance 
of 
symptoms 
indicating 
hepatitis 
(eg, 
worsening fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, 
rash, or eosinophilia).
Note: The Sponsor or its delegate should be 
immediately contacted when a subject is discontinued 
from trial medication or trial medication is interrupted 
because of an AE or a laboratory safety test 
abnormality.
Discontinuation from Treatment, but Continue in 
Trial
The subject takes a prohibited medication during the 
trial. 
This deviation should be documented, and the 
Sponsor 
should 
be 
consulted 
regarding 
the 
management of the subject.
Subjects who report suicidal ideation with intent, with 
or without a place or method (ie, a positive response 
to items 4 or 5 in the assessment of suicidal ideation 
on the C-SSRS) or suicidal behavior may meet 
discontinuation criteria.  
Please refer to Section 7.1.2.2.11, 7.2.3.2 and the 
ECI guidance document for details.
 
 
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Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
 
 
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6.0 TRIAL FLOW CHART
Screening Period
Treatment Period
Disconti
nuation
Post-
Treatment
Placebo Run-in
Visit Number/Title:
1 
Screeninga, b
2
Screening 
PSG
3
Baseline
PSG
4
Randc
5
End of 
Week 2
6
End of Weekcc
4 - PSG
Discon
Follow-up 
TCd
Scheduled Week/Day
Day -21
Day -14/-13
Day-7/-6
Day 1
Day 15
Day 29/30
14 days 
Post-dose
Scheduling Window by Days:
+28e
-3/+3f
-3/+4
-3/+3
-3/+5
-3/+5
+2
Administrative Procedures
PMg
AM
PM g
AM
PMg
AM
Informed Consent – Subject
X
Informed Consent – Trial partner
X
Informed Consent – Future Biomedical Research (FBR)
X
Inclusion/Exclusion Criteria
X
X
X
X
X
Xh
Subject Identification Card
X
Medical History
X
Prior Medication Review
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
Monitor Trial Medication Compliance 
X
X
X
X
X
Call/Log-in to IVRS/IWRS
X
X
X
Xi
X
X
Dispense Trial Medication to Subject/Trial partner
Xj
X
Xi
Site Witnessed Trial Medication Dose prior to PSG
X
X
X
E-diary Training
X
E-diary monitoringk
         X-------------------------------------------------------------------------------X
X
Activity/Sleep Watch Training
X
Activity/Sleep Watch monitoring l
X-----------------------------------------------------------------X
Clinical Procedures/Assessments
PM
AM
PM
AM
PM
AM
AD Diagnosis: NIA-AA or DSM-5 criteria m
X
Mini-Mental State Examination (MMSE) n
X
X
X
X
Modified Hachinski Ischemia Score (MHIS)
X
Insomnia Diagnosis: DSM-5 criteria m
X
Insomnia Diagnosis: Insomnia Diagnostic Interview (IDI) m
X
Insomnia Diagnosis: Sleep History (SHX) m
X
15-item Geriatric Depression Scale (GDS)
X
Neuropsychiatric Inventory (NPI)
X
X
X
Clinical Global Impression – Severity (CGI-S), for insomnia
X
X
X
X
Columbia-Suicide Severity Rating Scale (C-SSRS) - Screening
X
Columbia-Suicide Severity Rating Scale (C-SSRS) - Since Last Visit
X
X
X
X
X
X
Xo
 
 
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Screening Period
Treatment Period
Disconti
nuation
Post-
Treatment
Placebo Run-in
Visit Number/Title:
1 
Screeninga, b
2
Screening 
PSG
3
Baseline
PSG
4
Randc
5
End of 
Week 2
6
End of Weekcc
4 - PSG
Discon
Follow-up 
TCd
Scheduled Week/Day
Day -21
Day -14/-13
Day-7/-6
Day 1
Day 15
Day 29/30
14 days 
Post-dose
Scheduling Window by Days:
+28e
-3/+3f
-3/+4
-3/+3
-3/+5
-3/+5
+2
Digit Symbol (DS) p
X
X
X
Polysomnography (PSG)
X
X
X
Neurological Examination (NE)
X
X
X
Physical Examination (PE)
X
X
X
12-Lead Electrocardiogram (ECG)
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
Height q
X
Weight q
X
X
X
Daily 
morning 
e-diary
Morning sleep questions r (trial partner- assessed)
         X-------------------------------------------------------------------------------X
X
Sleep Quality Rating (SQR) s (trial partner-assessed)
         X-------------------------------------------------------------------------------X
X
Sleep Disorders Inventory (SDI) t (trial partner-assessed)
    X----completed weekly----X
X
Activity/Sleep Watch  (wrist worn continuously)
       
X-----------------------------------------------------------------X
X
Single-item Sleep Quality Scale - Caregiver (SSQC) (trial partner-
endpoint) u
X
X
X
X
Modified Cataplexy Questionnaire (MCQ) v
         X---------------------------------------------------------------------------------------------------------- X
Adverse Experience Monitoring
         X-----------------------------------------------------------------------------------------------------------X
Laboratory Procedures/Assessments
PM
AM
PM
AM
PM
AM
Pharmacokinetic (PK) Sampling
X
X w
X x
Hematology
X
X
X
Urinalysis
X
X
X
Chemistry
X
X
X
Serum Follicle-stimulating Hormone (FSH) Blood Samples y
X
Urine Drug Screen z
X
X
X
X
Alcohol Breath Test aa
X
X
X
Blood for Genetic Analysis bb
X
a)
Assessments may be conducted over the course of more than 1 day to decrease subject/trial partner burden. See Section 7.1.5 for details.
b)
Subjects with screening values/findings outside ranges described in the protocol may, at the discretion of the investigator, be re-screened. Only 1 re-screen per subject will be 
allowed and they should retain their same screening number. See Section 7.1.1.6 and 7.1.5.1 for more information..
 
 
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c)
Assessments taken prior to randomized dosing at this visit reflect placebo run-in treatment and will serve as baseline values for analysis purposes. 
d)
Subjects will be contacted by telephone 14 days after their last dose of trial medication, regardless of when the Discontinuation visit is performed. This is to assess for any AEs 
as well as review concomitant medications that may have been initiated due to an AE.
e)
The +28 day visit window prior to Visit 2, is provided to accommodate up to a 4-week washout period for prohibited medications, resolve/stabilize any conditions or treatments, 
provide flexible scheduling, and repeat of study procedures, if needed.. 
f)
The minimum interval of time between Visits 2, 3, and 4 should be 4 days in order to allow for confirmation of PSG results from the central PSG reading center. 
g)
Measurements that are performed in the PM, with the exception of the PSG, will be conducted prior to trial medication. This applies to all PSG visits.
h)
Final eligibility should be confirmed prior to randomization.
i)
At Visit 5, if the subject has adequate tolerability and residual insomnia (defined as CGI-S ≥3), as assessed by the investigator, dose escalation to 20 mg suvorexant for the 
subject will occur. If tolerability issues by the subject occur after Visit 5, new medication may be dispensed via IVRS/IWRS when the subject returns for follow-up.
j)
If the PSG center is separate from the trial site, the PSG center should make arrangements with the trial site to obtain the subjects trial medication that will be administered the 
night of Visit 2 PSG. Trial medication should not be dispensed earlier than the actual PSG visit day.
k)
E-diary monitoring should begin after completion of Visit 1. 
l)
Activity/Sleep watch monitoring should begin after the completion of Visit 2.
m)
Source documentation to support the diagnosis of AD and insomnia should be available in the subject’s source documents.
n)
The subject’s MMSE score will be inputted into IVRS/IWRS during the Visit 2 IVRS transaction to stratify the subject. 
o)
C-SSRS may be done over the telephone during the post-treatment visit.
p)
Please refer to the Manual of Assessments (MOA) regarding visit specific versions to use.
q)
Body Mass Index (Appendix 12.6) will be calculated only at Visit 1 from weight and height. Please refer to Appendix 12.6 for calculation of BMI.
r)
The trial partner will complete a morning e-diary daily at home, preferably within an hour of the subject awakening for the day. See Section 7.1.2.2.15 for more details.
s)
The SQR will be completed daily by the trial partner in the e-diary following completion of the morning sleep questions. 
t)
The SDI will be completed weekly by the trial partner in the e-diary following completion of the morning sleep questions. This will be initiated at Visit 4.
u)
The Single-item Sleep Quality Scale – Caregiver is completed by the trial partner and is a self-assessment of the trial partner’s sleep.
v)
MCQ will be completed for any report of an AE of cataplexy, events suggestive of cataplexy, or falls/ataxia/worsening of balance (to rule out cataplexy).
w)
The PK sample taken at this visit should be drawn between 8.5 hours to 11 hours post-dosing on the AM portions of this visit. 
x)
A PK sample should only be taken if the subject discontinued the trial due to an AE. The trial partner should also be asked about AE(s) that the subject experienced.
y)
A blood sample for determining serum FSH should be collected only if serum FSH levels are required to determine childbearing potential as defined in Section 5.1.2.
z)
At Visit 1, urine drug screen test should be sent into central lab vendor for eligibility confirmation. At visits thereafter, subjects will undergo an on-site drug test. If a subject has 
a positive urine drug test, a sample must be sent to the central laboratory for confirmation and the PSG should be rescheduled.
aa)
Subjects should have a negative alcohol breath test on the PSG visit nights. If positive, the test may be repeated per investigator discretion; however the subject must have a 
negative result prior to the PSG
bb)
This sample will be drawn for APOE4 genotyping and for planned analysis of the association between genetic variants in DNA and drug response. Data analysis will be limited 
to APOE4 genotyping if the IRB/IEC does not approve of, or if there is a documented law or regulation prohibiting, the planned analysis of the association between DNA 
variations and drug response. Leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. This sample should be drawn at V4; 
however, in the event this is not possible, it can be drawn at a subsequent post-randomization visit.
cc)
Visit 6 PSG and associated assessments (eg, alcohol breath test, UDS, witnessed dose of trial medication, DS, PK sampling) are to be conducted at the PSG center; DS and PK 
samples are to be completed in the morning, after completion of the PSG. Safety and ancillary assessments (eg, ECG, labs, vital signs, physical exam, neurology exam, CGI-S, 
NPI, or C-SSRS, etc) may be completed as noted in the Trial Flow Chart or either on the day of the PSG PM Visit (Target Day 29) or PSG AM Visit (Target Day 30) . 
dd)
Subjects who initially screen failed based on exclusion criterion #33 (AHI and/or PLMA) on the Screening PSG may be considered for re-screening. If the Visit 2 Screening 
PSG would be eligible based on the amended criteria (ie, AHI <30 and PLMA <30 as confirmed by Central PSG vendor), subjects may be re-screened after consultation with 
the Sponsor. Details regarding the schedule of re-screening assessments will be provided in a Sponsor Communication Form. 
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. Documented consent from each subject’s trial partner 
(referred to as trial partner consent) will also be obtained by the investigator or qualified 
designee.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. Trial partner consent will similarly be 
documented by the trial partner’s dated signature on a consent form and the dated signature 
of the person conducting the consent discussion.
A copy of the respective signed and dated consent forms (subject and trial partner consents) 
should be given to the subject and trial partner before participation in the trial.
The initial subject and trial partner informed consent forms, any subsequent revised written 
informed consent forms and any written information provided to the subject/trial partner 
must receive the IRB/ERC’s approval/favorable opinion in advance of use.  The subject or 
his/her legally acceptable representative and the subject’s trial partner should be informed in 
a timely manner if new information becomes available that may be relevant to the 
subject’s/trial partner’s willingness to continue participation in the trial.  The communication 
of this information will be provided and documented via a revised consent form(s) or 
addendum to the original consent form(s) that captures the subject’s dated signature or by the 
subject’s legally acceptable representative’s dated signature, or by the trial partner’s dated 
signature.
 
 
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Specifics about a trial and the trial population will be added to the consent form template(s) 
at the protocol level.  
Informed consent(s) will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed at Visits 1, 2, 3, and 4 by the 
investigator or qualified designee to ensure that the subject (and trial partner) qualifies for the 
trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days before starting the trial. If the subject has used medications to treat their 
insomnia within the last 12 months prior to Screening (Visit 1) these should also be recorded. 
Prohibited medications will be discontinued in accordance with the schedule stated in . In the 
event that a subject requires an extended washout period (ie, greater than 2 weeks) for a 
prohibited medication(s) or other therapy, an abbreviated Visit 1 may be performed (see 
 
 
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Section 7.1.5.1.1). After a subject has completed the specified washout, he/she will return to 
complete the remaining Visit 1 procedures. Once the subject completes the Visit 1
procedures, he/she may proceed to Visit 2 if Visit 1 entry criteria are satisfied.
For sites who pre-screen subjects (eg, telephone calls prior to Visit 1), it is suggested that 
they review the subject’s medication list for any prohibited medications and discuss the 
washout requirements with the subject and trial partner. These earlier discussions will allow 
subjects to discuss discontinuation of prohibited medications with their primary care
physician once consented.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication(s), if any, taken by the subject 
during the trial. Any changes to medication(s) (ie, dose, frequency), including background 
AD therapy, should also be recorded. If the subject reports taking any prohibited medications 
during the study, this should be recorded as a study deviation. Concomitant medications 
should preferably not be changed during the course of study, without first consulting the 
investigator, except in cases of medical emergencies or other obvious exceptions. Please see 
Section 5.5 for more details.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1. 
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.8
Trial Compliance (Medication)
The trial partner is responsible for the following aspects of trial medication administration: 

Storing and dispensing the trial medication to the subject at home;
 
 
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
Witnessing the subject taking trial medication at bedtime (and aiding in dosing as
needed);

Recording the subject’s dosing time in the morning e-diary each day;

Returning trial medication/blister packs to the clinic at each study visit;

Assisting the site staff in providing any information regarding missed doses or 
overdoses of the trial medication. 
During PSG visits, administration of trial medication will be witnessed by the investigator 
and/or trial staff.
It is important that subjects have taken trial medication for at least 3 days prior to a PSG visit
(with the exception of Visit 2); therefore, in the event trial medication is interrupted on nights 
leading up to the end-of-treatment PSG visit (ie Visit 6), the visit should be rescheduled. The 
site should monitor trial medication compliance by the e-diary reports provided by the central 
e-diary vendor. 
Accounting of trial medication will be conducted as specified in the Trial Flow Chart. The 
trial medication will be returned to the clinic at each study visit (beginning at Visit 3). 
For assessment of compliance with trial medication at Visit 4 (see criterion in Section 5.1.2), 
the number of pills taken will be divided by (/) the number of nights from Visit 2 (inclusive) 
to the day prior to Visit 4. After Visit 4, trial medication compliance will be monitored and 
determined at each visit by subject/trial partner interview, pill count, and e-diary data. In the 
event that there is a discrepancy, please consult the data entry guidelines (DEGs) for specific 
information.
Instances of trial medication non-compliance (missed doses or overdose) should be 
documented as follows:  

Less medication was taken than prescribed:  Instances where a subject failed to take 
trial medication as prescribed and missed a dose(s) should be documented. The 
subject and trial partner will be counseled by the study staff regarding the importance 
of study drug compliance. 

More medication was taken than prescribed:  Instances where a subject/trial partner
reports taking more medication than prescribed could be considered an AE of 
“overdose.”  These AEs will be reported as Events of Clinical Interest (ECI) or as 
Serious Adverse Events (SAE); see Section 7.2.1 for details regarding reporting of 
overdoses.  
Monitoring for Potential Trial Medication Misuse:
To monitor for potential trial medication misuse, the site will document certain discrepancies, 
based on predefined criteria, where less trial medication during the 4-week double-blind 
treatment period is returned than expected based on the study interval and what the 
 
 
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subject/trial partner reports was taken. In such cases, the site will assess if the discrepancy 
meets the predefined criteria for an ECI of “potential trial medication misuse,” based on a 
discrepancy of missing trial medication of more than 1 pill per week (eg, more than 2 pills 
over a 2 week period). Refer to see Section 7.2.3.2 for standard reporting procedure of ECIs.  
Interruptions from the protocol specified treatment for 3 or more consecutive days require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on subject management.
7.1.1.9
Interactive Voice Response System/Integrated Web Response System
The investigator or designee will call/log into IVRS/IWRS as specified in the Trial Flow 
Chart. Upon confirmation of a subject’s eligibility at Visit 4, the investigator or designee will 
call IVRS or log into IWRS to randomize the subject. Subjects who do not meet eligibility 
criteria at Visit 4 will be screen-failed in IVRS/IWRS. For all randomized subjects, the 
investigator or designee will continue to call/log into IVRS/IWRS as per the Trial Flow 
Chart. For completed or discontinued subjects, the investigator or designee will make the 
final call/web action into IVRS/IWRS at their last trial visit. For additional information, 
please refer to Section 5.3.
7.1.1.10 Trial Medication Dispensing
At the visits specified in the Trial Flow Chart, the site will dispense trial medication using the 
IVRS/IWRS system. The site will provide the trial medication to the trial partner as well as 
inform the trial partner and subject of the dosing instructions.
Subjects will receive a blister pack to adequately cover the time period between each visit, 
according to the Trial Flow Chart. Subject/trial partner should be reminded that trial 
medication should remain in the blister pack provided; it should not be removed and put into 
another container (ie, pill box).
Specific for Visit 2:  If the PSG site is separate from the clinical site, arrangements should be 
between both sites to obtain the subject’s trial medication for the Visit 2 PSG. See footnote i 
in Trial Flow Chart.
7.1.1.11 E-diary and Activity/Sleep Watch Training and Monitoring
Please refer to Sections 7.1.2.2.15 for e-diary and 7.1.2.2.16 for activity/sleep watch for 
details.
 
 
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Clinical Procedures/Assessments
7.1.2
7.1.2.1
Physical Assessments/Examinations
7.1.2.1.1 Physical Examination/Neurological Examination (PE/Neuro Exam)
A complete physical examination (PE), including a neurological exam, will be performed by 
a primary investigator or sub-investigator (M.D., D.O., Nurse Practitioners (N.P.) or 
Physician’s Assistant (P.A.) in areas where N.P.s and P.A.s are licensed to perform a PE). 
This examination will also be performed in the event of early discontinuation. The following 
body systems should be included in these exams:

Head, Eyes, Ear, Nose, and Throat

Neck

Cardiovascular system

Respiratory system

Abdomen

Skin

Extremities

Neurological system (see Appendix 12.11)

Musculoskeletal system
Examination of the breast, rectum, and urogenital system are at the investigator’s discretion 
(ie, clinically indicated). If a physical or neurological abnormality is noted post-treatment, 
the investigator will indicate whether or not the result is clinically significant and if it 
constitutes an adverse event.
7.1.2.1.2 Lead Electrocardiogram
A 12-lead electrocardiogram will be performed according to the instructions in a separate 
ECG Instruction Manual by the central ECG vendor.
7.1.2.1.3 Vital Signs
Body Temperature:  Body temperature will be measured with an oral or tympanic 
thermometer. The same method (eg, oral or tympanic, ºF/ºC) should be used for all 
measurements for each individual subject and should be the same for all subjects throughout 
the trial.
Heart Rate (HR), Blood Pressure (BP) and Respiratory Rate (RR):  Subjects should be 
resting in a semi-recumbent position for at least 10 minutes prior to having vital sign 
measurements obtained. The same position should be used for all measurements for each 
individual subject and should be the same for all subjects throughout the trial. The correct 
size of the blood pressure cuff and the correct positioning on the subject’s arm is essential to 
increase the accuracy of blood pressure measurements. The same method (eg, manual or 
 
 
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automated) should be used for all measurements for each individual subject and should be the 
same for all subjects throughout the study.
7.1.2.1.4 Body Height/Weight
Height (cm/in) and body weight (kg/lbs) will be collected and recorded. Measurements 
should be recorded to the nearest centimeter/inch and kilogram/pound. Body weight data will 
be collected without shoes and with heavy clothing (such as coats) removed. Body weight 
should be performed on the same scale for the same individual throughout the study.
7.1.2.2
Clinical and Neurobehavioral Assessments
The role of trial raters and administrators is to elicit optimal effort from participating 
subjects, while adhering to standardized administration and scoring procedures, to maximize 
data quality and integrity. Recommended minimum education and experience standards will 
be determined for each neurobehavioral and clinical assessment. Education and experience 
credentials of potential raters will be compared to these criteria to pre-qualify raters for trial 
participation. Following credentials review, pre-qualified raters will undergo training (and 
certification if applicable) prior to trial initiation. After the start of the trial, similar 
procedures will be implemented for initiating any new raters. Details regarding the rater 
qualifications, training, and other specifications will be specified in the Manual of
Assessments (MOA). In order to qualify for the trial, all potential raters must be evaluated 
and approved by the Sponsor. Whenever possible, the same rater should conduct the same 
assessment(s) throughout the trial for a given subject and trial partner.
The MOA will also provide guidance on the order that clinical assessments should be 
conducted and provides estimated times for completion of the assessments. 
7.1.2.2.1 The National Institute on Aging – Alzheimer’s Association (NIA-AA) 
The NIA-AA criteria for AD may be used to confirm the diagnosis of the subject’s AD. 
These criteria can be found in Appendix 12.9.
7.1.2.2.2 The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-
5)
The DSM-5 criteria for AD may be used to confirm the subject’s AD diagnosis.  
The DSM-5 criteria for insomnia will be used to confirm the subject’s insomnia diagnosis.
These criteria can be found in Appendix 12.10.
7.1.2.2.3 Mini-Mental State Examination (MMSE)
The paper version of the MMSE [11] a brief cognitive screening measure, will be 
administered to the subject and scored by a qualified, trained rater as described in the MOA. 
Raters should make every effort to elicit subjects’ best effort to help ensure data validity (eg, 
 
 
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a subject is not too tired to complete the assessment). Additional detailed information 
concerning administration and scoring may also be provided in the MOA.
7.1.2.2.4 Modified Hachinski Ischemia Scale (MHIS)
The MHIS [22] a tool to identify the possibility of a vascular etiology for the subject’s 
dementia, will be completed by a subject and trial partner interview and scored in paper form 
by a qualified, trained rater, as described in the MOA. Additional detailed information 
concerning administration and scoring may also be provided in the MOA.
7.1.2.2.5
Insomnia Diagnostic Interview (IDI) 
The Insomnia Diagnostic Interview is an assessment tool which incorporates the DSM-5
Insomnia criteria into an interview format to aid in confirmation of the insomnia diagnosis  
and to rule out other possible causes for sleep difficulty (eg, other sleep related disorders, 
comorbid conditions, concomitant medications). This assessment will be completed in paper 
form by a qualified trained rater, by a subject and trial partner interview, as described in the 
MOA. 
7.1.2.2.6 Sleep History (SHX)
The Sleep History assessment collects information regarding number of nights per week of 
problematic sleep, hour of usual bedtime, total time asleep and time to fall asleep during the 
past 3 months. It also collects information regarding the subject’s napping habits as well as 
what medications the subject may have taken over the past year to treat their insomnia. This 
assessment will be completed in paper form by a qualified trained rater, by a subject and trial 
partner interview, as described in the MOA. 
7.1.2.2.7 Geriatric Depression Scale (GDS)
The 15-item GDS [21] is a paper, interview-based depression screening tool; it will be
completed and scored by a qualified trained rater, via subject/trial partner interview, as 
described in the MOA. Additional detailed information concerning administration and 
scoring may also be provided in the MOA.
7.1.2.2.8 Neuropsychiatric Inventory (NPI)
The NPI [20] is an interview-based tool that has been widely used in clinical trials to assess 
behavior in AD and other dementias. The NPI is organized into 12 behavioral domains 
including: Hallucinations, Delusions, Agitation/aggression, Dysphoria/depression, Anxiety, 
Irritability, Disinhibition, Euphoria, Apathy, Aberrant motor behavior, Sleep and night-time 
behavior change, Appetite and eating change. The Sleep and night-time behavior change
questions will be assessed via the e-diary in this trial. The assessment captures frequency and
severity of symptoms within these domains as well distress to the trial partner. The NPI 
(paper version) will be completed by an interview with the trial partner and scored by a 
qualified trained rater, as described in the MOA. Additional detailed information concerning 
administration, scoring and recording may also be provided in the MOA. 
 
 
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7.1.2.2.9 Clinical Global Impressions – Severity, for Insomnia (CGI-S)
The CGI-S
scale is a psychometrically validated instrument widely used in 
psychopharmacologic research to provide a global assessment of illness severity (CGI-S) 
[32]. In this trial, the CGI-S is intended to measure the severity of the subject’s insomnia. 
When administering the CGI-S, the rater should use his/her total clinical experience with this 
subject population to judge how ill the subject is at the time of the rating; this scale will be 
completed in paper form, and will be scored by a qualified trained rater, as described in the 
MOA.
7.1.2.2.10 Columbia-Suicide Severity Rating Scale (C-SSRS)
Suicidal ideation and behavior will be prospectively assessed during this study using the 
Columbia Suicide Severity Rating Scale (C-SSRS). The C-SSRS should be administered by 
trained raters at specified time points, as indicated in the Trial Flow Chart, as well as at 
unscheduled visits as clinically indicated. Site staff should review the contents of the C-SSRS 
for completeness. Note that the C-SSRS assessment is not considered complete until all 
available sources of information have been considered (eg, trial partner input may be 
necessary).
If the C-SSRS is administered by someone other than the Investigator, consider providing the 
completed C-SSRS to the Investigator for review, prior to their assessment of the subject, and 
to further inform their evaluation. 
The C-SSRS is not explicit about whether the subject specifically has ideation at the time of 
screening. If a subject reports a prior history of ideation/behavior, the assessor should also 
inquire and document if this is also present at the time of the screening visit.
Subjects who at any time during this trial report suicidal ideation or behavior that is
considered to be an adverse event, either between visits or during visit interviews, must be 
assessed by the Investigator. Subjects who report suicidal ideation with intent, with or 
without a plan or method (ie, a positive response to items 4 or 5 in the assessment of suicidal 
ideation on the C-SSRS) or suicidal behavior must be evaluated that day by a psychiatrist or 
other trained mental health professional who is a licensed psychologist, social worker or 
mental health nurse practitioner (or comparable professional qualification in countries 
outside the United States). Only subjects whose suicidal ideation is passive, who expressly 
deny any intent to act, and who, after evaluation, are not judged to be at serious risk for self-
harm during the course of the trial may continue in the study; others must be discontinued 
from trial participation and receive appropriate clinical follow-up care to ensure their safety. 
In addition, any reports of 1) suicidal behavior; 2) suicidal ideation with intent, with or 
without a plan or method; or 3) suicidal ideation considered to be a clinically significant 
change, including all cases of suicidal ideation that are treatment- emergent (ie, start or 
worsen after trial medication is initiated) must be recorded as an Event of Clinical Interest 
(See Section 7.2.3.2). Sites should designate which health care professionals are to be 
responsible for acute care on-site and to specify referral center(s) to be used for further 
evaluation.
 
 
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The C-SSRS will be completed in paper form, and will be scored by the qualified trained 
rater, via a subject (and trial partner if necessary) interview, as described in the MOA. 
Additional detailed information concerning administration and scoring may also be provided 
in the MOA.
7.1.2.2.11 Digit Symbol (DS)
The DS evaluates coordination and attention processes, and has been used extensively in the 
development of hypnotics [33],[34]. The DS should be administered to the subject preferably 
within 1 hour of getting out of bed on the morning after completion of the overnight PSG.
The DS will be administered in paper form, and will be scored by qualified trained rater as 
described in the MOA. Additional detailed information concerning administration and 
scoring may also be provided in the MOA.
7.1.2.2.12 Single-Item Sleep Quality Scale-Caregiver (SSQC) 
A single-item, self-rated, global sleep quality assessment called the Single-Item Sleep 
Quality Scale (SSQC, caregiver version) will be administered in paper form to the trial 
partner to assess their overall sleep quality over a 7-day recall period. The trial partner is
asked to consider core components of sleep quality such as:  how many hours of sleep they 
had, how easily they fell asleep, how often they woke up during the night, how often they 
woke up earlier than they had to in the morning, and how refreshing their sleep was. The 
SSQC will be administered to and completed by the subject’s trial partner and documented 
by the qualified trained designee as described in the MOA. Additional detailed information 
concerning the administration and scoring may also be provided in the MOA.
7.1.2.2.13 Modified Cataplexy Questionnaire (MCQ)
The Modified Cataplexy Questionnaire (MCQ) is a modified version of Part V of the 
Stanford Center for Narcolepsy Sleep Inventory (SCNSI), a 51-item questionnaire developed 
and validated for the assessment of cataplexy [35]. The MCQ is to be used to assess a single 
episode of a subject’s spontaneously-reported cataplexy-like behavior. The MCQ is 
completed by the subject (with trial partner assistance if needed) and will be assessed by the 
investigator or other qualified rater in conjunction with ECI reporting of the event, and as 
part of the ECI assessment of falls/ataxia/worsening of balance in order to rule out cataplexy. 
Additional information concerning the administration of the MCQ may also be provided in 
the MOA. 
All reports of cataplexy, cataplexy-like events, and falls/ataxia/worsening of balance must be 
recorded as ECIs. The MCQ, administered in conjunction with documentation of these 
events, will be provided to the clinical adjudication committee. Please refer to Section 7.2.3.2 
for additional information.
 
 
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7.1.2.2.14 Polysomnography (PSG)
PSG Definitions and Scoring
7.1.2.2.14.1
A polysomnogram consists of an electroencephalogram (EEG) for registration of brain 
activity during sleep, an electro-oculogram (EOG) for registration of the eye movements 
during sleep, and an electromyogram (EMG) for recording chin muscle activity during sleep. 
Sleep stage scoring will be performed in 30-second epochs according to the American 
Academy of Sleep Medicine Manual for the Scoring of Sleep and Associated Events [36]. 
The data will be captured electronically, in order to permit subsequent spectral analysis. PSG 
data will be scored by a centralized PSG reading center. Screening and baseline PSG results 
will initially be reviewed by qualified site scorers, prior to sending to the centralized PSG 
reading center for confirmation of subject eligibility.  
PSG Measurements
7.1.2.2.14.2
Efficacy measures used in this study will be completed as indicated below.
a.
PSG Recording and Evaluation Procedures
The central PSG vendor for the trial will provide a standard operating procedure 
(SOP) detailing how screening and other PSG sessions will be conducted. The SOP 
will address what types of recordings will be made (eg, the EEG electrode montages, 
EMG electrodes, cardiac electrodes, plethysmography (strain gauges) to assess 
respiratory effort) or other recordings to be specified in the SOP. Thus, the definitive 
set of recordings to be conducted during a PSG screening session will be specified in 
the SOP, and the SOP will detail which of the recordings will be used on subsequent 
PSG recording nights. 
b. Bedtime and Timing of PSG (Lights-Off and Lights-On)
The time of bedtime in the lab should approximate the subject's bedtime at home 
(median habitual bedtime), where "bedtime" is defined as the time when the subject 
intends/attempts to fall asleep, eg, lying down or reclining with eyes closed. The 
environment should be conducive for sleep (ie, a darkened room, a relatively quiet 
room, a room free from distractions). 
The Lights-Off time for Visit 2 Screening PSG is defined as approximately 
±10 minutes of the subject’s reported median habitual bedtime based on 
approximately 4 or more days of e-diary data accumulated up to Visit 2-PSG. The 
Lights-Off time for Visit 3 Baseline PSG is defined as approximately ±10 minutes of 
the subject’s reported median habitual bedtime based on the last 14 available days of 
e-diary data leading up to Visit 3. The median habitual bedtime for both Visits 2 and 
3 will be calculated by the e-diary and displayed via the vendor e-diary reports.
The Lights-Off time at Visit 6 will be based on the subject’s habitual sleep time 
determined at Visit 3.  
 
 
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The entire PSG recording period from Lights-Off to Lights-On will be 8 hours. 
Immediately prior to the Lights-Off time, the subject gets into bed, room lights are 
turned off (ie, the room is dark), and the technician exits the room. The Lights-Off 
time marks the initiation of the PSG recording period. Lights-Off time must be 
indicated on the technician’s log.
For the timing of electrode calibrations and other PSG activities, refer to the central 
vendor PSG SOP.
Alcohol Breathalyzer 
7.1.2.2.14.3
An alcohol breath test will be performed as specified in the Trial Flow Chart. Subjects should 
have a negative alcohol breath test on the PSG visit nights. If a subject has a positive alcohol 
breath test, the test may be repeated at the investigator's discretion and the repeat test must be 
negative prior to conducting the PSG recording session. If the repeat test continues to be 
positive, the investigator should determine if the subject should be excluded (Visits 2, 3) or 
discontinued (Visit 6) from the trial or the PSG visit should be rescheduled. If the decision is 
to reschedule the PSG, this PSG should take place no sooner than 24 hours and no later than 
48 hours. A breathalyzer will be provided to each site by the Sponsor.
7.1.2.2.15 Electronic Diary (e-diary)
Sites will be trained on the proper use of the e-diary by an external e-diary vendor. Sites will 
use the training e-diary and supplemental training materials provided by the vendor to train 
the trial partners on how to operate the e-diary and complete the e-diary entries, including the 
expectation that the trial partner report the subject’s actual times to the best of their ability. 
E-diary compliance will be monitored throughout the study by compliance reports that the 
site will review from the e-diary vendor (viewed via e-diary vendor web portal). They are 
expected to monitor subject data for the e-diary frequently throughout the trial. Sites should 
re-train trial partners who are not compliant with e-diary completion. Rigorous monitoring is 
especially important during the screening period (Visit 1 up to Visit 4), to ascertain problems 
with non-compliance as early as possible and to ensure that trial partners experiencing 
difficulties are re-trained, as appropriate, prior to subject’s randomization at Visit 4, where a 
specific e-diary compliance inclusion is assessed (see Inclusion Criteria). 
Trial partners will complete the Morning Diary questions via the e-diary every morning 
starting the morning after Visit 1 through the morning of Visit 6 (the end of the Week 4 
treatment period). The questions should be completed each morning. Trial partners should be 
instructed to bring the e-diary to the clinic at each visit. In some instances, when the 
subject/trial partner returns to the site for a visit, the site staff may need to download/upload 
data off of the e-diary to the vendor’s web portal.
In addition to the morning diary, the trial partner will complete The Sleep Quality Rating and
The Sleep Disorders Inventory for Dementia within the e-diary; specifics on these 
questionnaires are noted below.
 
 
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Morning Sleep Diary
7.1.2.2.15.1
The morning sleep diary consists of a set of questions assessing the subject’s previous night’s 
sleep, the time they wake up in the morning, napping, and administration of trial medication. 
These questions will be completed each morning within the e-diary by the subject’s trial 
partner, beginning with the morning after completion of Visit 1. The trial partner will be 
instructed to answer the e-diary questions to the best of their ability. Additional details will 
be provided in supplemental documents provided by the e-diary vendor. 
Sleep Quality Rating (SQR)
7.1.2.2.15.2
The SQR is a single-item questionnaire [28] consisting of 5 responses, that assesses the 
subject’s quality of sleep from the night before. It will be completed by the subject’s trial 
partner daily each morning in the e-diary. 
Sleep Disorders Inventory for Dementia (SDI)
7.1.2.2.15.3
The SDI is a 7-item questionnaire that captures the frequency, severity, and trial partner
distress of 7 sleep-disturbed behaviors during a period prior to its administration [34]. The 
SDI is based on an expansion of the sleep disturbance question in the NPI. The subject’s trial 
partner will complete the SDI weekly in the e-diary, initiating at Visit 4. 
7.1.2.2.16 Activity/Sleep Watch
The activity/sleep watch will be used to monitor the subject’s daytime and nighttime activity 
(eg, walking, sitting, napping, sleeping). This device is a wrist-worn device, mimicking a 
watch that someone might wear, and will be given to the subject after the completion of Visit 
2 PSG (assuming the subject remains eligible to continue). Subjects are expected to keep this 
device on at all times during the trial if possible (except when charging), and they should 
wear it to each of the clinic visits. Subjects should also wear the device during PSG 
assessments. The device is waterproof and may be worn during showering/bathing. In
instances where the subject needs to take the watch off, the watch should be put back on as 
soon as possible to limit missing data.
Sites will be trained on the proper operation and use of the activity/sleep watch, and trained 
site staff will then train the subject/trial partner. Training documentation and any 
supplemental documentation to assist the site and subject/trial partner on the use of this 
device will be provided by the activity/sleep watch vendor.
The staff will be responsible for monitoring the activity/sleep watch data via a dedicated web 
portal, frequently, using monitoring reports. In some instances, when the subject/trial partner 
returns to the site for a visit, the site staff may need to download/upload data off of the
activity/sleep watch to the web portal.  
The details of the activity/sleep watch data scoring and variables will be part of a 
supplemental document.
 
 
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7.1.2.2.17 Adverse Experience Monitoring
AE monitoring should be conducted throughout the entire trial. Please refer to Section 7.2 for 
additional information.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in Appendix 12.4.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry, Urinalysis, and 
Other)
7.1.3.1.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, urinalysis, and other study specific tests are 
specified in Table 5.
 
 
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Table 5
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other 
Hematocrit
Alanine 
aminotransferase (ALT)
Appearance
Vitamin B12
Hemoglobin
Albumin
Bacteria
Folate
Platelet count
Alkaline phosphatase
Bilirubin
Follicle-stimulating Hormone (FSH) –
female only, if applicable
RBC count
Aspartate 
aminotransferase (AST)
Blood
Thyroid-stimulating Hormone (TSH; with 
reflex free T4 and T3
if TSH abnormal)
WBC (total and 
differential)
Bicarbonate
Color
Urine Drug Screen
Bilirubin, Total
Glucose
Methylmalonic acid if B12 or Folate 
abnormal
Blood Urea Nitrogen 
(BUN)
Ketone
Homocysteine level if B12 or Folate 
abnormal
Calcium
Leukocyte esterase
Chloride
Microscopic exam, 
if abnormal results 
are noted
Creatine Phosphokinase
Mucus
Creatinine
Nitrite
Creatinine Clearance 
Estimation
pH
Glucose
Protein
Lactate dehydrogenase
RBC count
Magnesium
Specific gravity 
Phosphorus
WBC count
Potassium
Sodium
Uric Acid
Laboratory safety tests do not require subjects to be in a fasting state.
All laboratory samples will be collected as per the Trial Flow Chart and they will be analyzed 
by the central laboratory. Detailed instructions for specimen collection, packaging, and 
shipment will be provided in a Laboratory Manual by the Central Laboratory.
Subjects with screening laboratory values/findings outside ranges described in the protocol 
may, at the discretion of the investigator, have a repeat determination performed. If the repeat 
value satisfies the criterion, subjects may continue in the screening process. Only the specific 
out of range value/finding should be repeated (not the entire panel). See Appendix 12.12 for 
guidance on out of range laboratory values, and refer to a supplemental document for follow 
up requirements for evaluation of ALT and/or AST values elevated ≥3x ULN (Upper Limit 
of Normal).
 
 
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7.1.3.1.2 Urine Drug Screen
A urine drug screen (UDS) will be performed as specified in Trial Flow Chart. The Visit 1 
UDS must be sent to the central laboratory vendor for confirmation. The subject must have a 
negative UDS in order to move onto Visit 2.
For all other visits, an on-site urine drug screen will be performed at the site. If the test is 
positive, a confirmatory urine drug screen will be sent to the central laboratory for 
confirmation, and subject should be tentatively rescheduled until a confirmatory test is 
known. If the test is confirmed as positive, the Sponsor should be contacted to determine 
continued eligibility.
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
The final decision as to which plasma samples collected will be assayed for evaluation of 
pharmacokinetics/pharmacodynamics will be made by the Sponsor’s Departments of 
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism (PPDM) and the Clinical 
Monitor, (eg, samples at lower doses may not be assayed if samples at higher doses reveal 
undetectable drug concentrations). If indicated, these samples may also be assayed and/or 
pooled for assay in an exploratory manner for metabolites and/or additional 
pharmacodynamic markers.
7.1.3.2.1 Blood Collection for Plasma MK-4305
Sample collection, storage and shipment instructions for plasma samples will be provided in 
a laboratory manual provided by the central laboratory. 
7.1.3.3
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the laboratory manual provided by the central laboratory. See Appendix 
12.3 for the Pharmacogenomics Informational Brochure.
7.1.3.4
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:
Leftover DNA for future research.
See Appendix 12.2 for the Collection and Management of Specimens for Future Biomedical 
Research. 
 
 
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Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit, as outlined in Section 6.0 Trial Flow Chart, should be 
performed at the time of discontinuation.  Any adverse events which are present at the time 
of discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 7.2 - Assessing and Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
When the investigator or sub-investigator needs to identify the drug used by a subject and the 
dosage administered in case of emergency e.g., the occurrence of serious adverse 
experiences, he/she will contact the emergency unblinding call center by telephone and make 
a request for emergency unblinding.  As requested by the investigator or sub-investigator the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to the sponsor.  The emergency unblinding call center will make a record 
promptly however, the investigator or sub-investigator must enter the intensity of the adverse 
experiences observed,   their relation to study drug, the reason thereof, etc., in the medical 
chart etc., before unblinding is performed.  
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
 
 
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center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
7.1.4.3
Domiciling
Subjects and their trial partners will report to the clinical research unit (CRU)/PSG facility on 
the day of each PSG visit (Visits 2, 3, and 6) and remain in the unit until all procedures for 
that visit have been completed on the following day.
7.1.4.4
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

PSG equipment – details can be found in supplemental documentation at the site/or 
corresponding PSG facility.

Alcohol Breathalyzer – details can be found in supplemental documentation at the 
site, provided by the Sponsor.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Trial Partner Trial Specifics (non-inclusive):

For the trial partner to be eligible, they must be present in the same residence (awake 
or asleep) when the subject is sleeping at night.

While at home, the subject/trial partner should maintain their current sleeping 
arrangements. The trial partner does not need to be awake during the night in order to 
complete the morning e-diary questions.
 
 
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
Every effort should be made by the trial partner to accompany the subject to each 
visit. However, at the discretion of the investigator, exceptions are acceptable. In
circumstances where the trial partner is unable to accompany the subject to a visit, the 
trial partner should discuss alternative arrangements with the site (eg, subject 
transportation, return of trial medication) and availability of the trial partner to 
complete trial assessments (eg, by phone) as soon as possible. 

Depending on the subject, willing to spend the night at the PSG facility (separate 
room), if needed to assist in accurately completing the morning e-diary questions. If 
the trial partner is unable to spend the night, the trial partner should discuss with the 
site alternative arrangements.

Every effort should be made to maintain the same trial partner for the duration of the 
study. However, if the trial partner is unable to continue with the study requirements, 
the trial partner should discuss with the site whether a suitable replacement can be 
found. If a new trial partner is identified, the new trial partner will need to sign the 
trial partner informed consent. 
7.1.5.1
Screening
Each visit should be performed as noted in the Trial Flow Chart. For visits that require 
additional explanations, please see those specific visits below.
7.1.5.1.1 Visit 1 Screening
At Visit 1, subjects who provide informed consent will undergo a series of diagnostic and 
safety assessments to determine if they are eligible for the trial. A designated trial partner 
must also consent to participate and will be asked to complete certain assessments throughout 
the trial. Subjects planning to undergo elective procedures during the study (known prior to 
trial start) should not proceed until such procedures have been completed.
Documentation requirements to support the subject’s diagnoses of AD and insomnia, as well 
as trial partner eligibility (eg, inclusion 10) can be found in a supplemental source 
documentation guidance document.  
If a site wishes to split the subject’s Visit 1, they may do so for the following reasons:

Visit 1 may be split to decrease the burden of the subject/trial partner due to the 
length of the visit. 

Visit 1 may be split in the event that a subject requires an extended washout period 
(ie, greater than 2 weeks) for prohibited medication(s) or other therapy, in accordance 
with ; this is to help avoid the necessity to repeat any prior Visit 1 procedures 
assessed at the initial Visit 1.
 
 
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If the site chooses to split Visit 1 for either of the reasons noted above, the following is a 
recommendation of what procedures (non-inclusive) should be conducted at the initial 
portion of Visit 1:

Obtain informed consent

Review sleep and medical history

Preliminary review of inclusion/exclusion criteria

Review of prior and concomitant medications

Assignment of subject baseline/screening number from the data entry system
The final portion of Visit 1 should be conducted preferably within 2 days of the initial 
portion of Visit 1, if splitting due to visit length. Subjects required to washout of a 
prohibited medication will return to complete the final Visit 1 procedures once the 
washout has been completed. Subjects with positive UDS due to prohibited medication(s) 
at Visit 1 must repeat the UDS and have a negative UDS to move on to Visit 2. Once a 
subject completes Visit 1 in its entirety, he/she may proceed to Visit 2 one week later. 
Guidelines for how to enter data into the data collector will be provided in the DEGs.
Subjects who meet the overall criteria at the completion of Visit 1 will return home and their 
trial partner will begin reporting observed sleep times in the e-diary the following morning. 
A subject may be re-screened, but the Sponsor should be consulted prior to any re-screening. 
Re-screenings will be handled on a case-by-case basis. Only 1 re-screen is allowed per 
subject.
7.1.5.1.2 Visit 2 Screening PSG and Visit 3 Baseline PSG
Visit 2 Screening PSG:
Subjects/Trial Partners will return to the clinic for Visit 2, per the Trial Flow Chart, for an 
overnight Screening PSG. Subjects will be expected to have completed their washout of any 
prohibited medications, if applicable. Subjects/Trial partners will be instructed to arrive at the 
sleep lab approximately 2 hours prior to their median habitual bedtime (obtained by the site 
by viewing e-diary reports). Subjects/Trial partners should be advised to eat dinner prior to 
arrival at the sleep lab and subjects should be reminded to refrain from alcohol, caffeine, and 
smoking as recommended in Section 5.7.2.
The trial partner should bring the e-diary to the clinic and the site should review e-diary 
compliance and perform any re-training, if necessary. The site should also review applicable 
eligibility criteria prior to the PSG. For urine drug screen and alcohol breath test details, 
please see Sections 7.1.3.1.2 and 7.1.2.2.14.3, respectively. 
After subjects have met initial Visit 2 eligibility, the site will call/log into IVRS/IWRS where 
they will be prompted to enter the subject’s MMSE score obtained at Visit 1. This entry is 
critical for proper stratification. Please ensure no transcription errors occur within 
 
 
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IVRS/IWRS by reviewing the IVRS/IWRS output after the transaction has completed. If 
there is a transcription error, please contact the IVRS/IWRS vendor immediately to correct 
the score.
The site, via the IVRS/IWRS system, will then dispense single-blind placebo trial medication 
to the subject and the subject will be instructed to take their trial medication within 30 
minutes of their bedtime (“Lights-Off”) prior to the start of the PSG recording; dosing will be 
witnessed by site staff personnel. (Note: if the PSG center is separate from the trial site, the 
PSG center should make arrangements with the trial site to obtain the subject’s trial 
medication. The "Lights-Off" time will be at approximately the subject’s median habitual 
bedtime. Subjects will spend the night in the sleep laboratory for an 8-hour PSG recording 
session (Screening PSG) to determine trial eligibility based on screening PSG variables and 
detection of other sleep and neurological disorders. Depending on subject’s need, the trial 
partner or alternate person (e.g., family, children), if possible, should also be willing to spend 
the night at the sleep lab in an effort to help acclimate the subject and to be able to answer the 
morning e-diary questions accurately the following morning. Alternate arrangements can be 
made in the event that a trial partner is unable to attend all study visits. The following 
morning, the subject will be awakened (or will be allowed to get out of bed if already awake) 
after 8 hours of PSG recording and will complete their normal morning routine, followed by 
assessments, such as the DS and PK sampling as indicated in the Trial Flow Chart. The 
subject should continue to wear the activity/sleep watch. The e-diary should be completed by 
the trial partner prior to leaving the clinic. It is recommended that caffeinated products not be 
consumed until after completion of all morning procedures.
The Screening PSG will be initially reviewed by a Sponsor-approved PSG scorer at a PSG 
certified site, to determine if the PSG entry criteria have been met. It is highly recommended 
that the site scores the PSG for eligibility criteria immediately following completion of the 
PSG recording; this will prevent ineligible subjects from leaving the clinic with trial 
medication, the e-diary, and the activity/sleep watch. 
If after the initial review by the site, the subject has not met the criteria for Visit 2 Screening 
PSG, the subject should be excluded and the PSG recording should not be sent to the central 
PSG reading center. The e-diary should be returned to site personnel. (Note: if the subject’s 
PSG scores are borderline to the eligibility criteria, sites may send the PSG recording to the 
central PSG center for confirmation). 
If the subject is deemed eligible after the site has reviewed the PSG, the site will forward the 
Screening PSG recording to the Central PSG Reader for confirmation. The trial partner will 
be given the single-blind placebo trial medication, for the subject, with instructions to dose 
within 30 minutes of bedtime; the trial partner will be instructed to witness the nightly dosing 
and to continue completing the morning e-diary daily. The subject will be given the 
activity/sleep watch to wear continuously throughout their trial participation and will begin 
wearing the watch at the completion of Visit 2, prior to leaving the clinic. The site will train 
the subject/trial partner on the activity/sleep watch at this visit. In rare instances where the 
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later date, but a minimum of 3 days prior to Visit 3, to allow acclimation to the activity/sleep 
watch. 
Subjects who meet the PSG screening criteria at the completion of Visit 2, as assessed by the 
Central PSG vendor, will continue in the placebo run-in period. Sites should monitor subject 
data for both the e-diary and the activity/sleep watch using respective vendor monitoring 
reports.
Confirmation of the qualifying Screening PSG variables and other sleep and neurological 
disorders from the central PSG vendor must be received by the site prior to conducting the 
Visit 3 Baseline PSG. If the subject has not met entry criteria and they were released home 
prior to notification, sites should advise the subject/trial partner to return to the clinic to 
return trial medication, e-diary, activity/sleep watch, and any other trial supplies.
Subjects who initially screen failed based on exclusion criterion #33 (AHI and/or PLMA) on 
the Screening PSG may be considered for re-screening. If the Visit 2 Screening PSG would 
be eligible based on the amended criteria (ie, AHI <30 and PLMA <30 as confirmed by 
Central PSG vendor), subjects may be re-screened after consultation with the Sponsor. 
Details regarding the schedule of re-screening assessments will be provided in a Sponsor 
Communication Form. 
Visit 3 Baseline PSG:
If subjects continue to meet trial criteria, they and their trial partner will return to the clinic 
for Visit 3 Baseline PSG. This visit should be conducted in a similar manner as outlined 
above for Visit 2 Screening PSG (eg, subject/trial partner arrive per median habitual bedtime, 
site staff witness dose of trial medication, scoring of the subject’s PSG prior to subject/trial 
partner leaving, trial partner completes e-diary, etc.). Subjects should also be wearing the 
activity/sleep watch. For those subjects who do not meet eligibility criteria, they should 
return trial medication, e-diary, activity/sleep watch and any other trial supplies. Subjects 
who meet the Visit 3 Baseline PSG criteria, as assessed by the Central PSG vendor, will
continue the placebo run-in period until returning to the clinic for Visit 4 (randomization). 
7.1.5.2
Treatment Period – Visits 4 through 6
Each visit should be performed as noted in the Trial Flow Chart. For visits that require 
additional explanations, please see those specific visits below. 
Trial medication, the e-diary, and the activity/sleep watch should accompany the subject/trial 
partner at each visit for site review.
Visit 4:
Subjects will be assessed for final eligibility per Inclusion/Exclusion criteria as described in 
Section 5.1, including ensuring compliance with trial medication, e-diary, and activity/sleep 
watch. The subject may be randomized into the trial and will be assigned a randomization 
number (via IVRS/IWRS) only after ensuring that the subject meets all criteria. After final 
 
 
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eligibility has been determined, subjects will undergo assessments as noted in the Trial Flow 
Chart. Subjects/trial partners should not be informed of when they are transitioning into a 
different trial period (eg, treatment period).  
Visit 5:
At Visit 5, assessments will be conducted as stated in the Trial Flow Chart. For details on 
dose escalation, please refer to Section 5.2.1.2.  
Visit 6:
Subjects/Trial partners will return for their final in-clinic/overnight visit, Visit 6 End of Week 
4 PSG. Subjects/Trial partners will be instructed to arrive at the sleep lab approximately 2 
hours prior to their median habitual bedtime as calculated at Visit 3 Baseline PSG. 
Subjects/Trial partners should be advised to eat dinner prior to arrival at the sleep lab and 
subjects should be reminded to refrain from alcohol, caffeine, and nicotine as recommended 
in Section 5.7.2.
Subjects/Trial partners should be instructed to bring all trial supplies (eg, e-diary, 
activity/sleep watch, trial medication) to the site for final compliance and accountability. The 
subject should still be wearing the activity/sleep watch until completion of the PSG the 
following morning.
Visit 6 PSG and associated assessments are to be conducted at the PSG center the night of 
(ie, alcohol breath test, UDS, witnessed dose of trial medication) or the morning after (ie, DS 
and PK sampling) completion of the PSG. Safety and ancillary assessments (eg, ECG, labs, 
vital signs, physical exam, neurology exam, CGI-S, NPI, or C-SSRS, etc) may be completed 
as noted in the Trial Flow Chart either on the day of the PSG PM Visit (Target Day 29) or 
PSG AM Visit (Target Day 30) to provide flexibility for subjects and trial partners that need 
to travel between the primary research site and a PSG center or to assist site staff with 
scheduling. 
For trial medication dosing, please refer to Section 5.2.1.2. For urine drug screen and alcohol 
breath test details, please see Sections 7.1.3.1.2 and 7.1.2.2.14.3 , respectively.  
The PK sample taken at this visit should be drawn between 8.5 to 11 hours post-dosing of 
trial medication on the AM portion of the visit.  
The PSG recording for this visit does not need to be scored by the site. The Visit 6 PSG 
recording will be forwarded directly to the Central PSG Reader for scoring.  
7.1.5.3
Procedures for Subjects Who Discontinue Treatment But Continue in the Trial  
Every attempt should be made to have subjects remain on trial medication and continue to 
follow all protocol procedures.  Subjects who discontinue from trial medication, but choose 
to remain in the trial will follow the guidance below:
 
 
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
For subjects who discontinue trial medication prior to Visit 5, but will continue in the 
trial, Visits 5 and 6 are to be completed as per the Trial Flow Chart (with the 
exception of no trial medication being dispensed).

For subjects who discontinue trial medication after Visit 5, but will continue in the 
trial, Visit 6 is to be completed as per the Trial Flow Chart. 
In the event subjects (now off trial medication) want to discontinue trial participation at a 
later time, the Discontinuation Visit should be performed per the Trial Flow Chart (eg, in a
case where a subject continues trial medication prior to Visit 5 and completes Visit 5, but
then after Visit 5 discontinues the trial, a Discontinuation visit will be performed).
Details on how data will be entered into the data collector for these subjects can be found in 
the DEGs.
7.1.5.4
Post-Treatment Follow-up
Sites will be required to perform a follow-up phone call 14 days after the last dose of trial 
medication (regardless of the date of the Discontinuation Visit, if applicable) to determine if 
any AEs have occurred since the post-trial clinic visit.
If a subject (or trial partner on behalf of the subject) reports suicidal ideation and/or behavior, 
then the C-SSRS must be conducted. Subjects who report suicidal ideation with intent, with 
or without a plan or method or suicidal behavior must be taken to the site that same day to be 
evaluated by a psychiatrist or other trained mental health professional who is a licensed 
psychologist, social worker or mental health nurse practitioner (or comparable professional 
qualification in countries outside the United States), as noted in Section 7.1.2.2.10.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
 
 
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Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is any dose higher than the specified dose to be administered nightly 
in a calendar day (accidental or intentional).
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
 
 
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Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies  must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 6 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
 
 
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For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
 
 
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and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
Additional protocol specific ECIs for this trial include:
3. Suicidal ideation and/or behavior
4. Events associated with potential for abuse
5. Complex sleep-related behaviors
6. Hypnagogic or hypnopompic hallucinations
7. Somnolence resulting in dose reduction or discontinuation of trial medication
8. Sleep paralysis and sleep-onset paralysis (adjudicated)
9. Cataplexy (adjudicated)
10. Falls/ataxia/worsening of balance (adjudicated to rule out cataplexy)
11. Agitation – daytime or nighttime
12. Confusion or cognitive impairment - daytime or nighttime
Regarding items #11 and 12 above, agitation, confusion or cognitive impairment should be 
considered an ECI if in the investigator’s opinion an acute worsening from baseline has 
occurred, or there is an unusual or atypical presentation of symptoms for a given subject. 
A guidance document for the reporting of ECIs will be provided to sites to provide specific 
information relevant to the collection and reporting of these events.
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 6. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 6 for instructions in evaluating adverse events.
 
 
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Table 6
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.   (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Scientific Advisory Committee
7.3.1
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Clinical Adjudication Committee
7.3.2
A Clinical Adjudication Committee (CAC) will evaluate the following events for the 
purposes of confirming them according to the criteria in Section 8.0 – Statistical Analysis 
Plan, as well as evaluating the presence of confounding factors.
ECIs pre-specified for adjudication are those that suggest potential intrusion of REM into 
either:
1) Wakefulness (ie, cataplexy or events suggestive of cataplexy) or, 
2) Initiation of sleep (eg, sleep onset paralysis) or,
Falls/ataxia/worsening of balance will also be adjudicated to enhance data collection  for
these events, and to further evaluate whether an event might be due to cataplexy.
All personnel involved in the adjudication process will remain blinded to treatment allocation 
throughout the trial.  Specific details regarding endpoint definitions can be found in the 
Adjudication Charter.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9). Changes 
to exploratory or other non-confirmatory analyses made after the protocol has been finalized,
but prior to unblinding/final database lock, will be documented in a supplemental Statistical 
Analysis Plan (sSAP) and referenced in the Clinical Study Report (CSR) for the study. Post 
hoc exploratory analyses will be clearly identified in the CSR. Separate analysis plans (ie, 
separate documents from the sSAP) will be developed to detail other planned analyses (ie, 
those specific to the analysis of PK data and pharmacogenomics analysis).
 
 
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Statistical Analysis Plan Summary
8.1
All evaluations of suvorexant (with the exception of selected exploratory analyses) will be 
conducted without distinguishing the dose of suvorexant received (10 mg or 20 mg).
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 8.2 through 8.12.  
Study Design Overview
A Phase III Randomized, Placebo-Controlled Clinical Trial to Study 
the Safety and Efficacy of Suvorexant (MK-4305) for the Treatment of 
Insomnia in Subjects with Alzheimer’s Disease
Treatment Assignment
The study will be conducted as a double-blind study under in-house 
blinding procedures. Treatment .allocation/randomization will occur 
centrally using an interactive voice response system (IVRS). Subjects 
will be assigned randomly in a 1:1 ratio to either suvorexant or 
placebo. The randomization will be stratified according to MMSE 
score (mild: 21 to 26, moderate: 12 to 20) assessed at the screening 
visit. Randomization will be monitored to ensure that approximately 
30% of randomized subjects are in the moderate AD stratum.
Analysis Populations
Efficacy: Full Analysis Set (FAS)
The FAS population is defined as randomized subjects who had: 1) at 
least 1 post-randomization observation for the analysis endpoint 
subsequent to at least 1 dose of trial medication and, 2) baseline data 
for those analyses that require baseline data. The number of subjects 
included in the FAS population may vary across endpoints due to the 
degree of missing data for each endpoint.
Safety: All Subjects as Treated (ASaT)
The ASaT population includes all subjects who took at least 1 dose of 
randomized trial medication. Subjects will be analyzed according to 
the treatment actually received.
Primary Endpoint(s)
PSG-derived Total Sleep Time (TST) in minutes, at Week 4.
Key Secondary Endpoints
PSG-derived Wakefulness After Sleep Onset (WASO) in minutes, at 
Week 4.
Statistical Methods for Key 
Efficacy Analyses
The primary hypothesis will be evaluated by comparing suvorexant 
and placebo with respect to change from baseline in PSG-derived total 
sleep time (TST) in minutes, at Week 4. Analysis of covariance 
(ANCOVA) using a general linear model for change from baseline in 
TST at Week 4, with terms for baseline TST value, baseline severity 
category (MMSE score of 12 to 20, 21 to 26), age category (non-
elderly, elderly), gender, region, and treatment, will be used to evaluate 
the primary hypothesis.  The significance of the difference between 
suvorexant and placebo in least squares means for change from 
baseline in TST will be evaluated using an appropriate contrast of 
model parameters, and according to the multiplicity testing strategy 
described below.  
Statistical Methods for Key 
Safety Analyses
Program specific pre-specified adverse events of clinical  interest
(ECIs) will be assessed as Tier 1 events in this study. Estimates of the 
difference between treatments in the percentage of subjects with these 
events, 95% confidence intervals, and p-values, will be computed for 
these Tier 1 events. Tier 2 events are those events for which treatment 
differences and 95% confidence intervals (but not p-values) will be 
provided. Tier 3 safety parameters are those for which only descriptive 
statistics for treatment differences will be provided. Tier 1, 2 and 3 
 
 
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safety parameters are summarized in Table 8 of Section 8.6.2, 
Statistical Methods for Safety Analysis.
Interim Analyses
No interim analysis for efficacy or safety is planned for this study.
Multiplicity
Statistical significance for the primary and secondary efficacy 
hypotheses will be based on a fixed sequential multiplicity strategy to 
control the overall Type I error at the two-sided 5% significance level. 
If the comparison of the primary endpoint between treatments is 
significant at the 5% significance level, then the comparison of the 
secondary endpoint between treatments will be evaluated at the 5% 
level of significance.
Sample Size and Power 
This study will randomize approximately 130 subjects into the 
suvorexant group and approximately 130 subjects into the placebo 
group, for a total of 260 randomized subjects in order to obtain 117
evaluable subjects per treatment group.
Power for the primary hypothesis
With approximately 130 subjects randomized per treatment group and 
assuming a standard deviation of 68 minutes for change from baseline 
in TST (based on insomnia subjects ≥65 years who had PSG in MK-
4305 Protocols 028 and 029 pooled), a 2-sided α=0.05, and a dropout 
rate of 10% at Week 4 (approximately twice the drop-out rate observed 
for insomnia subjects ≥65 years who had PSG in MK-4305 Protocols 
028 and 029 pooled), the study has approximately 92% power to detect 
a true difference of 30 minutes between treatment groups with respect 
to change from baseline in TST at Week 4 (standardized effect size 
(SES) = 0.44); it has approximately 80% power to detect a 25-minute 
difference (SES = 0.37).
Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The study will be conducted as a double-blind study under in-house blinding procedures. The 
official, final database will not be unblinded until medical/scientific review has been 
performed, protocol violators have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
trial medication assignment. Randomization will be implemented by an interactive voice 
response system (IVRS).
Hypotheses
8.3
Objectives and hypotheses of the study are stated in Section 3.
 
 
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Analysis Endpoints
8.4
Key efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints. Exploratory efficacy endpoints will be documented in the sSAP.
Efficacy and Ancillary Endpoints
8.4.1
Rationale for the key efficacy endpoints is given in Section 4.2.3.1 and an initial description 
of the efficacy measures is included in Section 7.1.2.2. In general, if a baseline value exists 
for a particular efficacy measure, then the change from baseline in that value will be
evaluated. The primary efficacy evaluation period of this trial is the 1-month double-blind 
treatment period.
Primary Endpoint
The primary endpoint for this study is:

total sleep time (TST) as measured in the sleep laboratory by PSG during an 8-hour 
recording period beginning at the subject’s habitual bedtime, at Week 4 (minutes)
Secondary Endpoint
The secondary endpoint for this study is:

wakefulness after persistent sleep onset (WASO) as measured in the sleep laboratory 
by PSG during an 8-hour recording period beginning at the subject’s habitual 
bedtime, at Week 4 (minutes)
Exploratory Endpoints
The exploratory endpoints for this trial (eg other PSG parameters which further characterize 
the subject’s sleep, treatment response based on achieving a clinically relevant predefined 
improvement in TST, sleep and activity parameters measured continuously during the trial by 
the activity/sleep
watch, assessments of the subject’s and trial partner’s sleep, 
neuropsychiatric behavior inventory parameters and trial partner distress associated with the
identified behaviors, high level assessments of the subject’s mental state and performance, 
and trial medication titration history) will be detailed in the sSAP.
Safety Endpoints
8.4.2
An initial description of the safety measures is included in Sections 7.1.2.1, 7.1.2.2.10 and 
7.1.3.
Safety and tolerability will be assessed by statistical and clinical review of the following data 
collected throughout the study:  adverse experiences (AEs), laboratory values, ECGs, 
physical examinations, vital signs and treatment-emergent suicidality.
 
 
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The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to systematically and 
prospectively ascertain and document the occurrence of suicidal events (ie, ideation and 
behavior). Responses on the C-SSRS are classified according to 11 pre-specified categories 
as described in Appendix 12.14.
The primary time period for safety analyses is the 1-month double-blind treatment period; 
safety summaries for the 14-day follow-up period (following the treatment period) will also 
be summarized.
Safety endpoints are classified into 3 tiers (see Statistical Methods for Key Safety Analyses 
in Section 8.1 for Tier definitions).
Tier 1 Safety Endpoints include the following program-specific pre-specified events of 
clinical interest (ECIs):
1. Suicidal ideation and/or behaviors
2. Events associated with potential for abuse
3. Complex sleep-related behaviors
4. Hypnagogic or hypnopompic hallucinations
5. Somnolence resulting in dose reduction or discontinuation of trial medication
6. Sleep paralysis and sleep-onset paralysis (adjudicated)
7. Cataplexy (adjudicated)
8. Falls/ataxia/worsening of balance (adjudicated to rule out cataplexy)
9. Agitation (daytime/nighttime)
10. Confusion or cognitive impairment (daytime/nighttime)
Tier 2 Safety Endpoints include (the proportion of subjects with):
1. Any AE
2. Any Serious AE
3. Any Drug-Related AE
4. Any Serious and Drug-Related AE 
5. Discontinuation due to AE
6. Specific AEs, System Organ Class (SOC) AEs , and Predefined Limits of Change 
(PDLC) which have incidence of ≥4 subjects in 1 of the treatment groups
Tier 3 Safety Endpoints include:
1. Specific AEs, SOC AEs or PDLCs which have incidence <4 subjects in all of the 
treatment groups
2. Change from baseline results for labs, ECGs and vital signs
In addition to the pre-specified ECI of suicidal ideation and/or behaviors based on AE 
reporting, which will be analyzed as a Tier 1 safety endpoint as described above, suicidal 
ideation and/or behaviors as reported on the C-SSRS will also be considered as a Tier 1 
safety endpoint, in the event an investigator may determine for a given subject that suicidal 
 
 
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ideation reported on the C-SSRS is not in fact an adverse event. An analysis of this additional 
Tier 1 safety endpoint, based on positive responses on the C-SSRS rather than on AEs, will 
also be performed. Three pre-specified categories which summarize information reported on 
the C-SSRS (suicidal ideation, suicidal behaviors, and non-suicidal self-injurious behavior) 
and 5 pre-specified subcategories related to suicidal ideation and 5 pre-specified 
subcategories related to suicidal behaviors, as outlined in Appendix 12.14, will be considered
as either Tier 2 or Tier 3 events (depending on the number of subjects with events observed 
during the assessment period). Counts for these pre-specified categories and subcategories 
will be analyzed according the strategy outlined in Section 8.6.2, both with and without 
consideration of prior history of suicidal ideation and/or behaviors.
Derivations of Efficacy Endpoints
8.4.3
PSG Data
Sleep stage scoring of the PSG recordings will be performed for each 30-second epoch 
according to the 2007 American Academy of Sleep Medicine (AASM) scoring conventions 
by a central sleep scoring laboratory. Each 30-second epoch will be scored as wake, Stage 
N1, N2, N3 or R. For example, TST is defined as the sum of Stages N1+N2+N3+R (in 
minutes) and WASO is defined as the sum of all wake epochs beginning from persistent 
sleep (ie, the first epoch of 20 consecutive epochs of Stage N1, N2, N3 or R sleep) to lights 
on (in minutes). The primary and exploratory PSG endpoints for analysis will be derived by 
the central sleep scoring laboratory from this information according to pre-specified PSG 
endpoint definitions contained in a PSG endpoint definition document. The day range for 
PSG analysis endpoints is defined as follows:  Week 4 (+/-7 days from the target Day 30).
Derivations of Safety Endpoints
8.4.4
Cataplexy and sleep-onset paralysis are defined as ECIs in this study which will be 
adjudicated by an independent, external CAC. Falls/ataxia/worsening of balance will also be 
evaluated as part of this adjudication process to rule out cataplexy. The adjudicated events 
will be evaluated as Tier 1 events as part of the tiered analysis strategy (see Section 8.6.2). 
Specific adverse experience terms relating to these ECIs will be identified and confirmed as 
part of the adjudication process prior to final study unblinding. Other Tier 1 events (eg, 
selected events associated with potential for abuse and complex sleep-related behaviors) that 
consist of multiple AE terms will be defined separately prior to unblinding.
Changes from baseline during the treatment period will be evaluated for laboratory, vital 
signs, and ECG data in accordance with predefined criteria noted Appendix 12.13.
Analysis Populations
8.5
Efficacy Analysis Populations
8.5.1
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study. The FAS population consists of all randomized subjects who:
 
 
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•
Received at least 1 dose of trial medication,
•
Have at least 1 post-randomization observation for the analysis endpoint subsequent to 
at least 1 dose of trial medication
•Have baseline data for those analyses that require baseline data 
The number of subjects included in the FAS population may vary across endpoints due to the 
degree of missing data for each endpoint and the applicability of exclusion criteria to each 
endpoint (eg, need for baseline data only applies to those endpoints that are derived relative 
to baseline).
A supportive analysis using the Per-Protocol population will be performed for the primary 
and secondary efficacy endpoints. The Per-Protocol population excludes subjects due to 
important deviations from the protocol that may substantially affect the results of the primary 
and secondary efficacy endpoints. Potential violations that may be result in the exclusion of a 
subject from the Per-Protocol population will be defined and determined and documented in 
a separate memo prior to the unblinding of the database.
Subjects will be included in the treatment group to which they were randomized for the 
analysis of efficacy data using both the FAS and Per-Protocol populations. Details on the 
approach to handling missing data are provided in Section 8.6.1 Statistical Methods for 
Efficacy Analysis.
Safety Analysis Population
8.5.2
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized subjects who received at least 1
dose of trial medication. Subjects will be included in the treatment group corresponding to 
the trial medication they actually received for the analysis of safety data using the ASaT 
population. For most subjects this will be the treatment group to which they are randomized. 
Subjects who take incorrect trial medication for the entire treatment period will be included 
in the treatment group corresponding to the trial medication actually received. 
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of trial 
medication is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Statistical Methods
8.6
Statistical testing and inference for efficacy analyses is described in Section 8.6.1 and in 
Section 8.6.2 for safety analyses. Efficacy results that will be considered to be statistically 
significant after consideration of the strategy for controlling the Type I error are described in 
Section 8.8, Multiplicity. Nominal p-values may be computed for other efficacy analyses as a 
measure of the strength of the evidence of a treatment effect for an endpoint rather than a 
formal test of hypothesis. Unless otherwise stated, all statistical tests will be conducted at the 
5% level of significance (2-sided). All p-values will be displayed to 3 decimal places.
 
 
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All evaluations of suvorexant (with the exception of selected exploratory analyses) will be 
conducted without distinguishing the dose of suvorexant received (ie, 10 mg or 20 mg).
Statistical Methods for Efficacy Analysis
8.6.1
An analysis of covariance (ANCOVA) using a general linear model for change from baseline 
in TST at Week 4 with terms for baseline value, baseline severity category (MMSE score of 
12 to 20, 21 to 26), age category (non-elderly, elderly), gender, region, and treatment, will be 
used to evaluate the primary hypothesis. The significance of the difference between 
suvorexant and placebo in least squares means for TST will be evaluated using an 
appropriate contrast of model parameters. Sensitivity analyses using this ANCOVA model in 
conjunction with multiple imputation (MI) to estimate the missing data and measurements
collected following discontinuation of trial medication (if available) will also be performed. 
Details regarding the sensitivity analyses will be provided in the sSAP. The same ANCOVA 
model will be used to evaluate change from baseline in WASO at Week 4 according to the 
multiplicity testing strategy as described in Section 8.8. Statistical methods for the analysis of 
exploratory endpoints will be detailed in the sSAP.
Table 7 summarizes key efficacy analyses.
Table 7
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Timepoint)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary:
TST – Change from baseline at Week 
4
ANCOVA†
Full Analysis set
Primary: 
Observed data
Sensitivity: 
Multiple 
Imputation
(Tipping Point)
Secondary:
WASO – Change from baseline at 
Week 4
ANCOVA†
Full Analysis set
Primary: 
Observed data
Sensitivity: 
Multiple 
Imputation
(Tipping Point)
†ANCOVA model with terms for baseline value, baseline severity category (MMSE score of 12 to 20, 21 to 
26), age category (nonelderly, elderly), gender, region, and treatment.
ANCOVA = Analysis of Covariance
Observed data = data observed during Treatment Phase which does not include data collected following 
discontinuation of trial medication
Statistical Methods for Safety Analysis
8.6.2
Safety and tolerability will be assessed by statistical and clinical review of the following data 
collected throughout the study: adverse experiences (AEs), laboratory values, ECGs, vital 
 
 
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signs, and treatment-emergent suicidality derived from the C-SSRS. Safety will be evaluated 
with doses combined; selected safety analyses will be performed for doses separately.
The analysis of safety results will follow a tiered approach (Table 8). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons. Other safety parameters will be 
considered as Tier 2 or Tier 3. Tier 2 parameters will be assessed via point estimates with 
95% confidence intervals provided for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters. P-values and/or 95% confidence 
intervals for between-treatment differences in the percentage of subjects with events will be 
computed using the Miettinen and Nurminen (unstratified) method according to the safety 
parameter tier as defined above. 
Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change in laboratory, vital signs, and ECG parameters that are not pre-specified as 
Tier 1 endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number 
of events observed. Membership in Tier 2 requires that at least 4 subjects in any treatment 
group exhibit the event; all other adverse experiences and predefined limits of change will 
belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters that are not pre-specified as Tier 1 endpoints will be considered Tier 3 safety 
parameters. Summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.   
Program specific pre-specified adverse events of clinical interest (ECIs) including:  suicidal 
ideation and/or behaviors, events associated with potential for abuse, complex sleep-related 
behaviors, hypnagogic or hypnopompic hallucinations, somnolence resulting in dose 
reduction or discontinuation of trial medication, sleep paralysis and sleep-onset paralysis 
(adjudicated), cataplexy (adjudicated), falls/ataxia/worsening of balance (adjudicated to rule 
out cataplexy), agitation (daytime/nighttime), and confusion or cognitive impairment
(daytime/nighttime) are pre-specified as Tier 1 events. See Table 8 for a classification of 
safety endpoints as Tier 1, 2, or 3 and the corresponding analysis strategy for each endpoint.
 
 
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Table 8
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
p-Value§
95% CI for 
Treatment 
Comparison§
Descriptive 
Statistics
Tier 1
Adverse Events during the four-week treatment 
period:

Suicidal ideation and/or behaviors

Events associated with potential for abuse

Complex sleep-related behaviors

Hypnagogic or hypnopompic hallucinations

Somnolence resulting in dose reduction or 
discontinuation of trial medication

Sleep paralysis and sleep-onset paralysis 
(adjudicated)

Cataplexy (adjudicated)

Falls/ataxia/worsening of balance
(adjudicated to rule out cataplexy)

Agitation (daytime/nighttime)

Confusion or cognitive impairment
(daytime/nighttime)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
Discontinuation due to AE
X
X
X
X
Specific AEs, SOCs, or PDLCs (incidence ≥4  
subjects in 1 of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs ‡ (incidence <4 
subjects in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, 
Vital Signs)
X
† Adverse Event (AE) references refer to both Clinical and Laboratory AEs.
‡ Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier-2 endpoints.
§ P-value and CI for safety endpoints based upon Miettinen & Nurminen method
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X  = results will be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
8.6.3.1
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed . 
 
 
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Demographic variables (eg, age, gender, race), baseline characteristics, primary and 
secondary diagnoses, and prior and concomitant therapies will be summarized by treatment 
either by descriptive statistics or categorical tables.
Interim Analysis
8.7
No interim analyses for efficacy or safety are planned for this study because of the favorable 
efficacy and safety profiles observed for suvorexant in the Phase 3 program in insomnia 
subjects.  
Multiplicity
8.8
While nominal p-values will be computed for all comparisons of suvorexant with placebo, 
statistical significance for comparison of the primary and secondary efficacy endpoints 
between treatments will be based on a fixed sequential multiplicity strategy to control the 
overall Type I error at the two-sided 5% significance level. If the comparison of the primary 
efficacy endpoint between treatments is significant at the 5% significance level, then 
comparison of the secondary endpoint between treatments will be evaluated at the 5% level 
of significance. More specifically, the difference between treatments in change from baseline 
in TST at Week 4 will be tested at the 5% level. If the difference at Week 4 is significant, 
then the difference between treatments in change from baseline in WASO at Week 4 will be 
tested at the 5% significance level. If the difference between treatments in TST at Week 4 is 
not significant, then the difference between treatments for WASO at Week 4 will not be 
evaluated for significance.
Sample Size and Power Calculations
8.9
Sample size
This study will randomize approximately 130 subjects into the suvorexant group and 
approximately 130 subjects into the placebo group, for a total of 260 randomized subjects in 
order to obtain 117 evaluable subjects per treatment group.  
Power for the primary hypothesis
With approximately 130 subjects randomized per treatment group and assuming a standard 
deviation of 68 minutes for change from baseline in TST (based on insomnia subjects
≥65 years who had PSG in MK-4305 Protocols 028 and 029 pooled), a 2-sided α=0.05, and a
dropout rate of 10% at Week 4 (approximately twice the drop-out rate observed for insomnia 
subjects ≥65 years who had PSG in MK-4305 Protocols 028 and 029 pooled), the study has 
approximately 92% power to detect a true difference of 30 minutes between treatment groups 
with respect to change from baseline in TST at Week 4 (standardized effect size 
(SES) = 0.44). The study has approximately 80% power to detect a 25-minute difference in 
change from baseline in TST between treatment groups (SES = 0.37).
There are few studies in the literature which provide descriptive statistics for PSG endpoints 
in insomnia subjects with AD. The sample sizes for these studies are small relative to the size 
 
 
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of the suvorexant Phase 3 studies, and estimates of the standard deviation of TST (but not for 
change from baseline in TST) were reported. The studies also did not restrict the recording 
period to 8 hours so variability estimates from these studies are likely to be higher than those
for a study with a recording period restricted to 8 hours, as in this study. The standard 
deviation for TST varied considerably across these studies; some were smaller than the 
standard deviation for TST from Protocols 028 and 029, and others were larger. Since the 
number of insomnia subjects in the MK-4305 Phase 3 database is over 10-fold larger than the
studies in the literature, and for the other reasons given, estimates of standard deviation for 
calculating the sample size and power for this study were based on elderly insomnia subjects 
who had PSG in MK-4305 Protocols 028 and 029.
The standard deviation of 68 minutes for change from baseline in TST  was based on pooled 
data for the suvorexant low dose (15 mg for elderly and 20 mg for non-elderly) and placebo 
groups for the subset of elderly insomnia subjects (age ≥65) who had PSG in the MK-4305 
Phase 3 trials (Protocol 028 and Protocol 029). This standard deviation is similar to, but 
slightly higher than, the standard deviation observed for elderly and nonelderly insomnia 
subjects combined (67 minutes) in these trials. The assumed true difference of 30 minutes in 
TST between suvorexant low dose and placebo for elderly insomnia subjects is slightly 
smaller (ie, more conservative) than the observed difference of 33 minutes for elderly and 
non-elderly insomnia subjects combined. These more conservative estimates based on the 
subset of elderly subjects are appropriate to use for sample size determination as a greater 
proportion of elderly than non-elderly subjects are expected to be enrolled in this trial. Note 
that a 30-minute increase in change from baseline in TST can be thought of as resulting from 
a reduction in LPS by approximately 10 minutes (SES ≈ 0.19) plus a reduction in WASO by 
approximately 20 minutes (SES ≈ 0.34) or, approximately, the sum of any reductions in LPS 
and WASO which add to 30 minutes (eg, a reduction in LPS by approximately 15 minutes 
(SES ≈ 0.29) plus a reduction in WASO by approximately 15 minutes (SES ≈ 0.26)).
Table 9 summarizes the power for the primary endpoint (TST at Week 4) assuming a variety 
of values for the standard deviation and true difference between treatment groups.
Table 9
Power (%) for Comparing the Primary Efficacy Endpoint (TST at Week 4) 
Between the Suvorexant and Placebo Treatment Groups with approximately 130
Subjects Randomized to Each Treatment Group
Underlying Standard 
Deviation of Change 
from Baseline
(minutes)
Underlying Difference of Mean Change from Baseline for
Suvorexant minus Placebo
(minutes)
35
30
25
82
90%
80%
64%
71
96%
90%
77%
68
98%
92%
80%
65
98%
94%
83%
Note:  The power is calculated based on 117 evaluable subjects per treatment group, a 2-sided α=0.05, and a 
dropout rate of 10% at Week 4.
 
 
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Power for the secondary hypothesis
With approximately 130 subjects per treatment group and assuming a standard deviation of 
58 minutes for change from baseline in WASO, a 2-sided α=0.05, and a dropout rate of 10% 
at Week 4 (based on MK-4305 Protocols 028 and 029 insomnia subjects pooled), the study 
has approximately 91% power to detect a true difference of 25 minutes between treatment 
groups with respect to change from baseline in WASO at Week 4 (SES = 0.43). This is a 
slightly smaller difference than the difference of 27 minutes observed between low dose and 
placebo for elderly insomnia subjects (based on MK-4305 Protocols 028 and 029 subjects 
pooled), and the standard deviation is larger than the estimate of 54 minutes for the standard 
deviation for change from baseline observed at Week 4 for elderly plus nonelderly insomnia 
subjects for the 2 studies combined. The study has approximately 98% power to detect a 30-
minute difference in change from baseline in WASO between treatment groups (SES = 0.52)
and 75% power to detect a 20-minute difference in change from baseline in WASO between 
treatment groups (SES = 0.34).
Multiplicity-adjusted power
There is approximately 87% power to declare both treatment comparisons, change from 
baseline in TST at Week 4 for the primary hypothesis and change from baseline in WASO at 
Week 4 for the secondary hypothesis, as significant (computed from the marginal power for 
each hypothesis and a correlation of -0.77 between these endpoints at Month 1, estimated
from the pooled data for subjects ≥65 years who had PSG in Protocols 028 and 029) (see
Table 10).
Table 10
Power (%) for Comparing the Primary Endpoint (TST at Week 4) and the 
Secondary Endpoint (WASO at Week 4) Between Treatment Groups According 
to the Multiplicity Testing Strategy
Endpoint/Timepoint
Underlying Difference 
in Mean Change from 
Baseline for
Suvorexant minus 
Placebo
(minutes)
Marginal Power†
Multiplicity-adjusted Power
Both‡
Week 4 TST
30
92%
NA
Week 4 WASO
25
91%
87%
† Based upon a 5% (2-sided) t-test for each endpoint, and assuming N=130 subjects randomized per group, a dropout rate 
10% at Week 4, and a standard deviation of 68 minutes for change from baseline in TST at Week 4 and a standard 
deviation of 58 minutes for change from baseline in WASO at Week 4.  
‡ "Both" refers to both endpoints declared to be significant according to the multiplicity strategy (see Section 8.8
Multiplicity). NA stands for ‘not applicable’.
Subgroup Analyses 
8.10
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary and 
 
 
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secondary efficacy endpoints will be estimated and plotted within each category of the 
following classification variables:

Gender (female; male)

Age group (<65; ≥65 years)

Race (white; non-white)

Region (North America; Europe, Other)
▬
Note that if other countries are added to the study, they will be mapped to 1 of 
these regions and documented prior to unblinding.

Severity of baseline insomnia for each endpoint (ie, TST, WASO) will be evaluated 
according to their corresponding baseline value categories:  <baseline median; 
≥baseline median)

Severity of baseline MMSE category (mild=21 to 26, moderate=12 to 20)

AHI (<15, ≥15 to ≤30)
If APOE is determined, it will be included as an additional classification variable.
The consistency of the treatment effect over levels of the classification variables listed above 
will be assessed by running the appropriate analysis model separately for each subgroup of 
the primary efficacy analysis population. Treatment effects and nominal 95% confidence 
intervals by category for the classification variables listed above will be reported as well as 
presented graphically. Formal statistical testing of these interactions will not be performed.
Key safety analyses (such as Tier 1 and 2 events as well as Tier 3 AEs) may be evaluated by 
age group (<65; ≥65 years) and/or MMSE category (moderate=12 to 20, mild=21 to 26).
Compliance (Medication Adherence)
8.11
In this study, as part of the routine recording of the amount of trial medication taken by each 
subject, the number of tablets remaining in study packaging will be counted, reviewed, and 
recorded at regular intervals. These results will be used to calculate subject compliance.
A day within the study will be considered an “On-Therapy” day if the subject takes the 
required number of tablets as noted in Section 5.2.
For a subject who is followed for the entire 1-month Treatment period, the “Number of Days 
Should be on Therapy” is the total number of days from randomization to the last scheduled 
day for treatment administration for that subject. For a subject who discontinued from the 
study permanently, the “Number of Days Should be on Therapy” is the total number of days 
from randomization to the date of the last dose of trial medication.
For each subject, percent compliance will then be calculated using the following formula: 
 
 
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Summary statistics will be provided on percent compliance by treatment group for all 
subjects randomized.
Extent of Exposure
8.12
The total number of days each subject took a particular total daily dose of trial medication
will be identified and then summarized (as subject counts and percentages) within duration 
categories (eg, for the Treatment period:  <1 week, ≥1 week but <2 weeks, ≥2 weeks but <3 
weeks, ≥3 weeks but <4 weeks, and ≥4 weeks; where 1 week is defined as 7 days). 
Additionally, the mean number of days and range of days on study drug will also be 
provided.
Exposure will be evaluated for the entire study sample as well as by age group
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 11.
Table 11
Product Descriptions
Product Name & Potency
Dosage Form
MK-4305 10 mg1
1 Tablet
Placebo to match MK-4305 10 mg1
1 Tablet 
MK-4305 20 mg1,2
1 Tablet 
Placebo to match MK-4305 20 mg1,2
1 Tablet
1MK-4305 = SUVOREXANT
2Subjects may be titrated to a higher dose of 20 mg at 
investigator discretion.
All placebos were created by the Sponsor to match the active product.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive a single-blind 2 week blister card at Visit 2 and a double-blind 2 week 
blister card at Visits 4 and 5. No kitting is required.
 
 
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Clinical Supplies Disclosure
9.3
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask treatment identity. In the event that the emergency 
unblinding call center is not available for a given site in this trial, the central electronic 
treatment allocation/randomization system (IVRS/IWRS) should be used in order to unblind 
subjects and to unmask treatment identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded to treatment assignment.  Subjects 
whose treatment assignment has been unblinded (by the investigator, Merck subsidiary, or 
through the emergency unblinding call center) must be discontinued from study drug.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
For trials using Controlled Substances, all Federal, State, Province, Country, etc. regulations 
must be adhered to in regard to the shipping, storage, handling and dispensing of controlled 
substances. Additionally, the investigator should have the appropriate controlled drug 
license(s) as mandated by Federal, State, Province, Country, etc. laws in which the trial is 
being conducted.
 
 
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Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
 
 
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4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
 
 
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all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or 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.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
 
 
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a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007, 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, www.clinicaltrialregister.eu
or other local registries. Merck, as Sponsor of this trial, will review this protocol and submit 
the information necessary to fulfill these requirements. Merck entries are not limited to 
FDAAA or the EMA clinical trials directive mandated trials. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
 
 
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participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.   
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
 
 
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the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
[1]
Singer C, Tractenberg RE, Kaye J, Schafer K, Gamst A, Grundman M, et al. A 
multicenter, placebo-controlled trial of melatonin for sleep disturbance in 
alzheimer's disease. Sleep 2003;26(7):893-901.
[2]
Swearer JM, Drachman DA, O'Donnell BF, Mitchell AL. Troublesome and 
disruptive behaviors in dementia; Relationships to diagnosis and disease severity. 
JAGS 1988;36:784-90.
 
 
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[3]
Wu Y-H, Swaab DF. Disturbance and strategies for reactivation of the circadian 
rhythm system in aging and Alzheimer's disease. Sleel Medicine 2007;8:623-36.
[4]
Fronczek R, van Geest S, Frölich M, Overeem S, Roelandse FWC, Lammers GJ, et 
al. Hypocretin (orexin) loss in Alzheimer's disease. Neurobiol Aging 
2012;33:1642-50.
[5]
Stickgold R, Walker MP. Sleep-dependent memory triage: evolving generalization 
through selective processing. Nat Neurosci. 2013 Feb;16(2):139-45.
[6]
Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, et al. Sleep drives 
metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7.
[7]
Ju YE, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, Duntley SP, et al. 
Sleep quality and preclinical Alzheimer disease. JAMA Neurol. 2013 
May;70(5):587-93.
[8]
Liguori C, Romigi A, Nuccetelli M, Zannino S, Sancesario G, Martorana A, et al. 
Orexinergic system dysregulation, sleep impairment, and cognitive decline in 
Alzheimer disease. JAMA Neurol. 2014 Dec;71(12):1498-505.
[9]
Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, et al. Amyloid-beta 
dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 
13;326(5955):1005-7.
[10]
Serfaty M, Kennell-Webb S, Warner J, Blizard R, Raven P. Double blind 
randomised placebo controlled trial of low dose melatonin for sleep disorders in 
dementia. Int J Geriatr Psychiatry 2002;17:1120-7.
[11]
Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S. Double blind study of 
melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions 
in Alzheimer type dementia. J Nippon Med Sch 2003;70(4):334-41.
[12]
Gehrman PR, Connor DJ, Martin JL, Shochat T, Corey-Bloom J, Ancoli-Israel S. 
Melatonin fails to improve sleep or agitation in a double-blind randomized placebo-
controlled trial of institutionalized patients with Alzheimer's disease. Am J Geriatr 
Psychiatry 2009;17(2):166-9.
[13]
MRL Clinical Study Report (Synopsis), Multicenter Study: Takeda Global 
Research and Development Center, Inc. (TGRD); A randomized, double-blind, 
placebo-controlled study to assess the subjective response to treatment with 
ramelteon in adult subjects with chronic insomnia by utilizing an interactive voice 
response system (IVRS) for collecting diary data; Clinical Trial Synopsis 01-04-
375-041, NCT#00672724 .
 
 
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[14]
Salami O, Lyketsos C, Rao V. Treatment of sleep disturbance in Alzheimer's 
dementia. Int J Geriatr Psychiatry 2013;26:771-82.
[15]
Raji MA, Brady SR. Mirtazapine for treatment of depression and comorbidities in 
Alzheimer disease. Ann Pharmacother 2001;35:1024-7.
[16]
López-Pousa S, Garre-Olmo J, Vilalta-Franch J, Turon-Estrada A, Pericot-Nierga I. 
Trazodone for Alzheimer's disease: A naturalistic follow-up study. Arch Gerontol 
Geriatr 2008;47:207-15.
[17]
Neirenberg AA, Keck PE, Jr. Management of monoamine oxidase inhibitor-
associated insomnia with trazodone. J Clin Psychopharmacol 1989;9(1):42-5.
[18]
Thompson JW, Jr., Ware MR, Blashfield RK. Psychotropic medication and 
priapism: a comprehensive review. J Clin Psychiatry 1990;51(10):430-3.
[19]
Walsh JK, Erman M, Erwin CW, Jamieson A, Mahowald M, Regestein Q, et al. 
Subjective hypnotic efficacy of trazodone and zolpidem in DSMIII-R primary 
insomnia. Hum Psychopharmacol 1998;13:191-8.
[20]
Roehrs T, Roth T. Hypnotics:  efficacy and adverse effects. In: Kryger MH, Roth 
T, Dement WC, Zorab R, Carroll C, Cannon AL, eds. Principles and practice of 
sleep medicine. 3rd ed. Philadelphia: W.B. Saunders Company, 2000:414-8.
[21]
Ellul J, Archer N, Foy CML, Poppe M, Boothby H, Nicholas H, et al. The effects 
of commonly prescribed drugs in patients with Alzheimer's disease on the rate of 
deterioration. J Neurol Neurosurg Psychiatry 2007;78:233-9.
[22]
Elmståhl S, Stenberg I, Annerstedt L, Ingvad B. Behavioral disturbances and 
pharmacological treatment of patients with dementia in family caregiving: A 2-year 
follow-up. Int Psychogeriatr 1998;10(3):239-52.
[23]
Huang AR, Mallet L, Rochefort CM, Eguale T, Buckeridge DL, Tamblyn R. 
Medication-related falls in the elderly causative factors and preventive strategies. 
Drugs Aging 2012;29(5):359-76.
[24]
Moraes WS, Poyares DR, Guilleminault C, Ramos LR, Bertolucci PH, Tufik S. 
The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer 
disease: a double-blind placebo-controlled study. Sleep. 2006 Feb;29(2):199-205.
[25]
Herring WJ, Connor KM, Ivgy-May N, Snyder E, Liu K, Snavely DB, et al. 
Suvorexant in Patients with Insomnia: Results from Two 3-Month Randomized 
Controlled Clinical Trials. Biol Psychiatry. 2014 Oct 23. [Epub ahead of print].
 
 
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[26]
Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K, et al. Orexin 
receptor antagonism for treatment of insomnia.  A randomized clinical trial of 
suvorexant. Neurology 2012;79:2265-74.
[27]
Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, et 
al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with 
subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, 
placebo-controlled trial. Lancet Neurol. 2014 May;13(5):461-71.
[28]
Tractenberg RE, Sinton CM, Kaye JA. Symptoms of sleep disturbance in persons 
with alzheimer's disease and normal elderly. J Sleep Res 2005;14:177-85.
[29]
Vitiello MV, Bliwise DL, Prinz PN. Sleep in Alzheimer's disease and the sundown 
syndrome. Neurology 1992;42 [Suppl 6]:83-94.
[30]
Rose KM, Beck C, Tsai P-F, Liem PH, Davila DG, Kleban M, et al. Sleep 
disturbances and nocturnal agitation behaviors in older adults with dementia. Sleep 
2011;34(6):779-86.
[31]
Alzheimer's Association. 2014 Alzheimer's disease facts and figures. Alzheimers 
Dement. 2014 Mar;10(2):e47-92.
[32]
Guy W, editors. Clinical Global Impressions (CGI) Scale [Internet]. Washington 
(DC): American Psychiatric Association (APA); 2000. Available from: 
http://www.psywellness.com.sg/docs/CGI.pdf.
[33]
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4(2):213-26.
[34]
Tractenberg RE, Sinton CM, Cummings JL, Thal LJ. The sleep disorders 
inventory: an instrument for studies of sleep disturbance in persons with 
alzheimer's disease. J Sleep Res 2003;12:331-7.
[35]
Anic-Labat S, Guilleminault C, Kraemer HC, Meehan J, Arrigoni J, Mignot E. 
Validation of a cataplexy questionnaire in 983 sleep-disorders patients. Sleep 
1999;22(1):77-87.
[36]
Morgenthaler T, Alessi C, Friedman L, Owens J, Kapur V, Boehlecke B, et al. 
Practice parameters for the use of actigraphy in the assessment of sleep and sleep 
disorders: An update for 2007. Sleep 2007;30(4):519-29.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.4 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
 
 
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present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of patient consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
 
 
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will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
 
 
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accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (ie, only leftover samples are being retained). 
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Pharmacogenetics Informational Brochure for IRBs/IECs & Investigational Site Staff
12.3
     
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
12.4
Sample Types
Trial Visit/Period:
Screening 
Visit 1/ 
Screening
Visit 4 
Rand/ 
Treatment a
Visit 6 –
End of 
Week 4/ 
Treatment
Discon
Blood Parameter
Approximate Blood Volume (mL)
Hematology (~2 mL)
2 mL
2 mL
2 mL
Serum/Plasma Chemistry (~8.5 mL)
Includes TSH, Vitamin B12 and 
Folate
8.5 mL
8.5 mL
8.5 mL
Serum Follicle-stimulating Hormone 
(FSH)b (~3.5 mL)
3.5 mL
Methylmalonic acid and
homocysteinec
3 mL
Suvorexant PK 
(~4 mL)
4 mL
4 mL
4 mLd
Blood for Genetic Analysis
8.5 mL
Expected Total (mL)
10.5-17 mL
12.5 mL
14.5 mL
10.5-14.5 mL
a)
Lab values at randomization will be pre-treatment values since randomized trial medication does not 
initiate until the night of Day 1.
b)
A blood sample for determining serum FSH should be collected only if serum FSH levels are required to 
determine childbearing potential as defined in Section 5.1.2.
c)
A blood sample for serum methylmalonic acid and homocysteine should only be collected if B12 or 
folate levels are below the central laboratory’s normal range 
d)
Only drawn if subject discontinues due to an AE.
 
 
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List of Abbreviations and Definition of Terms
12.5
Abbreviation
Definition
AASM
American Academy of Sleep Medicine
Aβ
Amyloid Beta
AE
Adverse Experience
AD
Alzheimer’s disease
AHI
Apnea Hypopnea Index
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
APOE4
Apolipoprotein E4
ASaT
All Subjects as Treated
AST
Aspartate Aminotransferase
βhCG
Beta-Human Chorionic Gonadotropin
BMI
Body Mass Index
BP
Blood Pressure
BIPAP
Bi-Level Positive Airway Pressure
CAC
Clinical Adjudication Committee
CBC
Complete Blood Count
CFR
Code of Federal Regulations
CGI-S
Clinical Global Impressions of Insomnia Severity
CI
Confidence Interval
CNS
Central Nervous System
COPD
Chronic Obstructive Pulmonary Disease
CPAP
Continuous Positive Airway Pressure
CRU
Clinical Research Unit
CSF
Cerebrospinal Fluid
CSM
Clinical Specimen Management
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Scale
CYP
Cytochrome P450
DEGs
Data Entry Guidelines
DNA
Deoxyribonucleic Acid
DS
Digit Symbol
DSM-5
Diagnostic and Statistical Manual of Mental Disorder, 5th Edition
ECG
Electrocardiogram
ECI
Events of Clinical Interest
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EDS
Excessive Daytime Sleepiness
EEG
Electroencephalogram
EMG
Electromyogram
EOG
Electro-Oculogram
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FSH
Follicle-stimulating Hormone
GCP
Good Clinical Practice
GDS
Geriatric Depression Scale
GERD
Gastroesophageal Reflux Disease
Hg
Mercury
HIV
Human Immunodeficiency Virus
HR
Heart Rate
 
 
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Abbreviation
Definition
IA
Interim Analysis
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDI
Insomnia Diagnostic Interview
IEC
Independent Ethics Review Committee
IRB
Institutional Review Board
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
kg
Kilogram
lb
Pound
LFT
Liver Function Test
LPS
Latency to Onset of Persistent Sleep
MCQ
Modified Cataplexy Questionnaire
MHIS
Modified Hachinski Ischemia Scale
MI
Multiple Imputation
MMSE
Mini Mental State Examination
MOA
Manual of Assessments
MRL
Merck Research Laboratories
NAW
Number of Awakenings
NCS
Not Clinically Significant
NE
NIA-AA
Neurological Examination
National Institute on Aging – Alzheimer’s Association
NOA
Number of Arousals
NPI
Neuropsychiatric Inventory
NREM
Non-REM
NTIB
Nighttime Time in Bed
NTST
Nighttime Total Sleep Time
ORA
Orexin Receptor Antagonist
OTC
Over-the-Counter or (depending on context) On-Treatment Completers
PD
Pharmacodynamic
PDLC
Pre-Defined Limit of Change.
PE
Physical Examination
PGx
Pharmacogenomics
PK
Pharmacokinetic
PLM
Periodic Limb Movement
PPDM
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism
PSG
Polysomnography
REM
Rapid Eye Movement
RNA
Ribonucleic Acid
RR
Respiratory Rate
SAC
Scientific Advisory Committee
SAE
Serious Adverse Experience
SAP
Statistical Analysis Plan
SCNSI
Stanford Center for Narcolepsy Sleep Inventory
SD
Standard Deviation
SDI
Sleep Disorders Inventory
SE
Sleep Efficiency
SES
Standardized Effect Size
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SHX
Sleep History
SOC
System Organ Class
 
 
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Abbreviation
Definition
SOL
Sleep Onset Latency
SOP
Standard Operating Procedure
SQR
Sleep Quality Rating
sSAP
Supplemental Statistical Analysis Plan
SSQC
Single-item Sleep Quality Scale - Caregiver
T-BILI
Total Bilirubin
TIB
Time in Bed
TST
Total Sleep Time
TTA
Total Time Awake
UDS
Urine Drug Screen
UGT1A
Uridine Diphosphate Glucuronosyltransferase 1A1 Assessment
ULN
Upper Limit of Normal
WASO
Wakefulness After Sleep Onset
 
 
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Calculating Body Mass Index (BMI)
12.6
Formula and calculation for pounds and inches:
Calculate BMI by dividing weight in pounds (lbs) by height in inches (in) squared 
and multiplying by a conversion factor of 703.
Example: Weight = 150 lbs, Height = 5'5" (65")
Calculation: [150 ÷ (65)2] x 703 = 24.96
Formula and calculation for kilograms and meters (or centimeters):
Formula: weight (kg) / [height (m)]2
With the metric system, the formula for BMI is weight in kilograms divided by height 
in meters squared. Because height is commonly measured in centimeters, divide 
height in centimeters by 100 to obtain height in meters.
Example: Weight = 68 kg, Height = 165 cm (1.65 m)
Calculation: 68 ÷ (1.65)2 = 24.98
Source: www.cdc.gov
Source: www.nhlbi.nih.gov
 
 
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List of Caffeine Products and Caffeine Content
12.7
This list is not inclusive; many products contain caffeine, including over-the-counter 
medications, weight loss products, mineral and herbal supplements, etc. Please check the 
labels of any concomitant therapies, supplements, etc. for caffeine content. 
Product
Serving Size
(in fluid ounces [oz] 
and milliliters [mL])
Caffeine (mg)
Coffee
Brewed
8 oz. (237 mL)
95-200 mg
Brewed, decaffeinated
8 oz. (237 mL)
2-12 mg
Brewed, single-serve varieties
8 oz. (237 mL)
75-150 mg
Brewed, single-serve varieties, 
decaffeinated
8 oz. (237 mL)
2-4 mg
Espresso, restaurant-style
1 oz. (30 mL)
47-75 mg
Espresso, restaurant-style, decaffeinated
1 oz. (30 mL)
0-15 mg
Instant
8 oz. (237 mL)
27-173 mg
Instant, decaffeinated
8 oz. (237 mL)
2-12 mg
Specialty drink (latte or mocha)
8 oz. (237 mL)
63-175 mg
Tea
Brewed tea
Black tea
8 oz. (237 mL)
14-70 mg
Black tea, decaffeinated
8 oz. (237 mL)
0-12 mg
Green tea
8 oz. (237 mL)
24-45 mg
Iced tea
Instant, prepared with water
8 oz. (237 mL)
11-47 mg
Ready-to-drink, bottled
8 oz. (237 mL)
5-40 mg
Soft Drinks
A&W Root Beer
12 oz. (355 mL)
0 mg
Barq's Root Beer
12 oz. (355 mL)
16-18 mg
Coca-Cola
12 oz. (355 mL)
23-35 mg
Diet Coke
12 oz. (355 mL)
23-47 mg
Diet Pepsi
12 oz. (355 mL)
27-37 mg
Dr. Pepper, regular and diet
12 oz. (355 mL)
36-42 mg
Mountain Dew, regular and diet
12 oz. (355 mL)
42-55 mg
Mug Root Beer, regular and diet
12 oz. (355 mL)
0 mg
7UP
12 oz. (355 mL)
0 mg
Pepsi
12 oz. (355 mL)
32-39 mg
Sierra Mist, regular and diet
12 oz. (355 mL)
0 mg
Sprite, regular and diet
12 oz. (355 mL)
0 mg
Energy Drinks
Amp, regular or sugar-free
8 oz. (237 mL)
71-74 mg
5-Hour Energy shot
2 oz. (60 mL)
200-207 mg
Full Throttle, regular or sugar-free
8 oz. (237 mL)
70-100 mg
Red Bull, regular or sugar-free
8.4 oz. (248mL)
75-80 mg
Rockstar, regular or sugar-free
8 oz. (237 mL)
79-80 mg
Other Products
Chocolate chips, semisweet
1 cup (168 grams)
104 mg
Dark chocolate-coated coffee beans
28 pieces
336 mg
Energy mints
2 mints
95-200 mg
Source: www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/caffeine/art-20049372?pg=1
 
 
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DSM-5 Criteria for Major or Mild Neurocognitive Disorder Due to Alzheimer's 
12.8
Disease  
Diagnostic Criteria:
A. The criteria are met for major or mild neurocognitive disorder.
B. There is insidious onset and gradual progression of impairment in 1 or more cognitive 
domains (for major neurocognitive disorder, at least 2 domains must be impaired
C. Criteria are met for probable Alzheimer's disease as follows:
For major neurocognitive disorder: 
Probable Alzheimer's disease is diagnosed if either of the following is present:
1. Evidence of a causative Alzheimer's disease genetic mutation from family history or 
genetic testing. 
2. All 3 of the following are present:
a.
Clear evidence of decline in memory and learning and at least 1 other cognitive 
domain (based on detailed history or serial neuropsychological testing). 
b. Steadily progressive, gradual decline in cognition, without extended plateaus. 
c.
No evidence of mixed etiology (ie, absence of other neurodegenerative or 
cerebrovascular disease, or another neurological, mental, or systemic disease or 
condition likely contributing to cognitive decline). 
For mild neurocognitive disorder: 
Probable Alzheimer's disease is diagnosed if there is evidence of a causative Alzheimer's 
disease genetic mutation from either genetic testing or family history.
D. The disturbance is not better explained by cerebrovascular disease, another 
neurodegenerative disease, the effects of a substance, or another mental, neurological, or 
systemic disorder.
Reference: American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition. Arlington, VA, American Psychiatric Association, 2013.
 
 
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National Institute on Aging-Alzheimer’s Association (NIA-AA)
diagnostic 
12.9
guidelines for Alzheimer's disease
Recommendations for the diagnosis of dementia due to Alzheimer’s disease:
Criteria for all-cause dementia: Core clinical criteria
The diagnosis of dementia is intended to encompass the spectrum of severity, ranging from 
the mildest to the most severe stages of dementia. The methodology for staging of dementia 
severity was beyond the charge of the workgroup. Dementia is diagnosed when there are 
cognitive or behavioral (neuropsychiatric) symptoms that:
1. Interfere with the ability to function at work or at usual activities; and
2. Represent a decline from previous levels of functioning and performing; and
3. Are not explained by delirium or major psychiatric disorder;
4. Cognitive impairment is detected and diagnosed through a combination of (1) history-
taking from the patient and a knowledgeable informant and (2) an objective cognitive 
assessment, either a “bedside” mental status examination or neuropsychological testing. 
Neuropsychological testing should be performed when the routine history and bedside 
mental status examination cannot provide a confident diagnosis.
5. The cognitive or behavioral impairment involves a minimum of 2 of the following 
domains:
a.
Impaired ability to acquire and remember new information––symptoms include: 
repetitive questions or conversations, misplacing personal belongings, forgetting 
events or appointments, getting lost on a familiar route.
b. Impaired reasoning and handling of complex tasks, poor judgment––symptoms 
include: poor understanding of safety risks, inability to manage finances, poor 
decision-making ability, inability to plan complex or sequential activities.
c.
Impaired visuospatial abilities––symptoms include: inability to recognize faces or 
common objects or to find objects in direct view despite good acuity, inability to 
operate simple implements, or orient clothing to the body.
d. Impaired language functions (speaking, reading, writing)––symptoms include: 
difficulty thinking of common words while speaking, hesitations; speech, spelling, 
and writing errors.
e.
Changes 
in 
personality, 
behavior, 
or 
comportment––symptoms 
include: 
uncharacteristic mood fluctuations such as agitation, impaired motivation, initiative, 
apathy, loss of drive, social withdrawal, decreased interest in previous activities, loss 
of empathy, compulsive or obsessive behaviors, socially unacceptable behaviors.
 
 
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Probable AD dementia: Core clinical criteria
Probable AD dementia is diagnosed when the patient:
1. Meets criteria for dementia described earlier in the text, and in addition, has the following 
characteristics:
A. Insidious onset. Symptoms have a gradual onset over months to years, not sudden 
over hours or days;
B. Clear-cut history of worsening of cognition by report or observation; and
C. The initial and most prominent cognitive deficits are evident on history and 
examination in 1 of the following categories.
a.
Amnestic presentation: It is the most common syndromic presentation of AD 
dementia. The deficits should include impairment in learning and recall of 
recently learned information. There should also be evidence of cognitive 
dysfunction in at least 1 other cognitive domain, as defined earlier in the text.
b. Nonamnestic presentations:

Language presentation: The most prominent deficits are in word-finding, but 
deficits in other cognitive domains should be present.

Visuospatial presentation: The most prominent deficits are in spatial 
cognition, 
including 
object 
agnosia, 
impaired 
face 
recognition, 
simultanagnosia, and alexia. Deficits in other cognitive domains should be 
present.

Executive dysfunction: The most prominent deficits are impaired reasoning, 
judgment, and problem solving. Deficits in other cognitive domains should be 
present.
D. The diagnosis of probable AD dementia should not be applied when there is evidence 
of (a) substantial concomitant cerebrovascular disease, defined by a history of a 
stroke temporally related to the onset or worsening of cognitive impairment; or the 
presence of multiple or extensive infarcts or severe white matter hyperintensity 
burden; or (b) core features of Dementia with Lewy bodies other than dementia itself; 
or (c) prominent features of behavioral variant frontotemporal dementia; or (d) 
prominent 
features 
of 
semantic 
variant 
primary 
progressive 
aphasia 
or 
nonfluent/agrammatic variant primary progressive aphasia; or (e) evidence for 
another concurrent, active neurological disease, or a non-neurological medical 
comorbidity or use of medication that could have a substantial effect on cognition.
Note: All patients who met criteria for “probable AD” by the 1984 NINCDS–ADRDA 
criteria1 would meet the current criteria for probable AD dementia mentioned in the present 
article.
 
 
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Probable AD dementia with increased level of certainty
Probable AD dementia with documented decline
In persons who meet the core clinical criteria for probable AD dementia, documented 
cognitive decline increases the certainty that the condition represents an active, evolving 
pathologic process, but it does not specifically increase the certainty that the process is that of 
AD pathophysiology.
Probable AD dementia with documented decline is defined as follows: evidence of 
progressive cognitive decline on subsequent evaluations based on information from 
informants and cognitive testing in the context of either formal neuropsychological 
evaluation or standardized mental status examinations.
Probable AD dementia in a carrier of a causative AD genetic mutation
In persons who meet the core clinical criteria for probable AD dementia, evidence of a 
causative genetic mutation (in APP, PSEN1, or PSEN2), increases the certainty that the 
condition is caused by AD pathology. The workgroup noted that carriage of the ɛ4 allele of 
the apolipoprotein E gene was not sufficiently specific2 to be considered in this category.
Source: http://www.alzheimersanddementia.com/article/S1552-5260(11)00101-4/fulltext#sec4
1 The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on 
Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer’s & 
Dementia – The Journal of the Alzheimer’s Association. May 2011. Vol.7, Issue 3, 263-269.
2 Saunders, A.M., Shea, S., Mirra, S., Evans, D., Roses, A.D. et al. Utility of the apolipoprotein E genotype in 
the diagnosis of Alzheimer’s Disease. Alzheimer’s Disease Centers Consortium on Apolipoprotein E and 
Alzheimer’s Disease. N. England J Med. 1998; 338: 506-511
 
 
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DSM-5 Criteria for Insomnia Disorder
12.10
Diagnostic Criteria
A. predominant complaint of dissatisfaction with sleep quantity or quality, associated with 1
(or more) of the following symptoms:
1. Difficulty initiating sleep.
2. Difficulty maintaining sleep, characterized by frequent awakenings or problems 
returning to sleep after awakenings.
3. Early-morning awakening with inability to return to sleep.
B. The sleep disturbance causes clinically significant distress or impairment in social, 
occupational, educational, academic, behavioral, or other important areas of functioning.
C. The sleep difficulty occurs at least 3 nights per week.
D. The sleep difficulty is present for at least 3 months.
E. The sleep difficulty occurs despite adequate opportunity for sleep.
F. The insomnia is not better explained by and does not occur exclusively during the course 
of another sleep-wake disorder (eg, narcolepsy, a breathing-related sleep disorder, a 
circadian rhythm sleep-wake disorder, a parasomnia).
G. The insomnia is not attributable to the physiological effects of a substance (eg, a drug of 
abuse, a medication).
H. Coexisting mental disorders and medical conditions do not adequately explain the 
predominant complaint of insomnia.
Reference: American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition. Arlington, VA, American Psychiatric Association, 2013.
 
 
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General Neurological Exam
12.11
The General Neurological Examination will be performed at the timepoint(s) specified in the 
protocol flow chart.
Note to the investigator: If at any time abnormalities are observed in the General 
Neurological Exam, the Investigator should do additional examinations as needed based 
on his or her medical judgment.
The General Neurological Examination includes all of the modules listed below, with the 
exception of Module 1, and is intended to be a general screening examination and sufficient 
for this study and subject population.
MODULE 2 – CRANIAL NERVE ASSESSMENT
A. II – Visual Fields and acuity
B. II, III – Pupil Size and Reactivity
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus)
1. Observe for nystagmus during eye movements, increased nystagmus at the end of 
gaze or other oculomotor changes (mild nystagmus at extremes of gaze is normal). 
Note direction of nystagmus
D. V – Facial Sensation, Jaw Strength
E. VII – Muscles of Facial Expression (wrinkle brow, squeeze eyes shut, smile)
F. VIII – Auditory Acuity (assessed using a bed-side screening test eg by rubbing fingers on 
each side of subject’s head or by whispering numbers)
G. IX – Gag reflex
H. X – Swallow 
I.
XI – Shoulder shrug
J.
Tongue Protrusion (midline)
Score: left and right (except for G, H, J)
Grade: NORMAL or IMPAIRED and describe abnormality
MODULE 3 - MOTOR SYSTEM
A. Muscle Tone
1. Ask the volunteer to relax.
2. Flex and extend the volunteer’s elbows and knees (bilaterally).
3. There is a small, continuous resistance to passive movement.
 
 
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4. Observe for involuntary movements (eg, tremor, tics, fasciculations). Observe for 
resistance to passive movement; observe for decreased (flaccid) or increased 
(rigid/spastic) tone.
Score:  left and right
Grade: NORMAL, INCREASED or DECREASED
B. Muscle Strength
1. Ask the subject to stand up from sitting without using hands
Grade: NORMAL, IMPAIRED and describe abnormality
2. Test proximal limb strength by having the volunteer flex and extend the knees and 
elbows against your resistance.
Test bilaterally, and compare 1 side to the other.
Score:  left and right
Grade: 5/5: normal; 4/5: movement against resistance impaired; 3/5: movement 
against gravity but not against resistance; 2/5: visible movement but not against 
gravity; 1/5: visible contraction; 0/5: no visible activity
3. Test distal limb strength by having the volunteer conduct dorsiflexion and plantar 
flexion of the volunteer’s feet; finger abduction and handgrip strength against your 
resistance.
Test bilaterally, and compare 1 side to the other.
Score:  left and right
Grade: 5/5: normal; 4/5: movement against resistance impaired; 3/5: movement 
against gravity but not against resistance; 2/5: visible movement but not against 
gravity; 1/5: visible contraction; 0/5: no visible activity
C. Pronator Drift
1. Ask the volunteer to hold both arms straight forward with, palms up and eyes closed 
for ~10-15 seconds as tolerated; watch for how well the arm position is maintained.
2. Instruct the volunteer to keep both arms still while you tap them briskly downward. The 
volunteer should normally be able to maintain extension and supination. Inability to 
maintain extension and supination (and drift into pronation) indicates an upper motor 
neuron deficit.
Score:  left and right
Grade: NORMAL or IMPAIRED and describe abnormality
 
 
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MODULE 4 - REFLEXES
A. Biceps
B. Knee
Note: Other deep tendon reflexes may be tested at Investigator's discretion (eg elbow, wrist 
or Achilles tendon)
Score: left and right
Grade: NORMAL, INCREASED, DECREASED or ABSENT
C. Babinski
Score: left and right
Grade: NORMAL or ABNORMAL
MODULE 5 - COORDINATION AND GAIT
A. Rapid, Rhythmic Alternating Movements
1. Testing each hand separately, ask the volunteer to tap the distal thumb with the tip of 
each finger, in sequence, as fast as possible. 
Score: left and right
Grade: NORMAL or IMPAIRED
Reminder: If the rapid alternate movements are disturbed, the subject will be 
asked to strike his hand on the thigh, raise the hand, turn it over and 
then strike the back of the hand down on the same place.  (This test is 
impaired in cerebellar disease, extra pyramidal disease and upper MN 
weakness.)
B. Point-to-Point Movements
1. Ask the volunteer to touch your index finger and their nose alternately several times. 
Move your finger about as the volunteer performs this task.
Score: left and right
Grade: NORMAL or IMPAIRED
Reminder: If the point-to-point testing is disturbed, the subject will be asked to 
place 1 heel on the opposite knee and then run it down the shin to the 
big toe. Repeat this for both sides. (Impaired tests indicate cerebellar 
disease.)
 
 
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C. Romberg
1. Ask the volunteer to stand with both feet together and eyes closed for 20 to 
30 seconds without support.
2. Be prepared to catch the volunteer if they are unstable.
Grade: NORMAL or IMPAIRED
D. Gait
1. Ask the volunteer to walk across the room, turn and come back (assess posture, 
balance, swinging of arms and movement of the legs).
Grade: NORMAL or IMPAIRED and describe abnormality
2. Ask the volunteer to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
MODULE 6 - SENSORY
A. Light touch sense:  cotton wisp on skin of forearms and legs, bilaterally.
B. Pin prick: safety pin touched lightly to skin of forearms and legs, bilaterally.
C. Temperature: warm or cool object touched to skin of forearms and legs, bilaterally.
D. Vibration:  tuning fork vibration detection in hands, feet bilaterally.
E. Position sense:  perception of thumb and toe movement, bilaterally.
F. Stereognosis:  (identify common objects placed in hand, eg, coin, key).
Score: left and right
Grade: NORMAL OR IMPAIRED and describe abnormality (for each A to F)
 
 
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Algorithm for Assessing Out-of-Range Laboratory Values
12.12
For all laboratory values obtained at screening visit evaluation:
A.
If all protocol-specified laboratory values are normal, the subject may enter the study.
B.
If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the subject will be excluded 
from the study
C.
If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1.
The subject may be excluded from the study;
2.
The subject may be included in the study if the abnormal value(s) is not clinically 
significant (NCS) (the investigator must annotate the laboratory value “NCS” on the 
laboratory safety test source document);
3.
The subject may be included in the study if the abnormality is consistent with a pre-
existing medical condition which is not excluded per protocol (eg, elevated eosinophil 
count in a subject with asthma or seasonal allergies)(this should be annotated on the 
laboratory report); or
4.
The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
a.
If the repeat test value is within the normal range, the subject may enter the study.
b. If the repeat test value is still abnormal, the study investigator will evaluate the 
potential subject with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in 
question. If such diseases can be ruled out, and if the abnormal laboratory value is 
not clinically relevant, then the subject may enter the study.  
D.
If there is any clinical uncertainty regarding the significance of an abnormal value, the 
Subject will be excluded from the study.
 
 
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Predefined Limits Of Change Criteria
12.13
Table 1
Predefined Limits of Change Criteria for Laboratory Data
Laboratory Test
Criteria† as a % of a Limit of
Normal Range
Hematology
Hematocrit (M)
≤94.9% LLN
Hematocrit (F)
≤94.1% LLN
Hemoglobin (M)
≤90.5% LLN
Hemoglobin (F)
≤81.9% LLN
WBC
≤64.2% LLN
≥149.0% ULN
Neutrophils
≤37.0% LLN
Eosinophils
≥147.0% ULN
Platelets
≤57.7% LLN
≥177.7%ULN
Hepatic Function
Bilirubin
≥166.7% ULN
Alkaline Phosphatase
≥300% ULN
AST (SGOT)
≥300% ULN
ALT (SGPT)
≥300% ULN
Renal Function
Creatinine
≥142.9% ULN
Clinical Chemistry
Sodium
≤94.7% LLN
≥105.4% ULN
Potassium
≤88.2% LLN
≥111.1% ULN
† A laboratory value must represent a worsening from baseline (ie, be 
more abnormal in the direction of interest) to meet the definition.
LLN=Lower limit of normal.
ULN=Upper limit of normal.
 
 
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Table 2
Predefined Limits of Change Criteria for Vital Signs,
Weight, and Temperature
Measurement
Criteria
Systolic blood 
≥180 mm Hg and ≥20 mm Hg increase from baseline
  pressure
≤90 mm Hg and ≥20 mm Hg decrease from baseline
Diastolic blood 
≥105 mm Hg and ≥15 mm Hg increase from baseline
  pressure
≤50 mm Hg and ≥15 mm Hg decrease from baseline
Pulse
≥120 bpm and ≥15 bpm increase from baseline
≤50 bpm and ≥15 bpm decrease from baseline
Orthostatic 
blood 
pressure
>20 mm Hg systolic sitting to standing after treatment 
(but not in baseline)
Weight
≥7 % increase from baseline
≥7 % decrease from baseline
Temperature
≥101°F and ≥2°F increase from baseline (≥38.3°C and 
≥1°C increase from baseline)
Table 3
Predefined Limits of Change Criteria for ECGs
Measurement
Criteria
QTc Interval†
Prolongation compared to baseline ≥30 to ≤60 msec
Prolongation compared to baseline >60 msec
Value ≥500 msec‡
† Correction based on Bazett’s formula. 
‡  The QTc Interval value must also represent a worsening compared to baseline to 
meet the definition.
 
 
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Mapping Between the 11 Categories of Suicidal Ideation and Behavior, the C-
12.14
SSRS, and CDR for Programming Standard Tables
Table 1
Mapping Between the 11 Categories
of Suicidal Ideation and Behavior and the C-SSRS
Category
C-SSRS Question (from eCRF)†
Suicidal ideation
Passive
1. Wish to be dead
Active - nonspecific (no method, 
intent, or plan)
2. Non-specific active suicidal 
thoughts
Active - method, but no intent or 
plan
3. Active suicidal ideation with any 
methods (not plan) without intent 
to act
Active - intent, with or without a 
method, but no plan
4. Active suicidal ideation with 
some intent to act, without 
specific plan
Active - method, intent and plan
5. Active suicidal ideation with 
specific plan and intent
Suicidal behavior
Preparatory 
actions 
toward 
imminent suicidal behaviors
Preparatory acts or behavior
Aborted attempt
Aborted attempt
Interrupted attempt
Interrupted attempt
Suicide attempt
Actual attempt
Completed suicide
Completed suicide
Self-injurious 
behavior, 
no 
suicidal intent
Has subject engaged in non-
suicidal self-injurious behavior?
†Data are "yes" or "no" 
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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