Clinical trial NCT05227118
Conditions: Alzheimer's Disease
Sponsor: Merck Sharp & Dohme LLC
Start date: 2022-07-01; Completion date: 2023-01-10
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of multiple ascending doses of MK-8189 in participants with Alzheimer's Disease (AD) with or without symptoms of agitation-aggression and/or psychosis.

Detailed description:

Arms: arm 1: Participants will be assigned to one of the following regimens: Titration 1: 4 mg x 2 tablets Days 1-3; 4 mg x 1 tablet \& 12 mg x 1 tablet Days 4-28 OR Titration 2: 4 mg x 2 tablets Days 1-3; 4 mg x 1 tablet \& 12 mg x 1 tablet Days 4-6; 12 mg x 2 tablets Days 7-28 OR Titration 3: 4 mg x 1 tablet Days 1-3; 4 mg x 2 tablets Days 4-6; 4 mg x 1 tablet \& 12 mg x 1 tablet Days 7-9; 12 mg x 2 tablets Days 10-28. arm 2: Participants will be assigned to one of the following regimens: Titration 1: 2 tablets Days 1-28 OR Titration 2: 2 tablets Days 1-28 OR Titration 3: 1 tablet Days 1-3; 2 tablets Days 4-28.
Interventions: intervention 1: MK-8189 intervention 2: Placebo
Intervention descriptions: intervention 1: MK-8189 administered orally once a day (QD) at a titration via tablet in 4 mg and 12 mg dose strengths intervention 2: MK-8189 matching placebo administered orally QD

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:                NCT05227118
Document Date:            21-Jul-2022            
A Randomized Clinical Study to Evaluate the
Safety and Tolerability of MK-
8189 in Participants with Alzheimer’s Disease
with or without Symptoms of Agitation-
Aggression and/or Psychosis


PRODUCT: MK-8189  
1
PROTOCOL/AMENDMENT NO.: 017-04
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21-JUL-2022
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Randomized Clinical Study to Evaluate the Safety and Tolerability of MK-
8189 in Participants with Alzheimer’s Disease with or without Symptoms of Agitation-
Aggression and/or Psychosis
Protocol Number: 017-04
Compound Number: MK-8189
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
159736
Approval Date: 21 July 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04
21-JUL-2022
Exclusion criterion #22 was modified to clarify the use of permitted prescribed 
medications, which could generate a positive UDS, is not exclusionary.
Amendment 03
03-MAY-2022
Per FDA feedback, inclusion criteria were updated to include specific criteria
for hypertension and orthostatic hypotension assessments. Exclusion criteria 
were updated to exclude participants with a family history of prolonged QTc 
syndrome. 
Amendment 02
25-FEB-2022
Based on newly available preliminary pharmacokinetic data, the first dosing 
regimen to be evaluated has been modified such that participants will be 
titrated up to MK-8189 16 mg/placebo as opposed to initially titrating 
participants up to MK-8189 24 mg/placebo.  
Amendment 01
28-JAN-2022
Added the Columbia Suicide Severity Rating Scale (C-SSRS) to every visit.
Original Protocol
10-DEC-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendments:
Exclusion criterion #22 was modified to clarify the use of permitted prescribed medications, which could generate a positive UDS, is 
not exclusionary.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria
The following bolded statement was 
added to Exclusion #22:  Participants 
must have a negative UDS (with the 
exception of cannabis and/or prescribed 
medications permitted at the discretion 
of the PI and Sponsor) prior to 
randomization.
As the intention of this criterion is to exclude 
participants using illicit drugs or participants with a 
history of drug abuse, participants may be included if 
using permitted prescribed medications which generate 
a positive UDS.  
5.1 Inclusion Criteria
Inclusion #1 and Inclusion #9 were 
updated to include clarifications per PCL 
#1.
N/A
6.5 Concomitant Therapy
Added the continued use of medications 
that may cause somnolence must be 
discussed between the investigator and 
Sponsor prior to MK-8189 administration.
As adverse events of transient somnolence have been 
reported following administration of MK-8189, the 
investigator and Sponsor will discuss the continued use 
of other medications known to cause somnolence to 
minimize the potential for additive somnolent effects.
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Section # and Name
Description of Change 
Brief Rationale 
8.3.2.1 Resting Vital Signs
Wording was updated to clarify Day 1 
predose vital signs should be taken within
3 hours prior to dosing. 
The language is now consistent with the Schedule of 
Activities footnote.
10.2 Appendix 2: Clinical 
Laboratory Tests
A sentence was added to indicate routine 
urinalysis and urine pregnancy tests will 
be done locally at the site.
The central lab vendor will only be sent urinalysis 
samples if a microscopic examination is required.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................17
1.3
Schedule of Activities...........................................................................................18
2
INTRODUCTION..........................................................................................................22
2.1
Study Rationale....................................................................................................22
2.2
Background ..........................................................................................................22
2.2.1
Pharmaceutical and Therapeutic Background .............................................22
2.2.2
Preclinical and Clinical Studies ...................................................................23
2.2.3
Ongoing Clinical Studies.............................................................................24
2.2.3.1
Protocol 011.......................................................................................24
2.2.3.2
Protocol 012.......................................................................................27
2.2.3.3
Protocol 015.......................................................................................28
2.2.3.4
Protocol 008.......................................................................................28
2.3
Benefit/Risk Assessment......................................................................................28
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................29
4
STUDY DESIGN............................................................................................................30
4.1
Overall Design......................................................................................................30
4.2
Scientific Rationale for Study Design.................................................................31
4.2.1
Rationale for Endpoints ...............................................................................32
4.2.1.1
Efficacy Endpoints.............................................................................32
4.2.1.2
Safety Endpoints................................................................................32
4.2.1.3
Pharmacokinetic Endpoints ...............................................................33
4.2.1.4
Planned Exploratory Biomarker Research.........................................33
4.2.1.4.1
Planned Genetic Analysis ........................................................33
4.2.1.5
Future Biomedical Research..............................................................33
4.2.2
Rationale for the Use of Comparator/Placebo .............................................34
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................34
4.3
Justification for Dose...........................................................................................34
4.3.1
Starting Dose for This Study........................................................................34
4.3.2
Maximum Dose/Exposure for This Study ...................................................35
4.3.3
Rationale for Dose Interval and Study Design ............................................35
4.4
Beginning and End-of-Study Definition ............................................................35
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4.4.1
Clinical Criteria for Early Study Termination .............................................36
5
STUDY POPULATION ................................................................................................36
5.1
Inclusion Criteria.................................................................................................36
5.2
Exclusion Criteria................................................................................................39
5.3
Lifestyle Considerations......................................................................................41
5.3.1
Meals and Dietary Restrictions....................................................................41
5.3.1.1
Diet Restrictions.................................................................................41
5.3.1.2
Fruit Juice Restrictions ......................................................................42
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................42
5.3.2.1
Caffeine Restrictions..........................................................................42
5.3.2.2
Alcohol Restrictions...........................................................................42
5.3.2.3
Tobacco Restrictions..........................................................................42
5.3.3
Activity Restrictions ....................................................................................42
5.4
Screen Failures.....................................................................................................42
5.5
Participant Replacement Strategy......................................................................42
6
STUDY INTERVENTION............................................................................................43
6.1
Study Intervention(s) Administered...................................................................43
6.2
Preparation/Handling/Storage/Accountability .................................................45
6.2.1
Dose Preparation..........................................................................................45
6.2.2
Handling, Storage, and Accountability........................................................45
6.3
Measures to Minimize Bias: Randomization and Blinding..............................46
6.3.1
Intervention Assignment..............................................................................46
6.3.2
Stratification.................................................................................................46
6.3.3
Blinding........................................................................................................46
6.4
Study Intervention Compliance..........................................................................47
6.5
Concomitant Therapy..........................................................................................47
6.5.1
Rescue Medications and Supportive Care ...................................................48
6.6
Dose Modification (Escalation/Titration/Other)...............................................48
6.7
Intervention After the End of the Study............................................................49
6.8
Clinical Supplies Disclosure................................................................................49
6.9
Standard Policies..................................................................................................49
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................49
7.1
Discontinuation of Study Intervention...............................................................49
7.2
Participant Withdrawal From the Study...........................................................50
7.3
Lost to Follow-up .................................................................................................51
8
STUDY ASSESSMENTS AND PROCEDURES........................................................51
8.1
Administrative and General Procedures ...........................................................52
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8.1.1
Informed Consent.........................................................................................52
8.1.1.1
General Informed Consent.................................................................52
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................53
8.1.2
Inclusion/Exclusion Criteria ........................................................................53
8.1.3
Participant Identification Card.....................................................................53
8.1.4
Medical History ...........................................................................................53
8.1.5
Prior and Concomitant Medications Review...............................................53
8.1.5.1
Prior Medications...............................................................................53
8.1.5.2
Concomitant Medications..................................................................53
8.1.6
Assignment of Screening Number...............................................................54
8.1.7
Assignment of Treatment/Randomization Number.....................................54
8.1.8
Study Intervention Administration ..............................................................54
8.1.8.1
Timing of Dose Administration.........................................................54
8.1.9
Discontinuation and Withdrawal .................................................................55
8.1.9.1
Withdrawal From Future Biomedical Research ................................55
8.1.10
Participant Blinding/Unblinding..................................................................55
8.1.11
Calibration of Equipment.............................................................................56
8.1.12
Domiciling (optional)...................................................................................56
8.2
Efficacy Assessments ...........................................................................................57
8.3
Safety Assessments...............................................................................................57
8.3.1
Physical Examinations.................................................................................57
8.3.2
Vital Signs....................................................................................................57
8.3.2.1
Resting Vital Signs ............................................................................57
8.3.2.2
Orthostatic Vital Signs.......................................................................58
8.3.3
Electrocardiograms ......................................................................................58
8.3.4
Clinical Safety Laboratory Assessments .....................................................59
8.3.5
Pregnancy Testing........................................................................................59
8.3.6
Suicidal Ideation and Behavior Monitoring.................................................60
8.3.6.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................60
8.3.7
Rater Expectations and Training for Clinical and Cognitive 
Assessments.................................................................................................60
8.3.8
Rosen-Modified Hachinski Ischemia Scale.................................................61
8.3.9
Mini Mental State Examination Second Edition .........................................61
8.3.10
Neuropsychiatric Inventory .........................................................................61
8.3.11
Monitoring of Extrapyramidal Symptoms...................................................61
8.3.12
Neurological Exam ......................................................................................61
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8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................61
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................62
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......64
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...64
8.4.4
Regulatory Reporting Requirements for SAE .............................................64
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................65
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................65
8.4.7
Events of Clinical Interest............................................................................65
8.5
Treatment of Overdose........................................................................................65
8.6
Pharmacokinetics.................................................................................................66
8.6.1
Blood Collection for Plasma MK-8189 and/or Metabolites Assay .............66
8.6.2
Blood Collection for Plasma Donepezil Assay............................................66
8.6.3
Blood Collection for Plasma Memantine Assay..........................................66
8.7
Pharmacodynamics..............................................................................................66
8.8
Biomarkers ...........................................................................................................66
8.8.1
Planned Genetic Analysis Sample Collection..............................................66
8.8.2
Exploratory Plasma Biomarkers for Alzheimer’s Disease Diagnosis 
Sample Collection........................................................................................67
8.9
Future Biomedical Research Sample Collection...............................................67
8.10
Visit Requirements...............................................................................................67
8.10.1
Trial Partner/Caregiver Participation...........................................................67
8.10.2
Screening (Visit 1).......................................................................................67
8.10.3
Baseline (Visit 2) .........................................................................................68
8.10.4
Intervention Period Visit (Visits 3-9) ..........................................................68
8.10.5
Discontinued Participants Continuing to be Monitored in the Study ..........68
8.10.6
Poststudy (Visit10).......................................................................................69
8.10.7
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................69
9
STATISTICAL ANALYSIS PLAN .............................................................................70
9.1
Statistical Analysis Plan Summary.....................................................................70
9.2
Responsibility for Analyses.................................................................................70
9.3
Hypotheses/Estimation ........................................................................................71
9.4
Analysis Endpoints...............................................................................................71
9.5
Analysis Populations............................................................................................71
9.6
Statistical Methods...............................................................................................72
9.7
Interim Analyses ..................................................................................................72
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9.8
Multiplicity ...........................................................................................................73
9.9
Sample Size and Power Calculations .................................................................73
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................74
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........74
10.1.1
Code of Conduct for Clinical Trials.............................................................74
10.1.2
Financial Disclosure.....................................................................................76
10.1.3
Data Protection.............................................................................................77
10.1.3.1
Confidentiality of Data ......................................................................77
10.1.3.2
Confidentiality of Participant Records...............................................77
10.1.3.3
Confidentiality of IRB/IEC Information............................................77
10.1.4
Publication Policy........................................................................................78
10.1.5
Compliance with Study Registration and Results Posting Requirements ...78
10.1.6
Compliance with Law, Audit, and Debarment ............................................78
10.1.7
Data Quality Assurance ...............................................................................79
10.1.8
Source Documents .......................................................................................80
10.1.9
Study and Site Closure.................................................................................80
10.2
Appendix 2: Clinical Laboratory Tests..............................................................81
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................83
10.3.1
Definition of AE ..........................................................................................83
10.3.2
Definition of SAE ........................................................................................84
10.3.3
Additional Events Reported.........................................................................85
10.3.4
Recording AE and SAE ...............................................................................85
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................89
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................90
10.5
Appendix 5: Contraceptive Guidance................................................................91
10.5.1
Definitions....................................................................................................91
10.5.2
Contraception Requirements........................................................................92
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................93
10.7
Appendix 7: Country-specific Requirements....................................................98
10.8
Appendix 8: Blood Volume Table ......................................................................99
10.9
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values .....100
10.10 Appendix 10: General (Full) and Targeted Neurological Exam ...................101
10.11 Appendix 11: Abbreviations .............................................................................108
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11
REFERENCES.............................................................................................................111
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LIST OF TABLES
Table 1
Study Interventions....................................................................................44
Table 2
Sample Allocation Schedule......................................................................46
Table 3
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................63
Table 4
Protocol-required Safety Laboratory Assessments....................................81
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LIST OF FIGURES
Figure 1
Study Schema.............................................................................................17
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Randomized Clinical Study to Evaluate the Safety and Tolerability of MK-
8189 in Participants with Alzheimer’s Disease with or without Symptoms of Agitation-
Aggression and/or Psychosis
Short Title: MK-8189 Safety and Tolerability in Participants with Alzheimer’s Disease with 
or without Symptoms of Agitation-Aggression and/or Psychosis
Acronym: N/A
Hypotheses, Objectives, and Endpoints:
There are no hypotheses for this study.
In male or female participants with Alzheimer’s Disease with or without symptoms of 
agitation-aggression and/or psychosis.
Objectives
Endpoints
Primary
•
To evaluate the safety and tolerability of 
multiple ascending doses of MK-8189 in 
participants with Alzheimer’s Disease 
with or without symptoms of agitation-
aggression and/or psychosis
•
Adverse events
•
Adverse experiences leading to 
discontinuation of study intervention
Secondary
•
Not applicable
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Neuropsychiatric Symptoms in Dementia
Population
Male and female participants, 65-85 years of age,
inclusive, with clinically probable Alzheimer’s Disease
with or without symptoms of agitation-aggression and/or 
psychosis 
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Blinding Roles
Investigator, Care Provider, Participants or Subjects
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 16 months from the time the first 
participant (or their legally acceptable representative) 
provides documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Up to approximately 28 participants will be allocated/randomized such that at least 16 
evaluable participants complete the study as described in Section 9.
Note: Greater than 16 participants may be required to complete the study if additional study 
data are needed to further understand the safety and tolerability profile of MK-8189 in the 
AD population.
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Intervention Groups and Duration:
Intervention 
Groups
Interven-
tion Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admini-
stration
Regimen/ Treatment 
Period/ Vaccination 
Regimen
Use
Active
MK-8189
4 mg & 12 mg
QD
Oral
Titration 1
4 mg x 2 tablets 
Days 1-3; 
4 mg x 1 tablet & 
12 mg x 1 tablet 
Days 4-28
Titration 2
4 mg x 2 tablets 
Days 1-3; 
4 mg x 1 tablet & 
12 mg x 1 tablet 
Days 4-6;
12 mg x 2 tablets
Days 7-28
Titration 3
4 mg x 1 tablet 
Days 1-3;
4 mg x 2 tablets
Days 4-6; 
4 mg x 1 tablet & 
12 mg x 1 tablet 
Days 7-9; 
12 mg x 2 tablets
Days 10-28
Experi-
mental 
Treatment
Placebo
Placebo
0 mg
QD
Oral
Titration 1 & 2
2 tablets
Days 1-28
Titration 3
1 tablet
Days 1-3;
2 tablets
Days 4-28
Control
Abbreviations:
QD=Once a day
Total 
Number of 
Intervention 
Groups/
Arms
2
Duration of 
Participation
Each participant will participate in the study for approximately 3 months 
from the time the participant provides documented informed consent 
through the final contact. After a screening phase of 42 days, each 
participant will receive assigned intervention for approximately 28 days. 
After the end-of-treatment each participant will be followed for 14 days.
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Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Insert Other Oversight Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations is in Appendix 11.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
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1.3
Schedule of Activities
Screening
Baseline
Intervention
Poststudya
Visit
1
2
3
4
5
6
7
8
9l
10
Scheduled Visit Day plus 
Window
Up to -42
-5 to -3
1
4
7
10j
14±1 21±1 28+1
LD+14+2
Administrative Procedures
Informed Consent – Study 
Participant
X
Section 8.1.1.1
Informed Consent – Trial 
Partner
X
Section 8.1.1.1
Informed Consent for FBR
X
Section 8.1.1.2
Participant ID Card
X
Section 8.1.3
Inclusion/Exclusion Criteria
X
X
Section 5.1 & Section 5.2
Specific criteria may be reviewed 
before randomization
Medical History (includes 
psychiatric history and 
substance usage)
X
Substances: Drugs, alcohol, tobacco, and 
caffeine
Section 8.10.2
Prior/Concomitant Medication 
Review
X-----------------------------------------------------------------------------------X
Section 6.5, Section 8.10.2
Assignment of 
Treatment/Randomization 
Number
X
Study Intervention 
Administrationb
X---------------------------------------------X
The last dose will be on Day 28 regardless
of the Study Day Visit 9 falls on.
Study Intervention 
Dispensing/Review
X
X
X
X
X
X
X
Collect prior medication bottle before 
dispensing new one.
Study Intervention Diary
Dispensing/Review
X
X
X
X
X
X
X
Review diary upon participants return to 
the CRU.
Daily Phone Callc
X---------------------------------------------X
Optional Domiciling
X---------------------------------------------X
See Section 8.1.12
Safety Procedures
Full physical examination
X
X
X
Height
X
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Screening
Baseline
Intervention
Poststudya
Visit
1
2
3
4
5
6
7
8
9l
10
Scheduled Visit Day plus 
Window
Up to -42
-5 to -3
1
4
7
10j
14±1 21±1 28+1
LD+14+2
Weight
X
X
X
BMI to be calculated only at Screening
Full Neurological Exam
X
X
Section 10.10
Targeted Neurological Examd
X
X
X
X
X
Section 10.10
Vital Signs (pulse rate, blood 
pressure) e, f
X
X
X
X
X
X
X
X
X
Section 8.3.2.1
Orthostatic Vital Signs (pulse
rate, blood pressure)e
X
X
X
X
X
X
X
X
X
Section 8.3.2.2
Vital Signs (respiratory rate, 
body temperature)e
X
X
X
X
X
X
X
Section 8.3.2.1
12-lead ECGe, f
X
X
X
X
X
X
X
Section 8.3.3
Serum hCG Pregnancy Test (as 
needed in WOCBP only)
X
Section 5.1 & Section 8.3.5
Urine hCG Pregnancy Test (as 
needed in WOCBP Only)
X
X
X
X
X
X
Section 5.1 & Section 8.3.5
Serum FSH (as need in 
WONCBP only)
X
HIV, Hepatitis B and C Screen 
(per site SOP)
X
UDS/BDS (per site SOP)
X
X
Laboratory Safety Tests
(hematology, chemistry, 
urinalysis)g
X
X
X
X
X
X
X
Section 10.2
Columbia Suicide Severity 
Rating Scale (C-SSRS) –
Baseline Version
X
Section 8.3.6.1
Columbia Suicide Severity 
Rating Scale (C-SSRS) – Since 
Last Assessment Versiond
X
X
X
X
X
X
X
X
X
Section 8.3.6.1
Neuropsychiatric Inventory
(NPI)d, h
X
X
Section 8.3.10 & Section 8.10.2
Mini Mental State Examination
(MMSE-2)d
X
X
Section 8.3.9
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Screening
Baseline
Intervention
Poststudya
Visit
1
2
3
4
5
6
7
8
9l
10
Scheduled Visit Day plus 
Window
Up to -42
-5 to -3
1
4
7
10j
14±1 21±1 28+1
LD+14+2
Rosen-Modified Hachinski 
Ischemic Score (MHIS)
X
Section 8.3.8
Barnes Akathisia Rating Scale
(BARS)d, i
X
X
X
X
X
Xi
Section 8.3.11
Abnormal Involuntary 
Movement Scale (AIMS)d, i
X
X
X
X
X
Xi
Section 8.3.11
Simpson Angus Scale (SAS) d, i
X
X
X
X
X
Xi
Section 8.3.11
AE/SAE review
X----------------------------------------------------------------------------------X
Pharmacokinetics
Blood for Plasma MK-8189 
and/or Metabolites Assay
X
X
X
X
X
On days noted, 2 blood samples will be 
collected:
1) prior to dosing (fasted)  
2) 2-4 hours post dose
Note: If Visit 9 occurs on Day 29, , only 1
blood sample will be collected as there 
will be no dose on this day.
Blood for Plasma Donepezil
Assayk
X
X
X
X
X
Blood collected prior to dosing (fasted).
Blood for Plasma Memantine 
Assayk
X
X
X
X
X
Blood collected prior to dosing (fasted)
Biomarkers
Blood for Exploratory Plasma 
Biomarkers for AD Diagnosis
X
See Section 8.8.2
Blood for Genetic Analysism
X
Collect predose from enrolled participants 
only.
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Screening
Baseline
Intervention
Poststudya
Visit
1
2
3
4
5
6
7
8
9l
10
Scheduled Visit Day plus 
Window
Up to -42
-5 to -3
1
4
7
10j
14±1 21±1 28+1
LD+14+2
AE=adverse event; BDS=blood drug screen; C-SSRS=Columbia-Suicide Severity Rating Scale; DNA=deoxyribonucleic acid; ECG=electrocardiogram; FBR=future biomedical 
research; FSH=follicle stimulating hormone; hCG=human chorionic gonadotropin; ID=identification; SAE=serious adverse event; SOP=standard operating procedure; 
UDS=urine drug screen; VS=vital signs; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential
a.
Poststudy visit procedures should also be performed for participants who discontinued early from study intervention.
b.
QD dosing at approximately the same time each morning (Days 1-28) either in the CRU or at home. During scheduled CRU visits, participants should be 
administered study intervention fasted in the CRU. At home study intervention administration will be with or without food and will be recorded in study 
intervention diary by the participant/trial partner. Participants will be supervised for at least 6 hours following the first administration of study intervention 
and following the first administration of each study intervention titration (see Section 8.1.8).
c.
While participants are outpatient, site staff will call participants daily to check study administration compliance, review AEs, and remind participants of
their next scheduled visit (if applicable).
d.
Collected after dosing and an optional light breakfast on study treatment administration days.
e.
Collected prior to dosing on study treatment administration days.
f.
Vital sign measurements at Screening will be taken in triplicate. Day 1 ECGs and vital sign measurements will be taken in triplicate within 3 hours prior to 
dosing. Single ECGs and vital sign measurements will be collected on all other days. 
g.
Safety laboratory Baseline results will be reviewed prior to Day 1 dosing. All safety laboratory collection will be fasted and prior to dosing on study 
treatment administration days.
h.
For participants that must washout of prior antipsychotic treatment at Screening, the NPI is to be repeated prior to randomization after a minimum 2-week 
washout or 5 half-lives, whichever is longer.
i.
Poststudy assessment required only if clinically meaningful changes on Day 28.
j.
Visit 6 (Day 10) will only occur for Titration 3. 
k.
Sample will only be taken for participants currently taking donepezil and/or memantine.
l.
Every effort should be made to have participants return for Visit 9 on Day 28 however if necessary, participants may return on Day 29 to have all Visit 9 
assessments completed.  Participants will not be dosed on Day 29.
m.
This sample will be drawn for CYPC29 and for planned analysis of the association between genetic variants in DNA and drug response. If the IRB/IEC does not approve of 
the planned analysis of the association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, data analysis will be limited to
CYPC29. Leftover extracted DNA will be stored for FBR if the participant (or legally acceptable representative) provides documented informed consent for FBR.
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2
INTRODUCTION
2.1
Study Rationale
MK-8189, a PDE10A inhibitor, is being developed for the treatment of neuropsychiatric 
symptoms in dementia. Prior to conducting a larger proof of concept study, this study will 
explore the safety and tolerability of MK-8189 in the Alzheimer’s disease population with or 
without agitation-aggression and/or psychosis.
2.2
Background
Refer to the IB for detailed background information on MK-8189.
2.2.1
Pharmaceutical and Therapeutic Background
MK-8189 is a potent and selective inhibitor of PDE10A being developed as a novel
therapeutic for the treatment of schizophrenia as well as neuropsychiatric symptoms in 
dementia. In a Phase 2a study, POC has been established for the schizophrenia indication. 
The objective of this first study is to evaluate safety and tolerability in a similar patient 
population (participants with or without agitation-aggression and/or psychosis associated 
with Alzheimer’s disease) prior to conducting a larger POC study.  Current treatment for 
neuropsychiatric symptoms associated with dementia often involves the off-label use of 
atypical antipsychotics (AAPs). However, AAPs have a black box warning in the US with 
regards to the increased risk of death among elderly patients with dementia-related psychosis, 
which ultimately creates a therapeutic unmet need in elderly patients with dementia-related 
agitation and aggression [Marcinkowska, M., et al 2020]. Increased availability of D2 and D3 
receptors in the striatum as well as cortical dysfunction have been implicated in the 
pathophysiology of AAD [Kales, H. C., et al 2015].  The PDE10A enzyme metabolically
inactivates the ubiquitous second messengers, cAMP and cGMP [Bender, A. T. and Beavo, J. 
A. 2006] and is highly expressed in the target nucleus of the corticostriatal pathway, the
striatum and to a lesser extent the cortex and hippocampus [Seeger, T. F., et al 2003]. 
Preclinical pharmacology studies demonstrate that PDE10A inhibition increases
cAMP/cGMP signaling in the striatum which results in activation of the D2 pathway and 
potentiation of cortical striatal signaling leading to increased behavioral control [Grauer, S. 
M., et al 2009] [Schmidt, C. J., et al 2008]. 
PDE10A inhibitors have also been shown to decrease psychomotor activity, reverse deficits 
in pre-pulse inhibition, and inhibit conditioned avoidance responding in assays that are 
hypothesized to translate to efficacy on psychosis, agitation, and aggression [Smith, S. M., et 
al 2013] [Grauer, S. M., et al 2009]. In addition, PDE10A inhibitors have beneficial effects 
on preclinical measures of cognitive performance in nonhuman primates [Smith, S. M., et al 
2013] [Vardigan, J. D., et al 2016]. In the Phase 2a POC study, in an exploratory analysis, 
MK-8189 showed nominal improvement in the PANSS Marder Factor Hostility/Excitement 
Symptom Score and Disorganized Thought Symptom Score. Thus, based on preclinical and 
clinical evidence, MK-8189 will be evaluated for the treatment of neuropsychiatric 
symptoms in dementia.
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2.2.2
Preclinical and Clinical Studies
Preclinical and clinical study information can be found in the MK-8189 IB.
Summary of Completed Clinical Studies  
As part of the Phase 1 program, three single-dose clinical studies, one DDI study, and two
multiple-dose clinical studies have been completed with MK-8189. Overall, 146 participants
have received at least one dose of MK-8189; 71 healthy participants and 75 participants with
schizophrenia. Single doses of MK-8189 up to 6 mg have been given to 48 healthy men, 22
with an IR formulation and 26 with a CR formulation. Ten healthy male and female 
participants received multiple doses titrated up to 12 mg over 14 days (P003 Part 3) and 12
healthy male and female participants received doses titrated up to 24 mg over 18 days (P007 
Panel A). Thirty-three male and female participants with schizophrenia were titrated up to 
doses of 16 mg over 14 days (P003), 25 participants with schizophrenia were titrated up to 24 
mg over 18 days (P007 Panels B and C) and 17 participants with schizophrenia were titrated 
up to 48 mg over 15 days (P007 Panel D). All multiple-dose studies were conducted with a
CR formulation.
MK-8189 was generally well tolerated across the Phase 1 studies. The most common
treatment-related adverse events [AEs] (≥5%) following treatment of MK-8189 (n=146) 
across the completed 6 Phase 1 studies in healthy participants and participants with 
schizophrenia were headache (16.4%), somnolence (12.3%), decreased appetite (10.3%),
nausea (9.6%), fatigue (8.9%), dizziness (8.9%), vomiting (6.2%), diarrhea (6.2%), akathisia 
(6.2%), and anxiety (6.2%). Most AEs were mild to moderate in severity. There were no 
deaths and 2 SAEs. One healthy participant experienced an SAE of gastroenteritis in P003 
which was not considered treatment related. The other SAE of severe treatment-related 
psychosis occurred in a participant with schizophrenia following titration up to and 
administration of the 36 mg dose (P007). The participant discontinued MK-8189 treatment, 
was hospitalized, and received treatment with an antipsychotic and anxiolytic. The SAE 
resolved within 6 days.
In the Phase 2 study, P005, most episodes of dystonia lasted less than one day, with three
events lasting one or more days. Only one participant discontinued due to an AE of dystonia.
In summary, eight participants (8.9%) had an AE of dystonia and 2 participants (2.2%) had
an AE of oromandibular dystonia. The intensities of the dystonia AEs were mild and
moderate with most reported as mild. Onset of dystonia occurred mostly during the
intervention titration period at the 4 mg, 8 mg, and 12 mg dose levels with a duration range
of less than 1 day for most events and up to six days. One participant discontinued study 
intervention due to dystonia. Two participants experienced 2 episodes of dystonia each
during the intervention titration period. One participant experienced both events during the 8 
mg dose level (mild, moderate), while another participant experienced one event during the 4 
mg (moderate) and one during the 8 mg (mild) dose level. The AEs of dystonia, except for
one incident, were considered related to study intervention by the investigators.
Individual studies are summarized in the IB.
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Summary of MK-8189 Pharmacokinetics
Following multiple doses of the controlled release formulation, MK-8189 exposure increased 
approximately proportionally with dose over the range of doses tested (2 to 48 mg) in all 
populations. Median Tmax of MK-8189 as monotherapy ranged from 10 to 24 hours with a 
t1/2 of approximately 10.9 hours. Based on completed studies, data suggest that the 
exposures at steady state for a given dose are generally comparable between healthy 
participants and participants with schizophrenia administered MK-8189 as monotherapy.
Preliminary results from the ongoing study P011 (described in 2.2.3) suggest that PK 
exposures in elderly participants with and without schizophrenia are similar to one another 
and similar to those observed in adult participants < 60 years of age with schizophrenia. 
While there was significant overlap in the individual PK parameter values for elderly and 
non-elderly participants, in healthy elderly participants, on average, C24 values were 
approximately 50% higher than C24 values in non-elderly adults and elderly participants 
with schizophrenia. 
MK-8189 is a CYP3A substrate and in a DDI study (P006) the coadministration of extended 
release 240-mg diltiazem, a moderate CYP3A inhibitor, increased MK-8189 AUC and Cmax 
by approximately 2-fold and 1.3-fold, respectively.  In another ongoing DDI study (P015, 
described in 2.2.3) the coadministration of itraconazole, a strong CYP3A inhibitor, increased 
MK-8189 AUC and Cmax by approximately 1.2-fold and 1.14-fold, respectively, and were 
generally consistent with the results observed in the diltiazem study.  Collectively, these 
results confirm that MK-8189 is a CYP3A substrate.
2.2.3
Ongoing Clinical Studies
As of October 29, 2021, three Phase 1 trials and one Phase 2 trial are ongoing. All data
presented are preliminary.
2.2.3.1
Protocol 011
P011 is a Phase 1 multiple-dose randomized (Panels A/B/C/D/E - 3 active:1 placebo; Panel 
F/G - 5 active:1 placebo), double-blind, placebo-controlled, multicenter, 2-part study. Part 1
(Panel A/B/C) is evaluating the safety and tolerability of different titration regimens or 
initiating MK-8189 treatment without titration in participants ≤60 years of age with 
schizophrenia. Part 2 is evaluating the multiple dose safety, tolerability, and PK of MK-8189 
in elderly participants with schizophrenia (Panel D and Panel E) and healthy elderly 
participants (Panel F and Panel G) between 61 and 80 years of age (inclusive).  Panel E and 
Panel G will explore safety and tolerability at different titration regimens and will only be 
initiated after a safety and tolerability review from Panel D and Panel F, respectively.
In Part 1, Panel A, participants with schizophrenia initiated dosing with 16 mg of MK-
8189/placebo for 3 days and then were escalated to 24 mg/placebo for 4 days. In Panel B,
participants with schizophrenia initiated dosing with 24 mg of MK-8189/placebo (no 
titration) for 7 days. Part 1 is clinically complete and all data are preliminary and blinded. No
SAEs or deaths were reported.
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In Panel A, all 8 participants enrolled completed treatment. Most AEs were mild, and no AEs 
were severe in intensity. All AEs resolved. Of the 8 participants, one participant did not dose 
escalate to 24 mg/placebo due to moderate somnolence which lasted for 3 days. For the 
duration of the somnolence AE, the participant was also receiving hydroxyzine, a sedating 
antihistamine. Two participants reported an AE of dystonia. One participant reported mild 
transient dystonia which began 14 hours after the first dose and lasted 2 days. The dystonia 
was treated with benztropine until it resolved. The participant continued dosing with MK-
8189/placebo without recurrence of dystonia. Another participant reported mild transient 
dystonia which began 6.5 hours following the first dose and resolved in 22 hours. While 
experiencing dystonia the participant was treated with benztropine. The participant continued 
to dose with MK-8189/placebo and escalated to 24 mg/placebo without a recurrence of 
dystonia. AEs reported (including those already discussed) considered related to study drug
included decreased appetite (n=2), dystonia (n=2) somnolence (n=2), nightmare (n=1),
worsening psychosis (n=1), and insomnia (n=1).
In Panel B, enrollment and dosing are complete. Participants received MK-8189 24 
mg/placebo Days 1-7. Eighteen participants were randomized and 14 completed treatment 
per protocol. Of the 4 participants that discontinued treatment, 3 withdrew consent and 1 
participant discontinued due to AEs of nausea and vomiting that were not considered related 
to treatment. This participant had a history of gastroesophageal reflux disease that was 
ongoing throughout the trial. The other participants withdrew consent. No AEs were 
considered severe and the majority of AEs were mild. Except for an unrelated AE of 
ligament sprain, all AEs resolved. AEs considered related to treatment included somnolence 
(n=2), hypertonia (n=1), decreased appetite (n=1), musculoskeletal stiffness (n=1) and 
increased ALT (n=1). The participant with the AE of elevated ALT had an elevated 
screening value of 61 IU/L (normal range 7-52 IU/L). The Day -1 predose ALT value was 
also elevated (98 IU/L) and continued to increase on Day 7 (116 IU/L) and Day 9 (133 IU/L).
At the poststudy the ALT was still elevated but below the predose value (71 IU/L). ALP
(normal range 34-104 IU/L) followed a similar pattern with elevations at screening (130
IU/L), Day -1 predose (136 IU/L), Day 7 (143 IU/L), Day 9 (134 IU/L) and at the poststudy 
visit (124 IU/L). While AST was within the normal range (13-39 IU/L) at screening (26 
IU/L) and Day -1 predose (37 IU/L), values were elevated above the normal range on Day 7 
(44 IU/L) and Day 9 (51 IU/L). At the post study visit, AST was within the normal range (26 
IU/L). Bilirubin was normal throughout the study. Preliminary data suggest initiation of MK-
8189 at a 16 mg or 24 mg dose was generally well tolerated. No AEs of akathisia or dystonia
were reported. 
Panel C was not conducted per protocol since the regimens in Panel A and B were generally
well tolerated.
Treatment is ongoing in Part 2. Panel D is currently enrolling elderly participants with
schizophrenia. Participants will receive MK-8189 8 mg/placebo Days 1-3, MK-8189 16
mg/placebo Days 4-6 and MK-8189 24 mg/placebo Days 7-13. Twelve participants have 
been dosed to date. No deaths or SAEs have been reported. Most AEs were mild or moderate 
and 1 AE was severe (described below). All AEs reported to date have resolved except an 
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AE of a small forehead bump considered not treatment related. Four participants have 
discontinued the trial: 
One participant withdrew consent, and no treatment-related AEs were reported for this 
participant.
One participant reported an AE of severe somnolence which began following the 8 
mg/placebo dose and resolved on Day 3 following administration of the 8 mg/placebo dose.
On Day 3 following treatment with 8 mg/placebo, the participant had an AE of moderate 
dystonia which resolved in 2 days with a single-dose of cyclobenzaprine. This participant 
reported moderate akathisia following treatment with 8 mg/placebo which continued for 3
weeks. This participant had drug interrupted and subsequently discontinued following the
second 16 mg/placebo dose due to moderate treatment-related AEs of dermatitis and
conjunctivitis. No other treatment-related AEs were reported.
One participant experienced dystonia of the throat after the Day 3 16 mg/placebo dose which 
was treated with benztropine and alleviated the participant’s difficulty to swallow.  The 
participant continued to have tightness of throat muscles which the investigator considered to 
be mild dystonia which persisted for 2 weeks. The participant discontinued treatment prior to 
the Day 4 dose. The participant had also reported hypoesthesia, dizziness, dysgeusia and ear 
discomfort which were considered treatment related.
Another participant discontinued due to an AE of internal restlessness in the predawn hours
of Day 7. This participant also reported involuntary movement of lower extremities the 
evening prior. These AEs led the participant to withdrawal from the study and the participant 
discontinued dosing prior to the first dose of 24 mg/placebo.  This panel is still actively 
dosing and the following treatment related AEs have been reported to date (includes AEs 
which have been reported above); dystonia (n=2), internal restlessness (n=2), somnolence 
(n=1), akathisia (n=1), conjunctivitis (n=1), dermatitis (n=1), dizziness (n=1), dysgeusia 
(n=1), ear discomfort (n=1), oral hypoesthesia (n=1) and involuntary movement of lower 
extremities (n=1)
Panel F is clinically complete and enrolled 6 healthy elderly participants. The treatment 
regimen was the same as Panel D. Most AEs were mild in intensity and no severe AEs were 
reported. No deaths or SAEs have been reported. Except for hyponatremia (discussed below), 
all other reported AEs resolved. One subject discontinued the trial due to treatment related 
AEs of nausea, vomiting, dyspepsia, and hyponatremia. This participant also reported 
diarrhea prior to the onset of nausea and vomiting. The hyponatremia was resolving at the 
time of participant discharge. One participant was down-titrated from 24 mg/placebo to 16 
mg/placebo following the onset of moderate EPS. The EPS had a duration of approximately 
2 weeks and was managed intermittently with benztropine. This participant completed 
treatment and the study. The treatment-related AEs reported (including those discussed
above) were decreased appetite (n=1), dizziness (n=1), nausea (n=1), vomiting (n=1), 
dyspepsia (n=1), hyponatremia (n=1), somnolence (n=1), involuntary muscle contractions 
(n=1), tremor (n=1), extrapyramidal disorder (n=1) and salivary hypersecretion (n=1).
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Panel G completed dosing in healthy elderly participants. Participants received MK-8189 16
mg/placebo Days 1-3, MK-8189 24 mg/placebo Days 4-10. Fifteen participants were
enrolled. No deaths or SAEs were reported. Most AEs were mild and 3 AEs were severe (2 
participants with severe somnolence and 1 participant with severe hypnagogic hallucination) 
and are described below. All AEs resolved. Three subjects discontinued due to treatment 
related AEs. The evening of Day 7, following 2 days of dosing with MK-8189 24 
mg/placebo, through the early morning hours of Day 8, one participant reported mild 
akathisia (~20 hour), moderate tactile hallucinations (15 min), mild palpitations (2 min) and 
bilateral hand hyperhidrosis (5 hour) and in the predawn hours the participant reported severe
hypnagogic hallucinations (5 min). The participant did not report these AEs until the morning 
of Day 8, at which time the dose was held and the participant received treatment with 
benztropine and all AEs resolved. Later in the afternoon of Day 8, the participant had a 
recurrence of akathisia, bilateral hand hyperhidrosis, tactile hallucinations and reported sinus 
tachycardia, all which resolved with the treatment with benztropine. On Day 8 the participant 
discontinued treatment due to these AEs. This participant also had a brief episode (~30 min) 
of mild oral mandibular dystonia on Day 1 (16 mg/placebo) that resolved spontaneously.  
Another subject discontinued due to an AE of mild akathisia (~24 hour) following treatment 
with 16 mg/placebo dose on Day 3 which resolved with benztropine.
One subject discontinued after 2 days of dosing at the 24 mg/placebo dose (Day 5) due to 
moderate oromandibular dystonia (~6 hours) and moderate anxiety (<24 hours duration); 
both AEs responded to treatment.
In addition to the participant with the brief but severe hypnagogic hallucination, 2 
participants were reported to have severe somnolence. In both participants the somnolence 
began within 2 hours of their first dose of study intervention (16 mg/placebo) and resolved in 
≤ 10 hours. All treatment related AEs reported (including those discussed above) were
somnolence (n=4), akathisia (n=3), oromandibular dystonia (n=2), myalgia (n=2), tremor 
(n=2), headache (n=2), involuntary muscle contractions (n=2), tactile hallucination (n=1), 
palpitations (n=1), bilateral hand hyperhidrosis (n=1), hypnagogic hallucination (n=1), sinus 
tachycardia (n=1), restlessness (n=1), dyspepsia (n=1), vomiting (n=1), paresthesia (n=1), 
insomnia (n=1), apathy (n=1) dysphonia (n=1), salivary hypersecretion (n=1), anxiety (n=1), 
bilateral hands rapid alternating movements (n=1) and smell sensitivity (n=1). 
2.2.3.2
Protocol 012
P012 is an open-label single-dose Phase 1 study to evaluate the safety, tolerability, and PK in
participants with hepatic impairment and matched healthy participants. To date 6 participants 
with moderate hepatic impairment have received a single 4 mg dose of MK-8189. No SAEs 
or deaths have been reported. The following treatment related AEs (duration) have been 
reported by 3 participants: One participant had mild AEs of a hot flush (40 min), vomiting (1 
episode) and leg cramps (10 min). One participant had a mild AE of dizziness (<1 day)
which resulted in a fall. One participant had mild AEs of headache (<1 day), anxiety (30 min)
and affect lability (30 min).
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2.2.3.3
Protocol 015
P015 is a DDI trial to evaluate the effect of multiple-doses of itraconazole, a strong CYP3A
inhibitor, on the single-dose PK of MK-8189. In Period 1, 14 participants received a single
dose of 4 mg of MK-8189. In Period 2, participants received a loading dose of itraconazole
of 200 mg BID on Day 1 and received 200 mg QD on Days 2 to 8. On Day 4, participants
were coadministered 4 mg of MK-8189 with itraconazole. No deaths or SAEs have been 
reported. Of the 14 participants, 7 have reported at least one AE considered related to MK-
8189 and/or itraconazole (duration). One participant discontinued due to AE of mild rash (2
days) to itraconazole. In Period 1 on Day 1, one participant reported mild AEs of somnolence 
(1 day) and dizziness (8.5 hours) considered related to MK-8189. In Period 2 on Day 4, this 
same participant reported mild restlessness (20 hours) and an ECI of dystonia (12 hours) of 
moderate severity considered related to MK-8189 and itraconazole. The dystonia resolved 
without treatment. Following a blood draw, two other AEs, mild presyncopal event (5 min) 
and mild faint sensation (12 min), were also reported by this participant but neither were
considered related to study intervention. One other participant reported an AE of mild 
dystonia (~ 2 days) which began in Period 2 on Day 5. The dystonia resolved without 
treatment and was considered related to MK-8189 and itraconazole. One participant had mild 
AEs of somnolence (2 days) and diarrhea (9 days). The somnolence began in Period 1 on 
Day 1 and was considered related to MK-8189, and the diarrhea began in Period 2 prior to 
co-dosing of MK-8189 and was considered related to itraconazole. Three other participants 
reported mild diarrhea (5 hours, 3 days and 6 days) which began in Period 2 prior to MK-
8189 administration.
2.2.3.4
Protocol 008
P008 is an ongoing Phase 2B randomized, double-blind, placebo- and active controlled trial
of the efficacy and safety of MK-8189 in adult participants 18 to 50 years of age who are
experiencing an acute episode of schizophrenia according to DSM-V™criteria.
A total of 576 participants from approximately 80 sites across the USA, Europe and Asia will   
be recruited into this trial. Treatment duration will be for a period of 12 weeks and includes a
6-week acute treatment period followed by a 6-week extension period. Eligible participants
will be randomized to receive one of five treatment sequences with target doses of MK-8189
(8 mg, 16 mg, and 24 mg QD), risperidone (6 mg QD), or placebo. Placebo completers at 6
weeks will be allocated to receive MK-8189 24 mg for the remainder of the trial. This trial is
being conducted in a hospital/acute care setting followed by an outpatient setting. 
Recruitment was initiated in December 2020.
2.3
Benefit/Risk Assessment
Participants in clinical studies will not receive direct benefit from treatment during 
participation as clinical studies are designed to provide information about the safety and 
properties of an investigational medicine. 
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Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There are no hypotheses for this study.  
In male or female participants with Alzheimer’s Disease with or without symptoms of
agitation-aggression and/or psychosis.
Objectives
Endpoints
Primary
•
To evaluate the safety and tolerability of 
multiple ascending doses of MK-8189 in 
participants with Alzheimer’s Disease 
with or without symptoms of agitation-
aggression and/or psychosis
•
Adverse events
•
Adverse experiences leading to 
discontinuation of study intervention
Secondary
•
Not applicable
Tertiary/Exploratory
•
To evaluate the trough exposures of 
MK-8189
•
C24hr
•
To investigate the relationship between 
CYP2C9 genetic polymorphs and the 
PK of MK-8189. Genetic variation in 
CYP2C9 may be analyzed for 
association with any laboratory or 
clinical data collected in this study
•
Germline genetic variation in CYP2C9 
and association to clinical data collected 
in this study
•
To explore the relationship between 
genetic variation and response to the 
treatment administered, and mechanisms 
of disease. Variation across the human 
genome may be analyzed for association 
with clinical data collected in this study
•
Germline genetic variation and 
association to clinical data collected in 
this study
•
To explore changes in cognitive 
functioning, neuropsychiatric status and 
extrapyramidal symptomatology
•
MMSE-2 and NPI, BARS, AIMS, SAS
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, parallel-group, multisite, double-blind study of 
MK-8189 in participants with Alzheimer’s Disease with and without neuropsychiatric 
symptoms.  To most closely simulate the patient population for the indication evaluated, it is 
preferred that participants included in this study have symptoms of agitation-aggression or 
psychosis (defined as a severity of score ≥1 and frequency score of ≥2 on the NPI Agitation-
Aggression and/or Delusions and/or Hallucinations domains). 
Up to approximately 28 participants will be enrolled to ensure at least 16 participants 
complete the study. Note: Greater than 16 participants may be required to complete the study 
if additional study data are needed to further understand the safety and tolerability profile of 
MK-8189 in the AD population. 
This is an outpatient study as participants will be dosing at home and will require visits to the 
CRU per the SoA.  Therefore, participants must have a trial partner/caregiver as described in 
the inclusion/exclusion criteria.
The first 8 participants will be randomized to receive MK-8189 8 mg/placebo QD Days 1-3, 
16 mg/placebo QD Days 4-28 (Titration 1). Participants may be down-titrated by the 
investigator at any time without consultation of the Sponsor in the case of safety or 
tolerability issues.  Changes in the dosage regimen will be communicated to the Sponsor and 
the Sponsor will document changes in a Protocol Clarification Letter. After approximately 8 
participants have completed approximately 3 weeks of dosing, AE data will be reviewed to 
determine whether to continue to enroll participants at the Titration 1 regimen or whether 
participants should receive an alternate dosing regimen (e.g., MK-8189 8 mg/placebo QD 
Days 1-3, 16 mg/placebo QD Days 4-6, 24 mg/placebo Days 7-28 (Titration 2) OR MK-8189 
4 mg /placebo QD Days 1-3, 8 mg/placebo Days 4-6, 16 mg Days 7-9, 24 mg Days 10-28
(Titration 3)). Prior to initiation of an alternate regimen that includes escalation to a dose 
above 16 mg, the PK data from the initial cohort of participants will be required to be 
reviewed.  The decision will be made jointly between the investigators and the Sponsor and 
any change to the dosing regimen will be documented in a Protocol Clarification Letter. See 
section 6.6 for allowed dose modifications.
As MK-8189 is not a treatment for Alzheimer’s disease, participants may remain on their 
current Alzheimer’s treatment as outlined in Section 6.5 Concomitant Therapy.
Outpatient visits are required per the SOA. Visits required for the first dose of study 
administration and any day when the dose is to be titrated-up, participants must be observed 
by site staff for at least 6 hours following the treatment of study intervention. The 
investigator will have discretion to domicile the participant or determine a longer duration of 
observation to ensure participant safety. Following administration of study intervention at the
CRU, the participant should remain seated or semi-recumbent or ambulate with supervision.
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If the investigator considers it appropriate for an individual participant to be domiciled (i.e.,
exacerbation of dementia or behavioral symptoms not expected), the participant may be 
domiciled through the titration period or for the entire intervention period (Day 1-28) (refer 
to Section 8.1.12).  Any other duration of domiciling should be discussed with the Sponsor, 
except when considered necessary for participant safety.
Because this is a Phase 1 assessment of MK-8189 in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.10.7 for examples of modifications permitted within the protocol 
parameters.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
MK-8189 will be evaluated for the treatment of neuropsychiatric symptoms in dementia.
Prior to the conduct of a larger POC study, this smaller study (n=28, randomized such that 21 
are on MK-8189 and 7 on placebo) will be conducted as an initial assessment of safety and 
tolerability in a similar patient population. 
This will be a randomized, placebo-controlled study to ensure an objective assessment of 
safety and tolerability. An outpatient trial is preferred as changing the environment in this 
patient population may adversely affect cognitive status. However, if deemed appropriate by 
the investigator, a participant may be domiciled as described in Section 8.1.12.  An ongoing 
trial has evaluated MK-8189 doses titrated up to 24 mg over 10 to 13 days in 21 healthy
elderly participants and preliminary blinded data suggest MK-8189 is generally well 
tolerated, supporting outpatient dosing (refer to Section 2.2). However, as the tolerability 
may differ in a population with AD, the study will first enroll only 8 participants to ensure 
tolerability of the selected treatment regimen. If tolerability issues are found, a more 
conservative regimen will be administered to the remaining participants. At any time during 
treatment, the investigator may choose to down-dose a participant. The assessment of MK-
8189 safety and tolerability from this trial, in which participants with AD with or without 
agitation-aggression and/or psychosis will receive study treatment for one month, will be 
used to determine if longer term safety and efficacy trials can be supported. Daily telephone 
calls by study staff to the participant, weekly safety evaluations and the requirement for 
participants to have a trial partner/caregiver will help ensure participant safety and 
compliance with study intervention administration and protocol requirements throughout the 
study.
As efficacy will not be assessed in this study, participants without or with neuropsychiatric 
symptoms (agitation-aggression or psychosis) will be permitted in the study. Those who are 
currently taking antipsychotics to control neuropsychiatric symptoms may be enrolled if it is 
clinically appropriate to have participants wash off their medication (e.g., participant is not 
tolerating current treatment or is not likely receiving benefit from the treatment).  This will 
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ensure the safety and tolerability profile of MK-8189 is understood without confounding 
antipsychotic treatment.  However, if during the study, neuropsychiatric symptoms worsen, 
rescue therapy specified may be administered.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Not Applicable
4.2.1.2
Safety Endpoints
Safety and tolerability will be assessed throughout the study by monitoring participants for 
clinical AEs as well as through the conduct of physical and neurological examinations, 12-
lead ECGs, VS, and laboratory safety tests. 
The C-SSRS will be administered to monitor mood and suicidal ideation and behavior in all 
trial participants (see Section 4.2.3).
Exploratory Safety Endpoints
As EPS are associated with antipsychotics and have been observed in the MK-8189 clinical 
program, the BARS, AIMS and SAS will be used to evaluate EPS throughout the study per 
the SoA. The BARS, comprised of objective and subjective items, as well as a global rating, 
assesses drug-induced akathisia. The global rating score ranges from 0 to 5, where 0 
represents no evidence for akathisia, a score of 3 is moderate akathisia and a score of 5 is 
severe akathisia. The AIMS includes 12 items and uses a 5-point scale to assess abnormal 
movement in 3 areas (orofacial, extremities, trunk). The SAS is comprised of 10 items and 
uses a 5-point scale to measure symptoms of parkinsonism or parkinsonian side effects 
(including rigidity, tremor, bradykinesia/akinesia, and salivation).
The Mini-Mental State Exam, Edition 2, Standard Form (MMSE-2) assesses orientation, 
attention, memory, language, and visual-spatial skills and has a score range of 0-30, where 
higher scores reflect better performance. A score between 21 to 26 typically indicates that a 
participant is experiencing mild cognitive dysfunction impairment, while scores in the range 
of 10-20 are indicative of participants with more moderate cognitive impairment. The 
MMSE-2 administered at screening will be used for inclusion to ensure that enrolled 
participants fall into the cognitive impairment categories of mild to moderate severity. In 
addition, the MMSE-2 will be repeated as specified in the SoA to explore any changes in 
cognitive impairment. 
The Neuropsychiatric Inventory (NPI) assesses behavioral and psychological domains and 
symptoms, including delusions, hallucinations, agitation or aggression, dysphoria or 
depression, anxiety, euphoria or elation, apathy or indifference, disinhibition, irritability or 
lability, aberrant motor behavior, sleep/nighttime behavior and appetite/eating disturbances.  
The NPI includes both symptom frequency (scored 1-4) and severity ratings (scored 1-3), as 
well as trial partner/caregiver distress ratings.
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4.2.1.3
Pharmacokinetic Endpoints
An exploratory objective of this study is to characterize the trough exposures of MK-8189. 
Therefore, individual plasma concentration and actual sample collection times of MK-8189 
will be used to derive the PK parameter value for C24hr.
4.2.1.4
Planned Exploratory Biomarker Research
4.2.1.4.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME; mechanism of action of the drug; disease etiology; and/or 
molecular subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a sample will be collected for DNA analysis from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multistudy assessment of genetic factors involved 
in the response to understand study disease or related conditions.
In addition to studying variation across the human genome, polymorphs of CYP2C9 will
specifically be investigated for association with the PK and PD of MK-8189 since MK-8189
is partially metabolized by CYP2C9. Genetic variation in CYP2C9 may be analyzed for
association with any laboratory or clinical data collected in this study.
4.2.1.5
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR 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 participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in
Appendix 6.
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4.2.2
Rationale for the Use of Comparator/Placebo
As the safety and tolerability profile is under continued evaluation, a placebo-control will be
included in this trial to ensure objective assessment of AEs.
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring
Prospective assessment of suicidal ideation and behavior will be performed in this study 
using the C-SSRS. This assessment is being conducted in compliance with the 2012 FDA 
guidance requiring prospective assessment in clinical studies conducted under IND 
applications and studies that are intended for submission in a NDA to the Neurology or 
Psychiatry Divisions of the FDA or BLA, as well as assessment in studies that fall within the 
guidance for other reasons (e.g., CNS active/penetrant compounds, and known mechanisms 
or indications for which suicidal ideation/behavior has been previously identified as a 
potential concern).
4.3
Justification for Dose
Currently the efficacious dose of MK-8189 is unknown, however, based on data from in vivo 
preclinical assays (see Section 2.1 and the IB), enzyme occupancy of 30% is expected to be 
required for efficacy in neuropsychiatric symptoms associated with dementia. A dose of 8 mg 
is expected to result in a mean C24 (90% confidence interval) enzyme occupancy of
approximately 40% (34, 47). Proof of concept has been established for 12 mg of MK-8189 in 
schizophrenia patients (P005), however, doses up to and including 24 mg are being evaluated 
in a Phase 2b study (P008) to understand if greater efficacy is observed with higher doses. 
Recent literature suggests that for antipsychotics to be effective in the treatment of behavioral 
symptoms associated with dementia, doses may need to be similar to those used for the 
treatment of schizophrenia [Grossberg, G. T., et al 2020]. Preliminary PK data from P011 
suggest the median C24 value in healthy elderly following multiple doses of MK-8189 16 mg 
will be similar to that observed following multiple 24 mg doses of MK-8189 in non-elderly 
adults with schizophrenia.  Therefore, the initial titration regimen in the current study will 
escalate MK-8189 doses up to 16 mg. If multiple doses of MK-8189 16 mg is generally well 
tolerated in the initial cohort of ~8 participants and, based on a PK analysis of these
participants, MK-8189 exposure is less than anticipated and thus closer to exposures 
observed in younger (< 60 years of age) adult participants, an alternate titration regimen 
escalating to 24 mg of MK-8189 (Titration Regimen 2) may be explored.  
As this is a Phase 1 assessment of MK-8189 in humans, and the PK, pharmacodynamic and 
safety profiles of the compound are still being evaluated, modifications to the dose or dosing 
regimen may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants. Details of allowed 
modifications are provided in Section 8.10.7.
4.3.1
Starting Dose for This Study
The first 8 participants will receive the following treatment regimen: MK-8189 8 mg/placebo 
Days 1-3 and 16 mg/placebo Days 4-28. This regimen and initiating dosing at 16 mg of MK-
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8189 has been found to be generally well-tolerated in healthy elderly participants and young 
participants.  In young participants with schizophrenia, a starting dose as high as 24 mg has 
been evaluated and found to be well tolerated (see Section 2.2).  The remaining participants 
will receive the same dose treatment regimen or an alternate treatment regimen.  The starting 
dose for the selected regimen will not exceed 8 mg of MK-8189.
4.3.2
Maximum Dose/Exposure for This Study
Participants may be escalated to a maximum MK-8189 dose of 24 mg/placebo.  A daily dose 
of MK-8189 24 mg has been found to be generally well tolerated in healthy young (P007) 
and elderly participants (P011) and doses of MK-8189 48 mg have been generally well 
tolerated in participants with schizophrenia (P007). 
Based on a population PK model, the steady-state Cmax and AUC0-24hr at the 24-mg dose 
is predicted to be 0.975 µM and 19 µM.hr. Based on data from the chronic toxicology 
studies, the exposure multiple at the 24 mg dose for AUC0-24hr would be ~7-fold based on 
the 6-month rat study and ~9-fold based on the 9-month monkey study. Brief summaries of 
the chronic toxicology studies supporting dose escalation are provided below:
In the 6-month rat study, doses of 0, 25, 100 and 750 mg/kg/day were evaluated. Two high-
dose (750 mg/kg/day) female rats were found dead (Week 13 and Week 24) with acute 
tubular necrosis (with and without tubular mineralization). Therefore, the 100 mg/kg/day 
dose was considered the no observed adverse effect level (NOAEL) for this study (AUC0-
24hr = 130 μM∙hr), providing an exposure margin of ~7-fold over the predicted exposure of 
19 μM∙hr at the 24 mg dose.
In the 9-month monkey study, doses of 0, 30/10/3, 150 or 600/300 mg/kg/day of MK-8189 
were administered. Renal tubular degeneration was observed in the high-dose group (600/300 
mg/kg/day). The NOAEL for target organ toxicity is 150 mg/kg/day (AUC0-24hr = 170 
μM∙hr), providing ~9-fold over the predicted exposure of 19 μM∙hr at the 24-mg dose. 
Therefore, clinical and preclinical data support dose escalation to 24 mg in this study.
4.3.3
Rationale for Dose Interval and Study Design
MK-8189 has been developed as a CR formulation to ensure adequate exposures are 
maintained throughout the dosing interval with once-daily dosing. Initiating dosing at 8 mg 
for 3 days allows for tolerability to be assessed at steady-state exposures before titrating up 
and may improve tolerability. Dosing for a total of 28 days is expected to provide sufficient 
safety and tolerability data to determine if a larger and longer term POC study should be 
conducted. 
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
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A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Section 10.1.1), our studies include 
people of varying age, race, ethnicity, and sex. The collection and use of these demographic 
data is to follow all local laws and guidelines in keeping with the needs for participant 
confidentiality while supporting the study of the disease, its related factors, and the IMP 
under investigation. Prospective approval of protocol deviations to recruitment and 
enrollment criteria, also known as protocol waivers or exemptions, is not permitted.
This study will enroll male/female participants between the ages of 65 and 85 years 
(inclusive), with diagnosis of Alzheimer disease for at least 1 year. In addition, it is preferred 
participants enrolled have symptoms of agitation-aggression and/or psychosis (defined as a 
severity of score ≥1 and frequency score of ≥2 on the NPI Agitation-Aggression and/or 
Delusions and/or Hallucinations domains) for at least 4 weeks prior to Screening.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has a documented diagnosis of probable Alzheimer disease based on National Institute 
on Aging-Alzheimer Association criteria for AD, with a history of cognitive and 
functional decline with gradual onset and slow progression for at least 1 year before 
screening, that is either corroborated by an informant who knows the participant well or 
is documented in medical records. Note: PIs should ensure that non-neurological medical 
comorbidities, including treatable causes of dementia, have been ruled out at the time of 
diagnosis, including, but not limited to, hypothyroidism, B12, and folate deficiency as 
well as increased levels of homocysteine.
2. Has an MMSE-2 score between 10 and 24, inclusive at Screening.
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3. Lives in the community setting with a reliable trial partner/caregiver or lives alone in an 
assisted living facility, with supervision and has a reliable trial partner/caregiver.
4. Has a reliable and competent trial partner/caregiver who must have a close relationship 
with the participant and is knowledgeable of the participant’s condition and progress and 
able to read, understand and speak the designated language at the study site. The
trial partner/caregiver should understand the nature of the trial and adhere to 
trial requirements (e.g., dosing, visit schedules, and evaluations). The trial 
partner/caregiver must:

be willing to sign informed consent,

have face to face contact at least four days a week for a minimum of 8 waking 
hours a week (or more in accordance with local requirements), 

be willing to accompany the participant to all trial visits, as required per protocol 
(and arrange for an alternative transportation means when, on occasion, the trial 
partner/caregiver may not be available) and 

be willing to monitor compliance of study intervention administration and record 
study intervention administration. 
5. Can read at the 6th grade level/equivalent as determined by the investigator.
6. Has an academic and/or employment history sufficient to exclude intellectual disability 
and is able, in the opinion of the investigator, to fully participate in the study (e.g., speak, 
read, hear, understand trial staff language) and be able to comply with protocol
assessments.
7. Is in generally good physical health based on medical history, physical examination, VS 
measurements, and ECGs performed before randomization. Participants with chronic 
medical conditions such as hypothyroidism, diabetes, high BP, chronic respiratory 
conditions or other mild forms of these medical conditions could be considered as 
candidates for study enrollment if their condition is stable and the prescribed dose and 
regimen of medication is stable for at least 2 months prior to screening and there are no 
expected changes in co-medication during the study. Participants should have mean 
systolic blood pressure of ≤150 mmHg and mean diastolic blood pressure of ≤95 mmHg 
at screening. In addition, screening orthostatic vital sign changes should be 
asymptomatic with a standing systolic blood pressure of ≥90 mmHg.
8. Be in generally good health based on laboratory safety tests obtained at the screening 
visit and before administration of the initial dose of study intervention. Appendix 2 
provides a table of laboratory safety tests to be performed. Appendix 9 provides an 
algorithm for the assessment of out-of-range laboratory values.
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9. Participants receiving treatment with a cholinesterase inhibitor or other treatment for AD
(i.e. memantine and aducanumab), must have been on a stable regimen for 3 months prior 
to screening and there are no expected changes in co-medication during the study.
10. Is able to discontinue any antipsychotic medication they are taking at the time of 
Screening. The antipsychotic must be discontinued 2 weeks or 5 half-lives (whichever 
was longer) prior to Baseline. Investigators should not withdraw a prohibited medication 
for the purpose of enrolling them into the study unless discontinuation of the medication 
was deemed to be clinically appropriate (e.g., symptoms are not well-controlled, or the 
subject can’t tolerate the current medication).
11. Has a BMI > 18 and ≤35kg/m2, inclusive. See Section 8.3.1 for criteria on rounding to 
the nearest whole number. BMI = weight (kg)/height (m)2.
Demographics
12. Is male or female, 65 years to 85 years of age, inclusive, at the time of signing the 
informed consent.
13. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Not a WOCBP
OR
•
A WOCBP and:
-
Uses an acceptable contraceptive method, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 14 days after the last dose of study intervention. The investigator should 
evaluate the potential for contraceptive method failure (ie, noncompliance, recently 
initiated) in relationship to the first dose of study intervention. Contraceptive use by 
women should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies
-
Has a negative highly sensitive pregnancy test (serum or urine as required by local 
regulations) within 120 hours before the first dose of study intervention. (If a urine 
test cannot be confirmed as negative [eg, an ambiguous result], a serum pregnancy 
test is required. In such cases, the participant must be excluded from participation if 
the serum pregnancy result is positive.) Additional requirements for pregnancy testing 
during and after study intervention are in Section 8.3.5.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
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Informed Consent
14. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Additional Categories
15. Willing to comply with the study restrictions (see Section 5.3 for a complete summary of 
study restrictions).
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has agitation/aggression or psychosis that is attributable to concomitant medications, 
environmental conditions, substance abuse, or an active medical or psychiatric condition.
2. Has a MHIS Score > 4 at Screening (i.e., evidence of vascular dementia).
3. Has a known history of stroke or evidence from prior MRI scan (if available) that is 
clinically important in the investigator's opinion.
4. Has evidence of a clinically relevant neurological disorder other than the disease being 
studied (i.e., 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, posterior cortical atrophy, logopenic primary progressive aphasia, other 
types of dementia, intellectual disability, hypoxic cerebral damage, cognitive impairment 
due to other disorders, or head trauma with loss of consciousness that led to persistent 
cognitive deficits.
5. Has a history of seizures or epilepsy within the last 5 years before Screening.
6. Has evidence of a clinically relevant or unstable psychiatric disorder, based on DSM-5 
criteria, including schizophrenia, schizophrenia spectrum or other psychotic disorder, 
bipolar disorder, major depressive disorder, or delirium. Note: Major depressive disorder
in remission is not exclusionary and mild, stable, treated depression is not exclusionary.  
7. Is at imminent risk of self-harm, based on clinical interview or on the C-SSRS, or of harm 
to others in the opinion of the investigator. Participants must be excluded if they report 
suicidal ideation with intent, with or without a plan (i.e., suicidal ideation Item 4 or 5 on 
the C-SSRS) in the past 2 months or suicidal behavior in the past 6 months.
8. Has a history of alcoholism or drug dependency/abuse within the last 5 years before 
screening.
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9. Has a history of cancer (malignancy).
Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies that have been successfully treated with 
appropriate follow up and therefore unlikely to recur for the duration of the study, in the 
opinion of the investigator and with agreement of the Sponsor (e.g., malignancies that 
have been successfully treated ≥10 years prior to the prestudy [screening] visit).
10. Has a family history of prolonged QTc syndrome.
11. Has an estimated eGFR ≤50 mL/min/1.73 m2 based on the MDRD.
MDRD Equation:
eGFR (mL/min/1.73 m2) = 
175 x (serum creatinine)-1.154 x (age)-0.203 x (0.742 [if female]) x (1.212 [if black or 
African American])
At the discretion of the investigator a measured CrCl, as determined by a 24-hour urine 
collection, may be used in place of, or in conjunction with, the estimate of the eGFR.
Participants who have an eGFR or measured CrCl of up to 10% below of either 50 
mL/min (for CrCl) or 50 mL/min/1.73m2 (for eGFR) may be enrolled in the study at the 
discretion of the investigator.
12. Has a history of significant multiple and/or severe allergies (e.g., food, drug, latex 
allergy), or has had an anaphylactic reaction or significant intolerability (i.e., systemic 
allergic reaction) to prescription or nonprescription drugs or food.
13. Previously developed severe EPS following administration of any prescribed medication 
or study treatment. Severe EPS is defined as follows: Parkinsonism type symptoms 
persisting for ≥3 days, or induction of a tremor that interferes with daily living, dystonia 
persisting for > 24 hours, or objective restlessness consistent with akathisia.
14. Is positive for HBsAg, hepatitis C antibodies or HIV.
15. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit.
Prior/Concomitant Therapy
16. Has received treatment with monoamine oxidase inhibitors or unable to refrain from the 
use of co-medication with a moderate or strong inhibiting or inducing effect on CYP3A 
or moderate to strong inducing effect on CYP2C9 (CYP2C9 inhibitors are permitted) 
beginning approximately 2 weeks or 5 half-lives, whichever is longer, prior to 
administration of the initial dose of trial drug and throughout the trial.
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Prior/Concurrent Clinical Study Experience
17. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the prestudy (screening) visit. The window will be derived 
from the date of the last visit in the previous study.
Diagnostic Assessments
18. Has a QTc interval >450 msec.
Other Exclusions
19. Does not agree to follow the smoking restrictions as defined by the CRU.
20. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce]) per day. Participants who consume 4 glasses of alcoholic beverages 
per day may be enrolled at the discretion of the investigator.
21. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or 
other caffeinated beverages per day.
22. Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) 
abuse within approximately 3 years. Participants must have a negative UDS (with the 
exception of cannabis and/or prescribed medications permitted at the discretion of the PI 
and Sponsor) prior to randomization.
23. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
24. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Fasting requirements for laboratory safety evaluations are specified in Appendix 2.
Participants should fast overnight prior to all visits to the CRU including the screening and 
poststudy visits.  Otherwise, participants will consume their usual diet except for grapefruit 
products (section 5.3.1.2). At CRU visits, participants may be given a light breakfast 
following study treatment administration.
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5.3.1.2
Fruit Juice Restrictions
Participants should refrain from the consumption of more than 1 grapefruit or 1 glass (8 
ounces) of grapefruit juice a day, throughout the entire study period. Otherwise, participants
can consume their usual diet throughout the study period. 
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Caffeinated beverages or xanthine-containing products will be limited to no more than 
6 units per day (1 unit = 120 mg of caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours before all CRU visits 
including the screening and poststudy visits. Alcohol consumption is limited to no more than 
approximately 3 alcoholic beverages or equivalent servings (1 serving is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce]) per day.
5.3.2.3
Tobacco Restrictions
Participants will follow the smoking restrictions (and if applicable, the use of 
nicotine/nicotine-containing products) defined by the CRU during visits.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (i.e., weightlifting, running, 
bicycling, etc.) from the screening visit until administration of the initial dose of study 
intervention, throughout the study and until the poststudy visit.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. A minimal set of screen-failure information 
may be included, as outlined in the eCRF entry guidelines. Minimal information may include 
demography, screen-failure details, eligibility criteria, and any AEs or SAEs meeting 
reporting requirements.
5.5
Participant Replacement Strategy
If a participant discontinues from study intervention OR withdraws from the study a 
replacement participant may be enrolled if deemed appropriate by the investigator and 
Sponsor. The replacement participant will generally receive the same intervention or 
intervention sequence (as appropriate) as the participant being replaced. The replacement 
participant will be assigned a unique treatment/randomization number.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (MK-8189/placebo) will be packaged to support enrollment and 
replacement participants as required. When a replacement participant is required, the Sponsor 
or designee needs to be contacted before dosing the replacement participant. Clinical supplies 
will be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 1.
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Table 1
Study Interventions
Arm 
Name
Arm 
Type
Inter-
vention 
Name
Inter-
vention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admini-
stration
Regimen/Treatment 
Period/Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Active
Experi-
mental
MK-
8189
Drug
Tablet
4 mg
12 mg
All dosage 
levels
Oral
Titrations 1, 2 and 3
Experi-
mental
IMP
Provided 
centrally
Placebo
Placebo 
Compar-
ator
Placebo
Drug
Tablet
0 mg
All dosage 
levels
Oral
Titrations 1, 2 and 3
Experi-
mental
IMP
Provided 
centrally
IMP=investigational medicinal product; NIMP=noninvestigational medicinal product.
The classification of IMP and NIMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP/NIMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 1 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (e.g., not applicable in 
the case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study 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.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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 study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants will be assigned randomly according to a computer-generated allocation 
schedule.
The sample allocation schedule is provided in Table 2.
Table 2
Sample Allocation Schedule
Titration 1
Days 1-3
Days 4-28
MK-8189
N=21
8 mg QD
16 mg QD
Placebo
N=7
PBO
PBO
Titration 2
Days 1-3
Days 4-6
Days 7-28
MK-8189
N=21
8 mg QD
16 mg QD
24 mg QD
Placebo
N=7
PBO
PBO
PBO
Titration 3
Days 1-3
Days 4-6
Days 7-9
Days 10-28
MK-8189
N=21
4 mg QD
8 mg QD
16 mg QD
24 mg QD
Placebo
N=7
PBO
PBO
PBO
PBO
Note: The allocation scheduled will be stratified to AD participants with and without agitation-aggression 
and/or psychosis symptoms. Participants without agitation-aggression and/or psychosis symptoms will be 
assigned starting at the low allocation range and participants with agitation-aggression and/or psychosis 
symptoms (defined as a severity score of ≥1 and frequency score ≥2 on the NPI Agitation-Aggression and/or 
Hallucination and/or Delusion domains) will be assigned starting at the upper allocation range.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
1.
participants with and without agitation-aggression and/or psychosis symptoms
For example, participants without agitation-aggression and/or psychosis symptoms will 
be assigned starting at the low allocation range and participants with agitation-
aggression and/or psychosis symptoms will be assigned starting at the upper allocation 
range. For this protocol agitation-aggression and/or psychosis symptoms are defined as a 
severity score of ≥1 and frequency score of ≥2 on the NPI Agitation-Aggression and/or 
Delusions and/or Hallucinations domains.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-8189 will be packaged 
identically to the matching placebo so that blind is maintained. The participant, the trial 
partner/caregiver, the investigator, and Sponsor personnel or delegate(s) who are involved in 
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the study intervention administration or clinical evaluation of the participants are unaware of 
the intervention assignments.
6.4
Study Intervention Compliance

Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.

When participants self-administer study intervention(s) at home, daily phone calls will be 
made to check study intervention administration compliance. Compliance with study 
intervention will also be assessed at each subsequent visit by direct questioning and site 
review of the completed study intervention dosing diary as captured by the 
participant/trial partner/caregiver. In addition, compliance will be monitored via counting 
of returned tablets at selected CRU visits and documented in the source documents and 
eCRF. Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF.

A record of the number of MK-8189/placebo tablets dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start dates, including dates for intervention delays and/or dose 
reductions will also be recorded in the CRF.

When participants are dosed at the site, study intervention administration will be 
witnessed by the CRU staff. The staff will witness the participant/trial partner/caregiver 
record the dosing in the study intervention diary. 
6.5
Concomitant Therapy
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination 
during the ongoing study (i.e., after randomization or intervention allocation) must first be 
discussed between the investigator and Sponsor prior to administration, unless appropriate 
medical care necessitates therapy or vaccination should begin before the investigator and 
Sponsor can consult. The participant will be allowed to continue in the study if both the 
Sponsor and the investigator agree.
Acetaminophen and antacids (e.g., magnesium hydroxide) may be used for minor ailments 
without prior consultation with the Sponsor.
Moderate to strong inhibitors or inducers of CYP3A and moderate to strong inducers of 
CYP2C9 are not allowed as MK-8189 is being metabolized by these CYP enzymes and co-
administration of inhibitors or inducers may potentially alter the metabolism and PK of MK-
8189. See also Section 6.5.1 on rescue medication.
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In addition, the following concomitant medications/vaccinations are permitted:

Non-live vaccines may only be administered in consultation with the Sponsor.

COVID-19 vaccine may be administered. Study intervention must be given at least
72 hours following or at least 48 hours prior to any COVID-19 vaccination.
Exception: Investigational COVID-19 vaccines (i.e., those not licensed or approved
for Emergency Use) are not allowed.
Continued Medication Use 
Participants may continue treatment with their prescribed cholinesterase inhibitors, 
memantine and aducanumab for the treatment of AD during the trial. The prescribed dose 
and regimen of medication must be stable for at least 3 months prior to screening and there 
are no expected changes in co-medication during the study. 
In addition, medications to treat mild chronic conditions such as hypothyroidism, diabetes, 
high blood pressure, chronic respiratory conditions or other medical conditions are allowed 
during the study. For permitted medications, the prescribed dose and regimen of medication 
must be stable for at least 2 months prior to screening and there are no expected changes in 
co-medication during the study.
A participant’s continued use of medications that may cause somnolence, including but not 
limited to benzodiazepines and sedating antihistamines, must be discussed between the 
investigator and the Sponsor prior to MK-8189 administration. 
6.5.1
Rescue Medications and Supportive Care
If over the course of the study behavioral symptoms worsen, if medically appropriate, the 
participant may be administered quetiapine 50 mg.
6.6
Dose Modification (Escalation/Titration/Other)
The dose regimen for this trial is MK-8189 8mg/placebo Days 1-3 days followed by 
16 mg/placebo Days 4-28 (Titration 1). 
Following MK-8189/placebo treatment of approximately 8 participants for approximately 3 
weeks, a decision will be made to continue dosing newly enrolled participants with the 
current regimen or modify to an alternate regimen.  The following alternate treatment 
regimens may be explored during the study following a review of safety and tolerability data 
and a discussion with the investigators and the Sponsor. However, dose escalation above 16 
mg will not occur without a review of PK data from the initial cohort of approximately 8 
participants. Any change in the treatment regimen will be documented in a Protocol 
Clarification Letter.
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
8 mg/matched placebo Days 1-3, 16 mg/placebo Days 4-6 and 24 mg/placebo Days 7-28
(Titration 2)

4 mg/matched placebo Days 1-3, 8 mg/placebo Days 4-6, 16 mg/placebo Days 7-9 and 24 
mg/placebo Days 10-28 (Titration 3)

Other more conservative regimen
If medical care necessitates participants may:

Skip a single dose and dosing may continue at the same dose level or adjusted 
downwards.

Receive the same dose level to further explore safety and tolerability at that level.

Receive a lower dose of the study intervention.

Stop dosing.  
Any change in dosing regimen will be documented in a Protocol Clarification Letter.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention allocation/randomization 
schedule for the study to unblind participants and to unmask study intervention identity. The 
emergency unblinding call center should only be used in cases of emergency (see Section 
8.1.10). The Sponsor will not provide random code/disclosure envelopes or lists with the 
clinical supplies.
6.9
Standard Policies
Not Applicable
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.As 
certain data on clinical events beyond study intervention discontinuation may be important to 
the study, they must be collected through the participant’s last scheduled follow-up, even if 
the participant has discontinued study intervention. Therefore, all participants who 
discontinue study intervention before completion of the protocol-specified treatment regimen 
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will still continue to participate in the study as specified in Section 1.3 and Section 8.1.9, or 
per a PCL, if available.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study, for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant’s treatment assignment has been unblinded by the investigator, or through 
the emergency unblinding call center.
•
The participant interrupts study intervention administration for more than 2 consecutive 
days or has 4 cumulative missed doses.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a positive UDS except for allowed concomitant medication 
administered during trial, at any time during the study. The drug screen can be confirmed 
by a recheck at the discretion of the investigator after discussion with the Sponsor.
•
Any participant with EPS requiring treatment that is not or cannot be managed by down 
dosing.
•
The participant no longer has a trial partner/caregiver or the trial partner/caregiver 
withdraws consent and a substitute cannot be identified.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
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Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in Section 
8.1.9. The procedures to be performed should a participant repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
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•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 193.5 mL (Appendix 8).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Documented informed consent from each participant’s trial partner/caregiver (referred to as
trial partner informed consent) will also be obtained by the investigator or qualified designee.
Specifics about the study and the study population are to be included in the study informed
consent form.
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Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history, including psychiatric history and substance usage, will be obtained by the 
investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review and record medications taken by the 
participant within 3 months of the Screening visit. 
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
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8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.10.2.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Refer to the study operations manual for detailed procedures for requesting a 
treatment/randomization number.
8.1.8
Study Intervention Administration
Administration of study intervention will occur in the CRU on Day 1 and at CRU visits or at 
home as described in Section 1.3 Schedule of Activities.  
Participants will be supervised for at least 6 hours following the first administration of study 
intervention and following the first administration of each study intervention titration.  
Supervision will be done by the site staff. 
Participants will receive bottle(s) of study intervention on Day 1 and at each CRU visit.  
Prior to dispensing a new bottle of study intervention, the previous bottle dispensed will be 
collected. Each bottle will contain enough study intervention to cover the duration between 
each CRU visit.
Participants and their trial partner/caregiver will be instructed on how to administer at home 
study intervention by the CRU staff.  
8.1.8.1
Timing of Dose Administration
Study intervention should be administered orally in the morning at approximately the same 
time each day. Study intervention will be administered fasted (in CRU) or with/without food 
(at home) with approximately 240 mL of water.
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Trial partners/caregivers will record time of dosing in a study intervention dosing diary.  On 
days when study intervention is administered in the CRU, dose administration will be 
witnessed by the investigator and/or study staff.
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study and/or intervention. If a participant discontinues for 
any reason at any time during the course of the study and/or intervention, the participant may 
be asked to return to the clinic (or be contacted) for a poststudy visit as per the number of 
days described in Section 8.10.5  to have the applicable procedures conducted. However, the 
investigator may decide to perform the poststudy procedures at the time of discontinuation or 
as soon as possible after discontinuation. If the poststudy visit occurs prior to the safety 
follow-up time frame as specified in Section 8.4.1, the investigator should perform a follow-
up telephone call at the end of the follow-up period (Section 8.4.1) to confirm if any AEs 
have occurred since the poststudy clinic visit. Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
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and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is qualified physician should make reasonable attempts to enter the intensity
of the AEs observed, the relation to study intervention, the reason thereof, etc, in the medical 
record. If it is not possible to record this assessment in the medical record before the 
unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
Domiciling (optional)
For sites that have domiciling capability to keep participants overnight, the site may offer
study participants the option to stay in the CRU for the duration of the titration period or the 
entire intervention period (Day 1-28). Any other domiciling period will need to be discussed 
with the Sponsor. The study partner/caregiver is not required to stay overnight but may do so 
if requested by the study participant and the site can accommodate.
At the discretion of the investigator, participants will report to the CRU the evening before 
Day 1 and remain in the CRU until after the completion of study procedures on Day 7 
(Titration 1 and Titration 2)/Day 10 (Titration 3) or Day 28. Participants may be permitted to 
leave the unit, for emergency situations only, at the discretion of the investigator after 
discussion with the Sponsor.
Study staff will also witness the study medication and work with the participants/trial 
partners/caregivers in completing the dosing diary when the participants are in the CRU.
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Study drug administration fasting requirements will be required on the same days indicated 
in the SoA.
8.2
Efficacy Assessments
There are no direct efficacy assessments in this study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood to be drawn over the course of the study (from 
screening to poststudy visits), including approximate blood volumes drawn by visit and by 
sample type per participant, can be found in Appendix 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
BMI
BMI equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). BMI will be rounded to the nearest whole number according to the standard 
convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.2
Vital Signs
8.3.2.1
Resting Vital Signs
Pulse Rate, Blood Pressure, Respiratory Rate and Body Temperature
Participants should be resting in a quiet setting without distractions in a semi-recumbent 
position for at least 10 minutes before having VS measurements obtained. Semi-recumbent 
VS will include pulse rate, systolic and diastolic BP, RR, and body temperature at timepoints 
indicated in the SoA. The correct size of the BP cuff and the correct positioning on the 
participants' arm is essential to increase the accuracy of BP measurements.
The Screening and Day 1 predose (prior to dose) pulse rate and BP will be triplicate 
measurements, obtained at least 1 to 2 minutes apart.  The Day 1 predose triplicate 
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measurement will be taken within 3 hours prior to dosing MK-8189/placebo. The mean of 
these measurements will be used as the baseline to calculate change from baseline for safety 
evaluations (and for rechecks, if needed). All VS measurements after Day 1 dosing will be 
single measurements.
The same body temperature method must be used for all measurements for each individual 
participant and should be the same for all participants.
8.3.2.2
Orthostatic Vital Signs
Orthostatic VS (pulse rate and systolic and diastolic BP) will also be obtained. Participants 
should be semi-recumbent for at least 10 minutes and then stand upright for 2 minutes before
measurement of orthostatic VS.
8.3.3
Electrocardiograms
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry before lead placement. Participants may need to be shaved to ensure proper 
lead placement. Female participants may need to remove interfering garments.
Participants should be resting, semi-recumbent, for at least 10 minutes before each ECG 
measurement.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the CRU will decide whether to leave the electrodes in place or 
mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin-marker pen to ensure reproducible electrode placement.
Day 1 predose ECGs will be obtained in triplicate at least 1 to 2 minutes apart within 3 hours 
before dosing MK-8189. The mean of these measurements will be used as the baseline to 
calculate change from baseline for safety evaluations (and for rechecks, if needed).
If a participant demonstrates an increase in QTc interval ≥60 msec compared with mean 
baseline measurement, the ECG will be repeated twice within 5 minutes. The mean value of 
the QTc interval from the 3 ECGs will represent the value at that time point. If the mean QTc 
interval increase from baseline for any postdose time point is ≥60 msec, the participant will 
continue to be monitored by repeat 12-lead ECGs every 15 minutes for at least 1 hour or until 
the QTc is within 60 msec of baseline. If prolongation of the QTc interval ≥60 msec persists, 
a consultation with a study cardiologist may be appropriate and the Sponsor should be 
notified.
If a participant demonstrates a QTc interval ≥500 msec on a postdose ECG, the ECG will be 
repeated twice within 5 minutes. The mean value of the QTc interval from the 3 ECGs will 
represent the value at that time point. If the mean QTc interval is ≥500 msec, the Sponsor 
should be notified, and the ECGs should be reviewed by a cardiologist. The participant 
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should be telemetry monitored (until the QTc is <500 msec) or should be considered for 
transfer to a location where closer monitoring and definitive care (eg, a CCU or ICU) is 
available.
If the participant has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted on telemetry, the participant should be immediately transferred to an acute care setting 
for definitive therapy.
If prolongation of the QTc is noted, concomitant medications that prolong QTc should be 
held until the QTc is within 60 msec of baseline and the QTc is <500 msec.
A cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant abnormalities.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.
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8.3.6
Suicidal Ideation and Behavior Monitoring
8.3.6.1
Clinical Assessments for Suicidal Ideation and Behavior Monitoring
Suicidal ideation and behavior will be prospectively assessed during this study using the C-
SSRS. The C-SSRS should be administered by trained raters at the time points indicated in 
the SoA. In addition, C-SSRS will be administered at any unscheduled visit where safety 
assessments are performed. The C-SSRS will not be routinely administered at visits with a 
sole purpose of PK sampling and/or witnessed study intervention administration. Site staff 
should review the contents of the C-SSRS for completeness.
If the C-SSRS is administered by someone other than the investigator, consider providing the 
completed C-SSRS to the investigator for review, before their assessment of the participant 
and to further inform their evaluation.
The C-SSRS is not explicit about whether the participant specifically has ideation at the time 
of screening. If a participant reports a prior history of ideation/behavior at screening, the 
assessor should also inquire and document if this is also present at the time of the Screening 
Visit.
Participants who at any time during this study report suicidal ideation or behavior that is 
considered to be an AE, either between visits or during visit interviews, must be assessed by 
the investigator. Participants who report suicidal ideation with intent, with or without a plan 
or method (i.e., 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). After that evaluation, only those participants whose suicidal ideation is considered by 
the evaluator to be passive, and 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 study 
may continue in the study; other participants must be discontinued from study participation 
and receive appropriate clinical follow-up care to ensure their safety. In addition, all AEs of 
suicidal ideation or behavior must be recorded as an ECI (See Section 8.4.7). Sites are to 
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.
8.3.7
Rater Expectations and Training for Clinical and Cognitive Assessments
For this study, potential raters of clinical and/or cognitive assessments (BARS [Section 
8.3.11], SAS [Section 8.3.11], AIMS [Section 8.3.11], C-SSRS [8.3.6.1], MHIS [Section 
8.3.8], MMSE-2 [Section 8.3.9], and NPI [Section 8.3.10]) will be identified based on review 
of their reported credentials against target minimum credentials for education, prior 
experience with AD, MCI or similar populations and direct, hands-on experience with study-
specific or similar assessments.  Persons whose credentials meet or exceed those targets will 
then be considered ‘qualified’ as raters in this trial.  For the MMSE-2 and NPI, raters will 
subsequently complete overview, didactic, protocol-specific training before conducting 
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assessments in this trial.  It is recommended that the same rater conducts the same 
assessments throughout the study for a given participant, where feasible.
All clinical and cognitive assessments will be administered after dosing and following an 
optional light breakfast provided by the CRU.   
8.3.8
Rosen-Modified Hachinski Ischemia Scale
The MHIS will be completed by an experienced rater at timepoints specified in Section 1.3 
Schedule of Activities. 
8.3.9
Mini Mental State Examination Second Edition
The paper version of the MMSE-2 (Standard version, both Red and Blue forms) will be 
administered and scored by a qualified, trained rater at timepoints specified in Section 1.3 
Schedule of Activities. Additional information concerning administration, scoring and 
documentation may also be provided in rater training and in the MOA.
8.3.10
Neuropsychiatric Inventory
The paper version of the NPI (12 items) will be administered by a qualified, trained rater at 
timepoints specified in Section 1.3 Schedule of Activities. Additional information concerning 
administration, scoring and documentation may also be provided in rater training and in the 
MOA.
8.3.11
Monitoring of Extrapyramidal Symptoms
The Barnes Akathisia Ratting Scale (BARS), Abnormal Involuntary Movement Scale 
(AIMS) and Simpson Angus Scale (SAS) will be completed by a qualified rater at timepoints 
specified in Section 1.3 Schedule of Activities.
Refer to the MOA for additional information regarding the BARS, AIMS and SAS.
8.3.12
Neurological Exam
The General (Full) Neurological Exam will be performed at the Screening and Baseline 
visits.  The Targeted Neurological Exam will be administered at times specified in the SoA.  
The General and Targeted Neurological Exams are contained in Appendix 10.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
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Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator for randomized participants only if the event causes the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including, but not limited to washout or discontinuation of usual therapy, diet, placebo, or a 
procedure.
From the time of intervention allocation/randomization through 14 days after cessation of 
intervention, all AEs, SAEs and other reportable safety events must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator any time outside the period 
specified in the previous paragraph also must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of 
Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
(Randomized 
participants only)
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing 
to outcome)
Within 24 hours of 
learning of event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any protocol-
specified intervention 
(eg, procedure, washout 
or run-in treatment 
including placebo run-in)
Exception: A positive 
pregnancy test at the 
time of initial screening 
is not a reportable event.
Report all
Previously 
reported – Follow 
to completion/
termination; report 
outcome
Within 24 hours of 
learning of event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
ECI (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 calendar 
days of learning of 
event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning of 
event
(unless serious)
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Type of 
Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
(Randomized 
participants only)
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
Sponsor:
Overdose
Report if:
- receiving placebo run-
in or other run-in 
medication 
Report all
Not required
Within 24 hours of 
learning of event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
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8.4.5
Pregnancy and Exposure During Breastfeeding
Not applicable
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. An elevated AST or ALT laboratory value that is greater than or equal to 3X the ULN 
and an elevated total bilirubin laboratory value that is greater than or equal to 2X the 
ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2X 
the ULN, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note: These criteria are based on 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 study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
3. Severe EPS or EPS resulting in study intervention discontinuation
4. Suicidal ideation, suicidal behavior
5. Treatment-emergent adverse event of new or worsening tardive dyskinesia
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
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or the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
8.6
Pharmacokinetics
The decision as to which plasma samples collected will be measured for evaluation of PK 
will be collaboratively determined by the Sponsor (e.g., samples at lower doses may not be 
measured if samples at higher doses reveal undetectable drug concentrations). If indicated, 
these samples may also be measured and/or pooled for assay in an exploratory manner for 
metabolites and/or additional pharmacodynamic markers.
8.6.1
Blood Collection for Plasma MK-8189 and/or Metabolites Assay
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the laboratory manual.
8.6.2
Blood Collection for Plasma Donepezil Assay
Sample collection, storage, and shipment instructions will be provided in the laboratory
manual.
8.6.3
Blood Collection for Plasma Memantine Assay
Sample collection, storage, and shipment instructions will be provided in the laboratory
manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for Genetic Analysis
•
Blood for Exploratory Plasma Biomarkers for AD Diagnosis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample will be drawn for CYP2C9 genotyping and for planned 
analysis of the association between genetic variants in DNA and drug response. If the 
IRB/IEC does not approve of the planned analysis of the association between DNA variation 
and drug response, or if there is a local law or regulation prohibiting the same, data analysis 
will be limited to CYP2C9 genotyping. Leftover extracted DNA will be stored for FBR if the 
participant provides documented informed consent for FBR.
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Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the operations/laboratory manual.
8.8.2
Exploratory Plasma Biomarkers for Alzheimer’s Disease Diagnosis Sample 
Collection
Sample collection, storage, and shipment instructions for exploratory plasma biomarker
samples will be provided in the operations/laboratory manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover DNA for future research
•
Leftover main study plasma from MK-8189 and/or metabolites assay stored for future 
research.
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Trial Partner/Caregiver Participation
The trial partner/caregiver is required to accompany the participant to the Screening Visit, to
sign the trial partner informed consent. This trial partner/caregiver should be willing and 
make every effort to accompany the participant to all study visits. In the event the trial 
partner/caregiver in unable to attend a study visit, he/she should discuss alternative 
arrangements with the site (e.g., participant transportation, return of study intervention and 
dosing diary) and availability of the trial partner/caregiver to provide and receive input by 
phone as needed (e.g. questions/instructions related to dosing information captured on dosing 
diary).
Every effort should be made to maintain the same trial partner/caregiver for the duration of 
the study. However, if the trial partner/caregiver is unable to continue with the study 
requirements, the trial partner/caregiver should discuss with the site whether a suitable 
replacement can be found. If a new trial partner/caregiver is identified, the new trial
partner/caregiver will need to sign the trial partner/caregiver informed consent.
8.10.2
Screening (Visit 1) 
Approximately 6 weeks before intervention randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5. Any 
participants being treated with antipsychotics at Screening must wash off their medications if 
considered medically appropriate (see Inclusion Criterion No. 10). If a participant has 
washed-off antipsychotic therapy (minimum 2 week or 5 half-life washout, whichever is 
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longer) during Screening, the NPI for that participant should be repeated, and will be 
considered the baseline value.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to intervention randomization if there are 
Baseline procedures planned per protocol.
Please see the operations manual for eCRF screening data entry requirements prior to 
randomization.
8.10.3
Baseline (Visit 2)
Within 3-5 days prior to study intervention administration, participants will have Baseline 
safety evaluations per Section 1.3 Schedule of Activities.
8.10.4
Intervention Period Visit (Visits 3-9)
Day 1 (Visit 3)
Participants will return to the CRU on Day 1 for a predose assessments per the SoA. 
Participants will be administered study treatment by the CRU staff per section 8.1.8.  On Day
1, participants will remain at the CRU until the last study assessment is complete and for at 
least 6 hours following the first administration of study intervention (Day 1). 
Outpatient CRU Visits (Visits 4-9)
Participants, not domiciled, will return for CRU visits on Day 4, Day 7, Day 10 (Titration 3 
only), Day 14, Day 21 and Day 28. Participants should be fasted upon return to the CRU. 
Participants will be administered study intervention by CRU staff and safety and PK 
assessments will be performed per the SoA. Participants will remain at the CRU until the last 
study assessment is complete. If the dose is the first administration at the next titrated dose
level, participants will be required to be supervised by CRU staff for at least 6 hours post 
dose.
Participant Daily Home & CRU Requirements
Participants will self-administer study intervention (Section 8.1.8) on days not required to be 
in the CRU.  Participants or trial partners/caregivers will record dosing date, time and 
number of tablets taken in a study intervention diary.
CRU staff will call the participants daily to check study intervention compliance, 
review/record AEs and if necessary, remind participants of next scheduled visit.
8.10.5
Discontinued Participants Continuing to be Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, a subset of study procedures specified in the SoA may be completed at the discretion 
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of the investigator and with Sponsor agreement. The subset of study procedures completed 
will be communicated in a PCL.
8.10.6
Poststudy (Visit10)
Participants will be required to return to clinic approximately 14 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
14 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
8.10.7
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
See Section 6.6 for Dosing modifications permitted per protocol.
This is a Phase 1 assessment of MK-8189 in humans, and the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is written with some 
flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Modifications to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.
•
Repeat of or decrease in the dose and/or titration steps of the study intervention
administered.
•
Decrease in the duration of study intervention administration (e.g., number of days).
•
Addition of PK pause.
•
Instructions to take study intervention with or without food or drink may also be modified 
based on newly available data.
•
Modification of the PK sample processing and shipping details based on newly available 
data.
The PK sampling scheme currently outlined in the protocol may be modified during the study 
based on newly available PK or pharmacodynamic data (e.g., to obtain data closer to the time 
of peak plasma concentrations). If indicated, these collected samples may also be assayed in 
an exploratory manner for metabolites and/or additional pharmacodynamic markers.
Up to an additional 50 mL of blood may be drawn for safety, PK, and/or pharmacodynamic 
analyses. The total blood volume withdrawn from any single participant will not exceed the 
maximum allowable volume during his/her participation in the entire study (Appendix 8).
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The timing of procedures for assessment of safety procedures (e.g., vital signs, ECG, safety 
laboratory tests, etc.) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
It is understood that the current study may use some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 9.2).
Safety:
For the primary objective, all AEs and AEs leading to discontinuation of study intervention
will be summarized and tabulated.
Summary statistics and plots will be generated for raw laboratory safety tests, 12-lead ECGs, 
and/or VS as well as for change from baseline, as deemed clinically appropriate.  Depending 
on the safety parameter, the difference from baseline will either be computed on the original 
scale (raw change from baseline) or on the log scale and back transformed for reporting 
(percent change from baseline). 
For exploratory objectives, summary statistics and plots will be generated for Barnes 
Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS) and 
Simpson Angus Scale (SAS), as well as for change from baseline.  Responses to the C-SSRS 
will be listed. Additionally, summary statistics for change from baseline will be provided for 
MMSE-2, and NPI.
Pharmacokinetics: 
Descriptive summary statistics will also be provided for MK-8189 C24hr.
9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the
direct auspices of, the Early Clinical Development Statistics Department in collaboration
with the Quantitative Pharmacology and Pharmacometrics Department and Translational
Pharmacology Department of the Sponsor. If, after the study has begun, changes are made to 
the statistical analysis plan stated below, then these deviations to the plan will be listed, along 
with an explanation as to why they occurred, in the Clinical Study Report.
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9.3
Hypotheses/Estimation
Objectives:
Refer to Section 3 for primary and exploratory objectives.
9.4
Analysis Endpoints
Safety: Primary safety endpoints will include all types of AEs and AEs leading to 
discontinuation of study intervention.
Additionally, for exploratory purposes, laboratory safety tests, 12-lead ECGs, and VS will be 
summarized. For laboratory safety tests, baseline is defined as readings obtained prior to first 
dose (Note: Readings from screening (Visit 1) will not serve as baseline for these 
parameters). For 12-lead ECGs and VS, baseline is defined as Day 1 predose readings. 
Exploratory:
BARS, AIMS, and SAS for all participants. 
The Columbia Suicide Severity Rating Scale (C-SSRS) will be used to systematically and 
prospectively ascertain and document the occurrence of suicidal events (i.e., ideation and 
behavior). Responses on the C-SSRS are classified according to 11 prespecified categories 
as described in procedure manual. The most severe treatment-emergent ideation and 
behavior event reported at a visit will be used for analysis and reporting. An event is 
considered treatment-emergent during the assessment phase if it newly emerged or is more 
severe compared to recent history (i.e., protocol-defined recent history prior to entering the 
trial as stated in the Inclusion/Exclusion criteria for suicidal ideation/behavior, up to and 
including the randomization visit). Readings from Day -5 to Day-3 in Visit 2 will serve as 
baseline.
MMSE-2, and NPI for all participants.  Readings from screening (Visit 1) will serve as 
baseline. (Note: For NPI, if AP is washed off, the NPI readings obtained post washout will be 
used as baseline.)
9.5
Analysis Populations
The following populations are defined for the analysis and reporting of data.  All participants
will be reported, and their data analyzed, according to the treatment(s) they actually received. 
All Participants as Treated (APasT): The All Participants as Treated Population consists of 
all participants who received at least one dose of treatment.  This population will be used for 
assessments of safety and tolerability.
Per-Protocol (PP): The Per-Protocol Population consists of the set of data generated by the 
subset of participants who comply with the protocol sufficiently to ensure that these data will
be likely to exhibit the effects of treatment, according to the underlying scientific model. 
Compliance covers such considerations as exposure to treatment, availability of 
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measurements and absence of important protocol deviations.  Important protocol deviations 
will be identified to the extent possible prior to unblinding by individuals responsible for data 
collection/compliance, and its analysis and interpretation.  Any participants or data values 
excluded from analysis will be identified, along with their reason for exclusion, in the CSR.  
At the end of the study, all participants who are compliant with the study procedure as 
aforementioned and have available data from at least one treatment (dose level) will be 
included in the Per-Protocol dataset. This population will be used for the PK analysis.
9.6
Statistical Methods
Safety:
For primary objective, all AEs and AEs leading to discontinuation of study intervention will 
be summarized and tabulated. 
Summary statistics and plots will be generated for raw laboratory safety tests, 12-lead ECGs, 
and/or VS as well as for change from baseline, as deemed clinically appropriate.  Depending 
on the safety parameter, the difference from baseline will either be computed on the original 
scale (raw change from baseline) or on the log scale and back transformed for reporting 
(percent change from baseline). 
For exploratory purposes, summary statistics and plots will be generated for BARS, AIMS, 
SAS, as well as for change from baseline.  Responses to the C-SSRS will be listed.  
Additionally, summary statistics for change in MMSE-2 and NPI from baseline will be 
provided.
Pharmacokinetics:   
Individual C24hr values will be listed, and the following (non-model-based) descriptive 
statistics will be provided: N (number of subjects with non-missing data), arithmetic mean, 
standard deviation, arithmetic percent CV (calculated as 100 x standard deviation/arithmetic 
mean), median, minimum, maximum, geometric mean, and geometric percent CV (calculated 
as 100 x sqrt(exp(s2) - 1), where s2 is the observed variance on the natural log-scale).
The exploratory objective pertaining to the assessment of relationship between CYP2C9 
genetic polymorphs and the laboratory and PK of MK-8189, and the relationship between 
genetic variation and response to the treatment may be addressed in a separate report.
9.7
Interim Analyses
During the in-life portion of the trial, descriptive summary level results (safety labs, VS, 
ECGs) will be prepared as needed to support decision-making meetings. No individual
participant level results will be provided. There are no planned interim analyses to test any 
formal hypotheses.
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9.8
Multiplicity
Since there are no pre-specified hypotheses, no adjustments for multiplicity are needed.
9.9
Sample Size and Power Calculations
Since there are no hypotheses, no power calculations are provided
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, 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 participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD 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 that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
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 MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
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Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. 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 such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). 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. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants 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.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
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C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD 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.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
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, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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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.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
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 IRB, IEC, 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 study 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.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. 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 
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and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-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 study or its results to those 
registries.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
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The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study 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 or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 4 will be performed by the central laboratory.
Exception: Routine urinalysis and urine pregnancy tests will be done locally at the site. A
urinalysis sample will only be sent to the central lab if microscopic examination is 
required, i.e. blood or protein is abnormal. 
•
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are used 
to make either a study intervention decision or response evaluation, the results must be 
entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 4
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
above the ULN)
Albumin
Bicarbonate or 
Total CO2
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose (fasting)
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick
•
Microscopic examination (if blood or protein is abnormal)
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Laboratory 
Assessments
Parameters
Pregnancy 
Testing
•
Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP)
Other Screening 
Tests
•
FSH (as needed in WONCBP only)
•
Urine alcohol and drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)
•
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody)
•
All study-required laboratory assessments will be performed by a central laboratory.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-stimulating 
hormone; [HBsAg=hepatitis B surface antigen]; hCG=human chorionic gonadotropin; [HIV=human immunodeficiency 
virus]; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; SGOT=serum 
glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; ULN=upper limit of normal; 
WBC=white blood cell; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing 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 preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
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number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following
categories:
- Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
- Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE 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 product and the AE 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 AE:
- Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
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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 studies 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.
- 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 study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
- Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
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 study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
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 PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
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•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
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:
◦
Participant 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 participant with overdose without an associated 
AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not Applicable
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen- only contraceptive implantc,d
•
IUSc,e
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
- Oral
- Intravaginal
- Transdermal
- Injectable
•
Progestogen-only hormonal contraceptionc,d
- Oral
- Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
•
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action
•
Male or female condom with or without spermicide
•
Cervical cap, diaphragm, or sponge with spermicide
•
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods).
a   Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies.
b   Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
[If hormonal contraception efficacy for a female participant is potentially decreased due to interaction(s) with study 
intervention(s), add the following footnote. If hormonal contraception is prohibited, or if hormonal contraception efficacy 
is NOT decreased due to interaction with study intervention(s), delete the following footnote:]
c   Male condoms must be used in addition to female participant hormonal contraception.
d   If locally required, in accordance with CTFG guidelines, acceptable hormonal contraceptives are limited to those which 
inhibit ovulation. 
e   IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
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 consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
•
The biology of how drugs/vaccines work
•
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
•
Other pathways with which drugs/vaccines may interact
•
The biology 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.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant 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 participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention 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 study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, 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 will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
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
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot 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 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 study 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 
study, the study 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 
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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 study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to
rapidly report this information to doctors and participants. Participants 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 participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
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 emailed directly to 
clinical.specimen.management@merck.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not Applicable
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10.8
Appendix 8: Blood Volume Table
All Participants
Screening/
Baseline
Intervention
Poststudy
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Laboratory Safety Tests
2
4
1
7
6
42
HIV/Hepatitis Screen (at the 
discretion of the investigator)
1
1
5
5
Blood for Genetic Analysis 
1
1
8.5
8.5
Blood for Exploratory Plasma 
Biomarkers for AD 
Diagnosis
1
1
18
18
Blood for MK-8189 and/or 
Metabolites Assay
10
10
4
40
Blood for Plasma Donepezil 
Assay
5
5
3
15
Blood for Plasma Memantine 
Assay
5
5
3
15
Total Blood Volume per Participanta
143.5 mL
a If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) 
may be obtained. 
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10.9
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant 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 participant 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:
a.
The participant may be excluded from the study;
b. The participant may be included in the study if the abnormal value(s) is NCS (the 
investigator must annotate the laboratory value “NCS” on the laboratory safety 
test source document).
c.
The participant 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 participant with asthma or seasonal allergies), the medical 
condition should be annotated on the laboratory report.
OR
d. 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 participant may 
enter the study.
b. If the repeat test value is still abnormal, the study investigator will 
evaluate the potential participant 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 
participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
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10.10 Appendix 10: General (Full) and Targeted Neurological Exam
The General (Full) and Targeted Neurological Examination will be performed at the time 
points specified in the Schedule of Activities (Section 1.3).
Note to the investigator: If at any time abnormalities are observed in the General or 
Targeted Neurological Exams, the Investigator should do additional examinations as 
needed based on his or her medical judgment.
The General (Full) Neurological Examination
The General (Full) Neurological Examination includes all of the modules listed below and is
intended to be a general screening examination.
MODULE 1 – MENTAL STATUS EXAMINATION
A. General Level of Arousal: Generally assess general level of alertness, attentiveness, and 
concentration throughout the interview. Regarding attentiveness, note evidence of 
impaired attention or concentration. For example, difficulty remembering or following 
instructions or distractibility may be signs of inattention.
B. Thought Processes and Language: Generally assess logic, relevance, organization and 
coherence of volunteer’s use of language throughout the interview.
C. Orientation (time, place, person)
D. Attention/Concentration
Ask the subject to count backwards from 100 by 7’s (“Serial 7’s”) or ask to recite months 
backwards or spell a 5 unique letter word (e.g. “WORLD”) backwards.  
Note: to avoid learning effects, switch between tests throughout the study
E. Memory:   Test registration of 3 objects; then test immediate recall 5 minutes later.
Grade: NORMAL or IMPAIRED and describe abnormality (for each, A to E, 
above).  Normal performance on Serial 7’s is getting to 65 with no more than one 
error. 
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)
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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 e.g. 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 at the knees (bilaterally). 
3. There is a small, continuous resistance to passive movement.
4. Observe for involuntary movements (e.g., 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.
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Test bilaterally, and compare one 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 one 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 (e.g. 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 
one 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, e.g., coin, key).
Score: left and right
Grade: NORMAL OR IMPAIRED and describe abnormality (for each A to F)
Targeted Neurological Exam
The Targeted Neurological Examination, which is intended to focus on tests where drug 
effects can be seen, includes the following tests only:
MODULE 1 – MENTAL STATUS EXAMINATION
A. General Level of Arousal: Generally assess general level of alertness, attentiveness, and 
concentration throughout the interview. Regarding attentiveness, note evidence of 
impaired attention or concentration. For example difficulty remembering or following 
instructions or distractibility may be signs of inattention)
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MODULE 2 – CRANIAL NERVE ASSESSMENT
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
MODULE 3 - MOTOR SYSTEM
B. Muscle Tone
1. Ask the volunteer to relax.
2. Flex and extend the volunteer’s elbows (may also move wrists simultaneously) and at 
the knees (bilaterally). When testing the upper limbs, do this again while the subject 
makes large repetitive movements with the opposite arm (e.g. patting the palm of the 
hand on the knee).
3. There is a small, continuous resistance to passive movement.
Score: left and right
Grade: NORMAL, IMPAIRED, or DECREASED and describe abnormality
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.)
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D. Gait
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.
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event 
AIMS
Abnormal Involuntary Movement Scale
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
BARS
Barnes Akathisia Rating Scale
BDS
blood drug screen
BID
twice daily
BMI
body mass index
BP
blood pressure
CCU
Cardiac care unit
CI
confidence interval
Cmax
maximum plasma concentration
CNS
central nervous system 
CL
clearance
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form 
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale 
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group 
CYP
cytochrome P450
DDI
drug-drug interaction
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EPS
Extrapyramidal Symptoms
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
GI
gastrointestinal
HBsAg
hepatitis B surface antigen
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Abbreviation
Expanded Term
HIV
human immunodeficiency virus
HR
heart rate
IA(s)
interim analysis(ses)
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
LAM
lactational amenorrhea method
MDRD
Modification of Diet in Renal Disease
MHIS
Modified Hachinski Ischemia Scale
MMSE-2
Mini Mental State Examination Second Edition
MOA
Manual of Assessments
MRI
magnetic resonance imaging
NCS
not clinically significant
NDA
New Drug Application 
NPI
Neuropsychiatric Inventory
PCL
Protocol Clarification Letter
PK
pharmacokinetic
po
orally
PP
per-protocol
PR
partial response
PRO
patient-reported outcome
QD
Once a day
QP2
Department of Quantitative Pharmacology and Pharmacometrics
QTc
Corrected QT interval
RNA
ribonucleic acid
RR
respiratory rate
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SAS
Simpson-Angus Scale
SGOT
serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transminase
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SOP
Standard Operating Procedures
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Abbreviation
Expanded Term
SUSAR
suspected unexpected serious adverse reaction
Tmax
Time to maximum plasma concentration
t1/2
half life
UDS
urine drug screen
ULN
upper limit of normal
VS
vital signs
WBC
white blood cell
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
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11
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