Conditions: Alzheimer's Disease
Keywords: Alzheimer's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 99
Healthy volunteers: no

Brief summary:
The main purpose of this study was to assess the safety and efficacy of MK-1942 as adjunctive therapy in participants with mild to moderate Alzheimer's Disease (AD) dementia.

Detailed description:

Arms:
arm 1: Participants will receive a single 5 mg MK-1942 capsule twice daily (BID), taken orally for 12 weeks. A mock titration will be done to maintain the study blind despite no changes in dose. arm 2: Participants will receive a single 8 mg MK-1942 capsule twice daily (BID), taken orally for one week. Then the dose is titrated up to 15 mg MK-1942 capsule twice daily (BID), taken orally for up to 11 weeks. arm 3: Participants will receive a placebo capsule twice daily (BID), taken orally for 12 weeks. A mock titration will be done to maintain the study blind despite no changes in dose.

Interventions: intervention 1: MK-1942 intervention 2: Placebo
Intervention descriptions: intervention 1: MK-1942 oral capsule intervention 2: Placebo oral capsule

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT05602727  
Document Date: 
07-JUL-2022
A Phase 2a/2b Randomized, Placebo-Controlled Clinical Study to 
Evaluate the Safety and Efficacy of MK-1942 as Adjunctive 
Therapy in Participants with Mild to Moderate Alzheimer’s Disease 
Dementia


PRODUCT: MK-1942  
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Title Page
THIS PROTOCOL 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 Phase 2a/2b Randomized, Placebo-Controlled Clinical Study to Evaluate 
the Safety and Efficacy of MK-1942 as Adjunctive Therapy in Participants with Mild to 
Moderate Alzheimer’s Disease Dementia
Protocol Number: 008-00
Compound Number: MK-1942
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
139557
EudraCT
2021-006336-94
Approval Date: 07 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
Original Protocol
07-JUL-2022
Not applicable
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities...........................................................................................17
2
INTRODUCTION..........................................................................................................21
2.1
Study Rationale....................................................................................................21
2.2
Background ..........................................................................................................21
2.2.1
Pharmaceutical and Therapeutic Background .............................................21
2.2.2
Nonclinical and Clinical Studies..................................................................22
2.2.3
Ongoing Clinical Studies.............................................................................24
2.2.4
Information on Other Study-related Therapy ..............................................24
2.3
Benefit/Risk Assessment......................................................................................24
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................24
4
STUDY DESIGN............................................................................................................27
4.1
Overall Design......................................................................................................27
4.2
Scientific Rationale for Study Design.................................................................28
4.2.1
Rationale for Endpoints ...............................................................................28
4.2.1.1
Efficacy Endpoints/QoL Endpoints...................................................28
4.2.1.2
Safety Endpoints................................................................................29
4.2.1.3
Pharmacokinetic Endpoints ...............................................................29
4.2.1.4
Pharmacodynamic Endpoints.............................................................30
4.2.1.5
Planned Exploratory Biomarker Research.........................................30
4.2.1.5.1
Planned Genetic Analysis ........................................................30
4.2.1.5.2
Exploratory Biomarker Analysis .............................................30
4.2.1.6
Future Biomedical Research..............................................................30
4.2.2
Rationale for the Use of Placebo .................................................................31
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................31
4.3
Justification for Dose...........................................................................................31
4.3.1
Starting Dose for This Study........................................................................31
4.3.2
Maximum Dose/Exposure for This Study ...................................................32
4.3.3
Rationale for Dose Interval and Study Design ............................................32
4.4
Beginning and End-of-Study Definition ............................................................32
4.4.1
Clinical Criteria for Early Study Termination .............................................32
5
STUDY POPULATION ................................................................................................33
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5.1
Inclusion Criteria.................................................................................................33
5.2
Exclusion Criteria................................................................................................35
5.3
Lifestyle Considerations......................................................................................39
5.3.1
Meals and Dietary Restrictions....................................................................39
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................40
5.3.3
Activity Restrictions ....................................................................................40
5.4
Screen Failures.....................................................................................................40
5.5
Participant Replacement Strategy......................................................................40
6
STUDY INTERVENTION............................................................................................41
6.1
Study Intervention(s) Administered...................................................................41
6.1.1
Medical Devices...........................................................................................43
6.2
Preparation/Handling/Storage/Accountability .................................................43
6.2.1
Dose Preparation..........................................................................................43
6.2.2
Handling, Storage, and Accountability........................................................43
6.3
Measures to Minimize Bias: Randomization and Blinding..............................44
6.3.1
Intervention Assignment..............................................................................44
6.3.2
Stratification.................................................................................................44
6.3.3
Blinding........................................................................................................44
6.4
Study Intervention Compliance..........................................................................44
6.5
Concomitant Therapy..........................................................................................45
6.5.1
Rescue Medications and Supportive Care ...................................................45
6.6
Dose Modification (Escalation/Titration) ..........................................................45
6.7
Intervention After the End of the Study............................................................46
6.8
Clinical Supplies Disclosure................................................................................46
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................46
7.1
Discontinuation of Study Intervention...............................................................46
7.2
Participant Withdrawal From the Study...........................................................48
7.3
Lost to Follow-up .................................................................................................48
8
STUDY ASSESSMENTS AND PROCEDURES........................................................49
8.1
Administrative and General Procedures ...........................................................50
8.1.1
Informed Consent.........................................................................................50
8.1.1.1
General Informed Consent.................................................................50
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................50
8.1.2
Inclusion/Exclusion Criteria ........................................................................51
8.1.3
Participant Identification Card.....................................................................51
8.1.4
Medical History ...........................................................................................51
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8.1.5
Prior and Concomitant Medications Review...............................................51
8.1.5.1
Prior Medications...............................................................................51
8.1.5.2
Concomitant Medications..................................................................52
8.1.6
Diagnostic Assessment and External Verification of Diagnosis .................52
8.1.7
Assignment of Screening Number...............................................................52
8.1.8
Assignment of Treatment/Randomization Number.....................................53
8.1.9
IRT Visit Registration, IRT Randomization, and Study Intervention 
Dispensing....................................................................................................53
8.1.10
Study Intervention Administration ..............................................................53
8.1.10.1
Timing of Dose Administration.........................................................53
8.1.11
Witnessed Dose............................................................................................54
8.1.12
Study Intervention Accountability...............................................................54
8.1.13
Telephone Contacts (Site to Study Partner).................................................54
8.1.14
Discontinuation and Withdrawal .................................................................55
8.1.14.1
Withdrawal From Future Biomedical Research ................................55
8.1.15
Participant Blinding/Unblinding..................................................................55
8.1.16
Calibration of Equipment.............................................................................56
8.2
Efficacy/QoL/Screening Assessments.................................................................56
8.2.1
Participant Assessed.....................................................................................57
8.2.1.1
MMSE................................................................................................57
8.2.1.2
Modified Hachinski Ischemia Scale ..................................................57
8.2.1.3
ADAS-Cog.........................................................................................58
8.2.1.4
CERAD Verbal Fluency Test ............................................................58
8.2.1.5
Controlled Oral Word Association Test ............................................58
8.2.1.6
Coding................................................................................................58
8.2.1.7
Trail Making Test ..............................................................................58
8.2.2
ADCS-CGIC................................................................................................58
8.2.3
Study Partner Assessed................................................................................59
8.2.3.1
ADCS-ADL .......................................................................................59
8.2.3.2
Neuropsychiatric Inventory - Questionnaire (NPI-Q) .......................59
8.2.3.3
EuroQol 5-Dimensional Health-Related Quality of Life Scale 
(EQ-5D-5L)........................................................................................59
8.3
Safety Assessments...............................................................................................59
8.3.1
Physical Examination...................................................................................60
8.3.2
Neurological Examination ...........................................................................60
8.3.3
Vital Signs, Height, and Weight ..................................................................60
8.3.4
Electrocardiograms ......................................................................................61
8.3.5
Clinical Safety Laboratory Assessments .....................................................61
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8.3.6
Suicidal Ideation and Behavior Monitoring.................................................62
8.3.6.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................62
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................62
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................63
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......65
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...65
8.4.4
Regulatory Reporting Requirements for SAE .............................................65
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........................................................................................66
8.6
Pharmacokinetics.................................................................................................66
8.6.1
Blood Collection for Plasma MK-1942 .......................................................67
8.7
Pharmacodynamics..............................................................................................68
8.8
Biomarkers ...........................................................................................................68
8.8.1
Planned Genetic Analysis Sample Collection..............................................68
8.9
Future Biomedical Research Sample Collection...............................................68
8.10
Health Economics Medical Resource Utilization and Health Economics.......68
8.11
Visit Requirements...............................................................................................68
8.11.1
Screening......................................................................................................70
8.11.1.1
Rater Training Vendor Review of Participant Eligibility..................71
8.11.1.2
MRI....................................................................................................71
8.11.2
Treatment Period..........................................................................................72
8.11.3
EOT/DC Visit ..............................................................................................72
8.11.4
Participants Discontinued From Study Intervention but Continuing to 
Be Monitored in the Study...........................................................................72
8.11.5
Postdose Follow-up Visit.............................................................................73
8.11.6
Poststudy......................................................................................................73
9
STATISTICAL ANALYSIS PLAN .............................................................................73
9.1
Statistical Analysis Plan Summary.....................................................................74
9.2
Responsibility for Analyses/In-house Blinding .................................................75
9.3
Hypotheses/Estimation ........................................................................................75
9.3.1
Estimands.....................................................................................................75
9.4
Analysis Endpoints...............................................................................................77
9.4.1
Efficacy Endpoints.......................................................................................77
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9.4.2
Safety Endpoints..........................................................................................78
9.4.3
Pharmacokinetic Endpoints .........................................................................78
9.5
Analysis Populations............................................................................................79
9.5.1
Efficacy Analysis Populations.....................................................................79
9.5.2
Safety Analysis Populations ........................................................................79
9.5.3
Pharmacokinetic Analysis Populations........................................................79
9.6
Statistical Methods...............................................................................................80
9.6.1
Statistical Methods for Efficacy Analysis....................................................80
9.6.2
Statistical Methods for Safety Analysis.......................................................82
9.6.2.1
Overall Safety Assessment ................................................................82
9.6.2.2
Assessment of Safety Topics of Special Interest ...............................83
9.6.3
Statistical Methods for Pharmacokinetic Analysis ......................................85
9.6.4
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................85
9.7
Interim Analyses ..................................................................................................85
9.8
Multiplicity ...........................................................................................................88
9.9
Sample Size and Power Calculations .................................................................88
9.9.1
Efficacy Parameter Estimates ......................................................................88
9.9.2
Sample Size and Power for Efficacy Analyses............................................89
9.9.3
Sample Size and Power for Safety Analyses ...............................................90
9.10
Subgroup Analyses...............................................................................................90
9.11
Compliance (Medication Adherence).................................................................91
9.12
Extent of Exposure...............................................................................................91
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................92
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........92
10.1.1
Code of Conduct for Clinical Trials.............................................................92
10.1.2
Financial Disclosure.....................................................................................94
10.1.3
Data Protection.............................................................................................95
10.1.3.1
Confidentiality of Data ......................................................................95
10.1.3.2
Confidentiality of Participant Records...............................................95
10.1.3.3
Confidentiality of IRB/IEC Information............................................95
10.1.4
Committees Structure...................................................................................96
10.1.4.1
External Data Monitoring Committee ...............................................96
10.1.4.2
Scientific Advisory Committee..........................................................96
10.1.4.3
Executive Oversight Committee........................................................96
10.1.5
Publication Policy........................................................................................96
10.1.6
Compliance with Study Registration and Results Posting Requirements ...97
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10.1.7
Compliance with Law, Audit, and Debarment ............................................97
10.1.8
Data Quality Assurance ...............................................................................98
10.1.9
Source Documents .......................................................................................98
10.1.10
Study and Site Closure.................................................................................99
10.2
Appendix 2: Clinical Laboratory Tests............................................................100
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................102
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................102
10.3.2
Definition of AE ........................................................................................102
10.3.3
Definition of SAE ......................................................................................103
10.3.4
Additional Events Reported.......................................................................104
10.3.5
Recording AE and SAE .............................................................................105
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................108
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................110
10.5
Appendix 5: Contraceptive Guidance..............................................................111
10.5.1
Definitions..................................................................................................111
10.5.2
Contraception Requirements......................................................................112
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................113
10.7
Appendix 7: Country-specific Requirements..................................................118
10.8
Appendix 8: Abbreviations ...............................................................................119
11
REFERENCES.............................................................................................................122
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LIST OF TABLES
Table 1
Prohibited Medications and Specified Washout Period...................................37
Table 2
Study Interventions..........................................................................................42
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................64
Table 4
PK Sampling Information................................................................................67
Table 5
Analysis of Key Efficacy Variables.................................................................81
Table 6
Analysis Strategy for Safety Parameters..........................................................84
Table 7
Summary of Interim Analysis Strategy............................................................86
Table 8
Operating Characteristics of the Interim Futility Analysis..............................87
Table 9
Assumed Variances and Correlations Used in the Power Simulations............89
Table 10
Power Calculations for ADAS-Cog11 Total Score and CGIC........................89
Table 11
Protocol-Required Safety Laboratory Assessments.......................................101
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................16
Figure 2
Formal Hypothesis Testing Strategy.........................................................88
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2a/2b Randomized, Placebo-Controlled Clinical Study to Evaluate 
the Safety and Efficacy of MK-1942 as Adjunctive Therapy in Participants with Mild to 
Moderate Alzheimer’s Disease Dementia
Short Title: Phase 2a/2b Study of MK-1942 in Participants with Alzheimer’s Disease
dementia
Acronym: not applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In male and female participants with mild to moderate Alzheimer’s Disease dementia:
Objectives
Endpoints
Primary
•
To assess the efficacy of MK-1942 
at 5 mg and 15 mg bid as 
adjunctive therapy on the ADAS-
Cog11 score compared with 
placebo at Week 12.
Hypothesis: At least one MK-1942 
dose is superior to placebo with 
respect to change from baseline in 
the ADAS-Cog11 score at 
Week 12.
•
To evaluate the safety and 
tolerability of MK-1942 as 
adjunctive therapy.
•
Change from baseline in the ADAS-Cog11 
score at Week 12
•
AEs
•
Discontinuation of study intervention due to 
AEs
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Objectives
Endpoints
Secondary
•
To assess the efficacy of MK-1942 
at 5 mg and 15 mg bid as 
adjunctive therapy on the ADCS-
CGIC Overall score compared with 
placebo at Week 12.
Hypothesis: At least one MK-1942 
dose is superior to placebo with 
respect to ADCS-CGIC Overall 
score at Week 12.
•
To assess the efficacy of MK-1942 
at 5 mg and 15 mg bid as 
adjunctive therapy on the ADCS-
ADL Total score as compared with 
placebo at Week 12.
•
Hypothesis: At least one MK-1942 
dose is superior to placebo with 
respect to the change from baseline 
ADCS-ADL Total score at 
Week 12.
•
ADCS-CGIC Overall score at Week 12
•
Change from baseline in the ADCS-ADL 
Total score at Week 12 
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Treatment of AD dementia
Population
Participants with mild to moderate AD dementia
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo-controlled
Study Blinding
Double-blind with in-house blinding
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Blinding Roles
Investigator
Sponsor
Participants or Subjects
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 41 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:
Approximately 408 participants will be allocated/randomized such that approximately 
324 evaluable participants complete the study as described in Section 9.9.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Treatment 
Period
Use
MK-1942 5 mg
MK-1942
5 mg
bid
oral
Week 1-
Week 12
Test Product
MK-1942 
15 mg
MK-1942
8 mg
bid
oral
Week 1
Test Product
MK-1942
15 mg
bid
oral
Week 2-
Week 12
Test Product
Placebo
Placebo
0 mg
bid
oral
Week 1-
Week 12
Placebo
bid=twice daily
Note 1: The dose of MK-1942 for participants in the MK-1942 15-mg dose group will be up-titrated 
as follows: 8 mg bid (Visit 2/Day 1 to Visit 3/Week 1) and 15 mg bid (Visit 3/Week 1 to Visit 
4/Week 2). Placebo and MK-1942 5 mg treatment groups will undergo a mock titration to maintain 
the study blinding.
Total 
Number of 
Intervention 
Groups/
Arms
3
Duration of 
Participation
Each participant will participate in the study for approximately 26 weeks 
from the time the participant provides documented informed consent
through the final contact. After a screening phase of up to 12 weeks, each 
participant will receive assigned intervention for approximately 12 weeks. 
After the end of treatment, each participant will be followed for 14 days.
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Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations is in Appendix 8.
1.2
Schema
The study design is depicted in Figure 1.
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Figure 1
Study Design
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1.3
Schedule of Activities
Study Period:
Screen
-ing
Double-Blind Treatment Period
Postdose 
Follow-up 
Period
Notes
Visit Number/Title:
1
2
3
4
5
6
7
8/EOT/
DCa
9/
14 days 
postdose
Scheduled Visit Week/Day:
Wk -
12
Wk 0/ 
Day 1
Wk 1/ 
Day 8
Wk 2/ 
Day 15
Wk 4/ 
Day 29
Wk 6/ 
Day 43
Wk 9/ 
Day 64
Wk 12/ 
Day 85
Wk 14/
Day 99
Screening period may be 
<12 weeks and can be split across 
>1 visit if needed 
(see Section 8.11.1)
Visit Window (Days)
0
±2
±2
±3
±3
±5
±5
+3
Administrative Procedures
Informed Consent (Participant 
and Study Partner)
X
Informed Consent for FBR
X
Participants remain eligible for 
the main study if they opt out of 
FBR
Inclusion/Exclusion Criteria
X
X
Participant Identification Card
X
X
Randomization number will be 
added to the card at Visit 2
Medical History 
X
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
Diagnostic Verification Form 
Review
X
Assignment of Screening Number
X
IRT Visit Registration
X
X
X
X
X
X
X
X
IRT Randomization 
X
Study Intervention Dispensing
X
X
X
X
X
X
Participants should fast for 1 hour 
before and 1 hour after dosing. 
See Section 5.3.1
Study Medication Guidance 
Dispensing and Review
X
X
X
X
X
X
X
Witnessed Dose
X
X
X
To be taken after all assessments 
and procedures are complete, 
except Visit 6 where dose to be 
taken after first PK draw.
Study Intervention Accountability
X
X
X
X
X
X
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Study Period:
Screen
-ing
Double-Blind Treatment Period
Postdose 
Follow-up 
Period
Notes
Visit Number/Title:
1
2
3
4
5
6
7
8/EOT/
DCa
9/
14 days 
postdose
Scheduled Visit Week/Day:
Wk -
12
Wk 0/ 
Day 1
Wk 1/ 
Day 8
Wk 2/ 
Day 15
Wk 4/ 
Day 29
Wk 6/ 
Day 43
Wk 9/ 
Day 64
Wk 12/ 
Day 85
Wk 14/
Day 99
Screening period may be 
<12 weeks and can be split across 
>1 visit if needed 
(see Section 8.11.1)
Visit Window (Days)
0
±2
±2
±3
±3
±5
±5
+3
Telephone Contacts After Visits
X
X
TCs will be made 2-4 days after 
Visits 2 and 3, if applicable (see 
Section 8.1.13).
Efficacy Procedures: 
See Section 8.2 for recommended 
efficacy assessment order
MMSE
X
X
X
X
ADAS-Cog13
X
X
X
X
To be administered to every 
participant; however, ADAS-
Cog11 will be primary efficacy 
endpoint
CERAD Verbal Fluency Test
X
X
X
X
COWAT
X
X
X
X
Trail Making Test Parts A and B
X
X
X
X
Coding
X
X
X
X
ADCS-CGIC
X
X
X
Participant and Study Partner 
assessed (See Section 8.2.2)
Efficacy Procedures: study 
partner assessed
ADCS-ADL
X
X
X
NPI-Q 
X
X
X
EQ-5D-5L (caregiver 
self-assessment version)
X
X
X
EQ-5D-5L (proxy version)
X
X
X
Screening Procedures
MHIS
X
MRI
X
Digital MRI performed within 18
months before Screening Visit is 
acceptable if images are available 
and suitable for central review
08K6VN


PRODUCT: MK-1942  
19
PROTOCOL/AMENDMENT NO.: 008-00 
MK-1942-008-00 FINAL PROTOCOL
07-JUL-2022
Study Period:
Screen
-ing
Double-Blind Treatment Period
Postdose 
Follow-up 
Period
Notes
Visit Number/Title:
1
2
3
4
5
6
7
8/EOT/
DCa
9/
14 days 
postdose
Scheduled Visit Week/Day:
Wk -
12
Wk 0/ 
Day 1
Wk 1/ 
Day 8
Wk 2/ 
Day 15
Wk 4/ 
Day 29
Wk 6/ 
Day 43
Wk 9/ 
Day 64
Wk 12/ 
Day 85
Wk 14/
Day 99
Screening period may be 
<12 weeks and can be split across 
>1 visit if needed 
(see Section 8.11.1)
Visit Window (Days)
0
±2
±2
±3
±3
±5
±5
+3
Safety Procedures
Full physical examination 
X
X
Neurological Examination
X
X
Height
X
Weight
X
X
X
X
Vital Signs (temperature, blood 
pressure, pulse rate, and 
respiratory rate)
X
X
X
X
X
X
X
X
12-lead ECG (centrally read)
X
X
X
X
Measured in triplicate at each 
visit (see Section 8.3.4)
Serum Follicle-Stimulating 
Hormone (FSH) (if applicable)
X
FSH may be measured to confirm 
postmenopausal state. (See 
Appendix 5).
Chemistry and Hematology
X
X
X
X
X
X
X
X
Visit 9 laboratory assessments 
may be performed at a local
laboratory, as needed. See 
Appendix 2.
Urinalysis
X
X
X
X
INR
X
TSH
X
with reflex FT4
AE/SAE review
X
X
X
X
X
X
X
X
X
Visit 9 AE monitoring may be 
performed by TC, as needed
C-SSRS Baseline/Screening 
version
X
C-SSRS Since Last Visit
X
X
X
X
X
X
X
X
Visit 9 C-SSRS may be 
performed by TC, as needed.
08K6VN


PRODUCT: MK-1942  
20
PROTOCOL/AMENDMENT NO.: 008-00 
MK-1942-008-00 FINAL PROTOCOL
07-JUL-2022
Study Period:
Screen
-ing
Double-Blind Treatment Period
Postdose 
Follow-up 
Period
Notes
Visit Number/Title:
1
2
3
4
5
6
7
8/EOT/
DCa
9/
14 days 
postdose
Scheduled Visit Week/Day:
Wk -
12
Wk 0/ 
Day 1
Wk 1/ 
Day 8
Wk 2/ 
Day 15
Wk 4/ 
Day 29
Wk 6/ 
Day 43
Wk 9/ 
Day 64
Wk 12/ 
Day 85
Wk 14/
Day 99
Screening period may be 
<12 weeks and can be split across 
>1 visit if needed 
(see Section 8.11.1)
Visit Window (Days)
0
±2
±2
±3
±3
±5
±5
+3
PK and Biomarkers
MK-1942/Placebo Plasma PK 
sample
X
X
X
Two PK samples will be drawn at 
Visit 6. See Section 8.6 for 
details.
AChEI Plasma PK sample
X
X
X
See Section 8.6 for details
Will be collected for all 
randomized participants.
Memantine Plasma PK sample
X
X
X
Will be collected for participants 
taking memantine 
(see Section 8.6).
Blood for Genetic Analysis 
X
Sample will be collected predose 
in randomized participants only 
(see Section 8.8).
Plasma for  Exploratory Research
X
Genotyping for CYP2C19
X
Blood Sample for APOE4
X
Blood Sample for AD 
Biomarkers
X
X
AChEI=acetylcholinesterase inhibitor, AD=Alzheimer’s Disease Dementia; ADAS-Cog13=Alzheimer’s Disease Assessment Scale- 11-item cognitive subscale; 
ADCS-CGIC=Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change; ADCS-ADL=Alzheimer’s Disease Cooperative Study Activities of Daily Living; 
AE=adverse event; APOE=apolipoprotein E; hCG=human chorionic gonadotropin; CERAD=Consortium to Establish a Registry for Alzheimer’s Disease; COWAT=Controlled 
Oral Word Association Test; C-SSRS=Columbia Suicide Severity Rating Scale; DC=discontinuation from study intervention or discontinuation from study; EOT=End of 
Treatment; FBR=future biomedical research; FSH=follicle-stimulating hormone; ID=identification; INR=international normalized ratio; IRT=interactive response technology; 
MMSE=Mini-Mental State Examination; MRI=Magnetic Resonance Imaging; NPI-Q=Neuropsychiatric Inventory; PK=pharmacokinetic; SAE=serious adverse event; 
TC=telephone contact; TSH=thyroid-stimulating hormone
Note:  For HBV, HCV, and HIV testing at screening, see Appendix 7 (Country-specific Requirements).
a If a participant discontinues study intervention prematurely (before Visit 8) and continues with study visits off study intervention, a visit will still be completed at the scheduled 
Visit 8. If the participant who discontinues study intervention discontinues the study before Visit 8, a study DC visit will be conducted at that time with the same procedures as the 
EOT visit. See Section 8.11.4 for details.
08K6VN


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.91


PRODUCT: MK-1942  
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2.2.3
Ongoing Clinical Studies
One clinical study of MK-1942 is ongoing. Further details can be found in the IB Section 5.
P006 is a Phase 2a double-blind, placebo-controlled, multiple-dose clinical study to evaluate 
the efficacy and safety of MK-1942 added to stable antidepressant therapy in participants 
with treatment-resistant depression.
2.2.4
Information on Other Study-related Therapy
This section does not apply to the current study.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Phase 1 clinical studies to date have shown that treatment with MK-1942 is generally well
tolerated. Participants may also experience headaches that are mild to moderate in intensity. 
Episodes of dizziness and headache may be accompanied by feelings of nausea with or 
without emesis. There are limited treatment options and tolerability issues with current 
treatments for participants with mild to moderate AD dementia, and given the available 
nonclinical and clinical data for MK-1942 summarized above and in the IB, the 
benefit-to-risk assessment for conducting the current study is considered favorable.
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
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
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In male and female participants with mild to moderate Alzheimer’s Disease dementia:
Objectives
Endpoints
Primary
•
To assess the efficacy of MK-1942 at 5 mg 
and 15 mg bid as adjunctive therapy on the 
ADAS-Cog11 score compared with placebo 
at Week 12.
Hypothesis: At least one MK-1942 dose is 
superior to placebo with respect to change 
from baseline in the ADAS-Cog11 score at 
Week 12.
•
To evaluate the safety and tolerability of 
MK-1942 as adjunctive therapy.
•
Change from baseline in the 
ADAS-Cog11 score at Week 12
•
AEs
•
Discontinuation of study 
intervention due to AEs
Secondary
•
To assess the efficacy of MK-1942 at 5 mg 
and 15 mg bid as adjunctive therapy on the 
ADCS-CGIC Overall score compared with 
placebo at Week 12.
Hypothesis: At least one MK-1942 dose is 
superior to placebo with respect to ADCS-
CGIC Overall score at Week 12.
•
To assess the efficacy of MK-1942 at 5 mg 
and 15 mg bid as adjunctive therapy on the 
ADCS-ADL Total score as compared with 
placebo at Week 12.
•
Hypothesis: At least one MK-1942 dose is 
superior to placebo with respect to the 
change from baseline ADCS-ADL Total 
score at Week 12.
•
ADCS-CGIC Overall Score at 
Week 12
•
Change from baseline in the 
ADCS-ADL total score at Week 12
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Objectives
Endpoints
Tertiary/Exploratory
•
To assess the efficacy of MK-1942 at 5 mg 
and 15 mg bid as adjunctive therapy on the 
on the NPI-Q Total severity score as 
compared with placebo at Week 12.
•
Change from baseline in the NPI-Q 
total severity score at Week 12
•
To assess the efficacy of MK-1942 at 5 mg 
and 15 mg bid as adjunctive therapy on the 
following scores compared with placebo 
over time up to Week 12:
•
ADAS-Cog11
•
ADAS-Cog13
•
ADCS-CGIC Scores (General Condition, 
Cognition, Behavior, Function, Overall)
•
COWAT
•
Coding
•
Trail Making Test Parts A and B
•
CERAD Verbal Fluency Test
•
MMSE
•
EQ-5D-5L
•
ADAS-Cog11 score over time up to 
Week 12
•
ADAS-Cog13 score over time up to 
Week 12
•
ADCS-CGIC scores (General 
Condition, Cognition, Behavior, 
Function, Overall) over time up to 
Week 12
•
COWAT score over time up to 
Week 12
•
Coding score over time up to Week 
12
•
Trail Making Test Parts A&B score 
over time up to Week 12
•
CERAD Verbal Fluency Test score 
over time up to Week 12
•
MMSE over time up to Week 12
•
EQ-5D-5L score over time up to 
Week 12
•
To assess the percentage of participants who 
have an improvement in the ADCS-CGIC 
Overall score at Week 12.
•
Improvement in the ADCS-CGIC 
Overall score at Week 12 (with a 
score of 1, 2, or 3 indicating 
improvement)
•
To assess the effect of MK-1942 on the 
composite scores of Memory, Executive 
function, and Attention over time up to Week 
12.
•
Composite score of Memory over 
time up to Week 12
•
Composite score of Executive 
function over time up to Week 12
•
Composite score of Attention over 
time up to Week 12
08K6VN


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Objectives
Endpoints
•
To assess the effect of MK-1942 on the 
ADAS-Cog11 score at the item-level over 
time up to Week 12.
•
Item response theory derived 
ADAS-Cog11 score over time up to 
Week 12
•
To identify molecular (genomic, metabolic, 
and/or proteomic) biomarkers that may be 
indicative of clinical response/resistance, 
safety, PD activity, and/or the mechanism of 
action of MK-1942.
•
Molecular (genomic, metabolic, 
and/or proteomic) determinants 
using blood
•
To explore the relationship between the 
germline genetic variation and the response 
to the treatment(s), and mechanisms of 
disease. Variation across the human genome 
may be analyzed for association with clinical 
data collected in the study.
•
Germline genetic variation
•
To evaluate the plasma PK of MK-1942.
•
MK-1942 plasma PK
•
To explore the relationship between MK-
1942 PK and treatment response on clinical 
measures of efficacy.
•
MK-1942 plasma PK and clinical 
efficacy measures (eg, ADAS-
Cog11)
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, parallel-group, multisite, double-blind study of 
MK-1942 as adjunctive therapy in participants with mild to moderate AD dementia. The 
study population will consist of male and female participants aged 55 to 90 years with mild
to moderate AD dementia according to clinical criteria (NINCDS-ADRDA) [McKhann, G., 
et al 1984]. Participants will continue taking their stable background AD therapy during the 
study.
Approximately 408 participants will be randomized in a 1:1:1 ratio to treatment with either 
(1) MK-1942 5 mg bid, (2) MK-1942 15 mg bid, or (3) placebo bid, respectively
(Section 1.2). MK-1942 or matching placebo will be administered as oral capsules, all of 
which are the same image. No more than ~ 60% of participants are to be enrolled in each of 
2 MMSE strata (MMSE ≤16, ≥17).
Note that initial dosing and titration of study intervention to target dose is described in 
Section 6.6.
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For each participant, this study will last approximately 26 weeks, with an initial screening 
period up to 12 weeks, followed by a treatment period of 12 weeks. The 12-week treatment 
period consists of an initial 1-week titration period to reach target dose for the 15-mg bid 
treatment group. A follow-up period consists of 14 days after the last dose of study 
intervention.
If the participant discontinues study intervention treatment before the intended last visit at 
Week 12, then an EOT visit should be completed as soon as possible after the last dose. For 
participants who continue study visits after the EOT visit, refer to Section 8.11.4.
A nonbinding futility IA may be performed when the first 50% of randomized participants 
have had the opportunity to treat for 12 weeks (ie, the IA will be based on a data cutoff that is 
12 weeks after the randomization of the 204th participant). An eDMC will review the results 
of the one unblinded futility analysis in addition to reviewing unblinded safety data on a 
regular basis.
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
This Phase 2a/2b study will evaluate the therapeutic effect of MK-1942 in participants with 
mild to moderate AD dementia on stable AChEI therapy, and to characterize the safety and 
tolerability of MK-1942 in this population. The treatment duration will be 12 weeks. This 
duration is sufficient to show the effect of MK-1942 on cognition and function. The study 
will use a double-blind, parallel-group design in the assessment of MK-1942 versus placebo. 
This design is compatible with standard of care and recruitment of a typical AD dementia 
population given the wide use of AChEIs. Rationale for doses is described in Section 4.3.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints/QoL Endpoints
The ADAS-Cog [Rosen, W. G., et al 1984]has become the standard instrument for 
demonstrating cognitive efficacy in AD drug trials. The traditional 11-item version of the 
ADAS-Cog (ie, the ADAS-Cog11) will be the primary endpoint. The ADAS-Cog13 (which 
includes all components of the ADAS-Cog11 in addition to Delayed Word Recall and 
Number Cancellation) will be administered to all participants.
Symptomatic treatments for AD dementia must show efficacy in terms of cognition and 
global function. The ADCS-CGIC Overall Score is a measure of global performance
[Becker, R. 1996]. Improvement on the ADCS-CGIC Overall Score at Week 12 will be a key 
secondary efficacy endpoint. The ADCS-ADL is a measure of daily function, assessing both 
instrumental and basic activities of daily living [Galasko, D., et al 1997]. Improvement on the 
ADCS-ADL Total score at Week 12 will be a secondary efficacy endpoint.
08K6VN


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The NPI-Q is a behavior instrument widely used in clinical trials of antidementia agents
[Cummings, J. L., et al 1994]. Improvement on the NPI-Q Total severity score at Week 12 
will be an exploratory efficacy endpoint.
There are some cognitive domains which are not well assessed by the ADAS-Cog11, 
specifically, executive functioning and working memory. The mechanism of action of 
MK-1942 is believed to positively impact these cognitive subdomains. Therefore, additional 
assessment items are included in this protocol to further interrogate these domains: Trail 
Making Tests [Reitan, R. M. 1955] [Reitan, R. M. and Wolfson, D. 1985], Coding
[Wechsler, D. 1981], CERAD Verbal Fluency Test [Morris, J. C., et al 1989], COWAT
[Lezak, M. D. 1995], and composite scores of memory, executive function, and attention.
MMSE is used extensively in clinical and research settings to detect and measure cognitive 
impairment [Folstein, M. F., et al 1975]. It is also used to estimate the severity and
progression of cognitive impairment and to follow the course of cognitive changes in an 
individual over time. All of the above will be exploratory endpoints.
Developed by the EuroQol Group, the EQ-5D [Herdman, M., et al 2011] is a simple, generic 
questionnaire, which is widely used in clinical trials around the world as a standardized 
measure of health-related quality of life. The EQ-5D-5L assesses health status in terms of 5
dimensions of health and is considered a “generic” questionnaire because these dimensions 
are not specific to any one patient group or health condition. This will be an exploratory 
endpoint.
4.2.1.2
Safety Endpoints
Safety and tolerability will be assessed throughout the study by monitoring participants for 
AEs. Physical examinations, neurological examinations, vital signs, 12-lead ECGs, and 
laboratory safety tests will be performed to detect any clinically meaningful effects. C-SSRS
will be administered to assess the presence and severity of possible suicidal ideation and 
behavior in all study participants (Section 4.2.3). Liver enzymes will be monitored every two 
to three weeks. 
4.2.1.3
Pharmacokinetic Endpoints
Plasma PK sampling for MK-1942, AChEIs, and memantine will be conducted. PK 
assessments of MK-1942 may be used to support exposure-response analyses and to 
understand PK variability. AChEI (donepezil, rivastigmine, or galantamine) and memantine 
(if applicable) PK will also inform PK variability and treatment compliance. The analysis 
(quantitative or semiquantitative) and reporting of any additional, yet to be identified 
metabolites may be conducted using collected PK samples.
The final decision as to which plasma samples will be measured will be made by the 
Sponsor’s Department of Quantitative Pharmacology and Pharmacometrics and the Clinical 
Monitor.
08K6VN


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4.2.1.4
Pharmacodynamic Endpoints
Pharmacodynamic endpoints are not applicable.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
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, CYP2C19/APOE4 will 
specifically be investigated and their impact on MK-1942 PK and drug response.
4.2.1.5.2
Exploratory Biomarker Analysis
The study will collect blood samples for exploratory analysis of biomarkers that may indicate 
the presence of AD pathology. These emerging biomarkers are being explored for utility as 
possible supportive markers to potentially corroborate the clinical diagnosis of AD dementia 
and indicate neurodegenerative pathology. The rationale for inclusion of exploratory analysis 
in this study is to ascertain the value of using the evaluated biomarker assays as potential 
screening tests for use in a mild/moderate AD dementia population. These exploratory 
analyses will be performed on a post hoc basis, including the possibility of using biomarker 
assays or panels that have not been specifically identified at the time of this protocol 
finalization, but are under development and are anticipated to be available by the completion 
of this study.
4.2.1.6
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.
08K6VN


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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1) this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines 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.
5.1
Inclusion Criteria
A participant is eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has mild to moderate AD dementia based on the NINCDS-ADRDA criteria [McKhann, 
G., et al 1984].
2. Has MMSE score between 12-22 (inclusive) at Screening.
Demographics
3. Is male or female, from 55 years to 90 years of age inclusive, at the time of providing 
documented informed consent.
Male Participants
4. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 7 days after the last dose of study intervention):
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause documented from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview
[Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
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•
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female Participants
5. A female participant is eligible to participate if:
-
She is a WONCBP, as defined in Appendix 5.
Informed Consent
6. The participant (or legally acceptable representative) has provided documented informed 
consent for the study in accordance with local requirements. The participant (or legally 
acceptable representative) may also provide consent for FBR. However, the participant 
may participate in the study without participating in FBR.
Additional Categories
7. Is using AChEI therapy for management of AD dementia at Screening and during the 
study. These medications must be at stable approved dose levels ≥3 months before the 
first dose of study intervention and the regimens must remain constant throughout the 
study to the extent that is clinically appropriate (see Section 8.1.5.2 for allowed AChEI 
therapies and doses).
8. Has an MRI scan at Screening that is consistent with the diagnosis of AD. MRI scans will 
be analyzed by a central MRI reviewer. A digital MRI performed within 18 months 
before the Screening Visit is acceptable provided the images are available and suitable 
for central review.
NOTE: If MRI is not available, it can be performed as part of study procedures. A CT 
scan instead of an MRI can be accepted with Sponsor consultation in certain cases (eg, 
participant has contraindication to MRI). See Section 8.11.1.2 for details. 
9. Is able to speak, read, hear, and understand the language and information provided by the 
study staff; and possesses the ability to respond verbally to questions, follow instructions, 
and complete clinical assessments, including cognitive assessments, based on the 
investigator’s judgment.
10. Is able and willing to adhere to dose and visit schedules in the investigator’s judgment,
and is willing to have selected interviews audio recorded.
11. Has a designated study partner who can fulfill the requirements of this study. The study 
partner will need to spend sufficient time with the participant to be familiar with their
overall function and behavior and be able to provide adequate information about the 
participant needed for the study including, knowledge of functional and basic activities of 
daily life, work/educational history, cognitive performance, emotional/psychological 
state, and general health status. The investigator will assess the study partner’s 
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capabilities to reliably assess the participant. See Section 8.11 for details of study partner 
responsibilities.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a known history of stroke or cerebrovascular disease that is clinically important in 
the investigator’s opinion.
2. Has diagnosis of a clinically relevant central nervous system disease other than AD 
dementia (eg, vascular dementia, Parkinson disease, Huntington disease, frontotemporal 
dementia, multi-infarct dementia, dementia with Lewy bodies, normal pressure 
hydrocephalus, amyotrophic lateral sclerosis, multiple sclerosis, progressive supranuclear 
palsy, neurosyphilis, posterior cortical atrophy, logopenic primary progressive aphasia, 
other types of dementia, cognitive developmental delay, hypoxic cerebral damage, 
cognitive impairment due to other disorders, or head trauma with loss of consciousness 
that led to persistent cognitive deficits) or other condition that negatively impacts 
cognition or cognitive status chronically.
3. Has structural brain disease or other features such as acute ischemic disease, 
hemorrhages, large infarct, lacunes in critical areas, (eg, thalamus or hippocampus) space 
occupying lesions, extensive white matter disease, or other brain abnormalities (eg,
normal pressure hydrocephalus) as assessed by blinded independent central review of 
MRI/CT scans.
4. Has a history of seizures or epilepsy within the 10 years preceding Screening.
5. Has any other major CNS trauma, or infections that affect brain function (eg, HIV, 
syphilis, and/or neurological sequelae of COVID-19, including impact on cognition).
6. Has evidence of a clinically relevant or unstable psychiatric disorder, based on criteria
from the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition), including 
schizophrenia or other psychotic disorder, bipolar disorder, major depression, or delirium. 
Major depression in remission is not exclusionary.
7. Has major medical illness or unstable medical condition within 3 months before 
Screening that, in the opinion of the investigator, may interfere with the participant’s 
ability to comply with study procedures and abide by study restrictions, or with the 
ability to interpret safety or efficacy data, including any physical disability (eg, blindness, 
deafness, non-AD-related speech impairment, sensory or motor dysfunction) that would 
prevent completion of study procedures or assessments.
8. Has a severe, acute, or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or administration of study 
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intervention or may interfere with the interpretation of study results and, in the opinion of 
the investigator or Sponsor, would make the participant inappropriate for entry into this 
study.
9. Has a history of malignancy occurring within the 5 years immediately before Screening, 
except for a participant who has been adequately treated for 1 or more of the following:
a. Basal cell or squamous cell skin cancer
b. In situ cervical cancer
c. Localized prostate carcinoma
d. Who has undergone potentially curative therapy with no evidence of recurrence for 
≥3 years post-therapy, and who is deemed to be at low risk for recurrence by their
treating physician
Note: Participants with stable chronic lymphocytic leukemia may participate in the 
study.
10. Has one of the following:
a. Vitamin B12 or folate deficiency confirmed by laboratory test results in the 
3 months immediately before Screening, or
b. Vitamin B12 or folate deficiency in addition to increased serum homocysteine or 
methylmalonic acid levels at Screening as determined by central laboratory normal 
values.
11. Has a risk factor for QTc prolongation as defined by:

A known history or current evidence of QTc interval >470 msec (men) or >480 
msec (women), OR

A known history of risk factors for Torsades de Pointes (eg, heart 
failure/cardiomyopathy or family history of long QT syndrome). Note that 
participants with stable history of congestive heart failure Stage A and B 
according to the ACC/AHA guidelines are eligible to participate in the trial.
Note: ECGs will be performed in triplicate. At Screening, the average of the 3 QTcF 
intervals based on the central vendor overread will be used to assess eligibility. At 
Visit 2 (Day 1), the average of the 3 QTcF intervals based on the local ECG printout 
will be used to assess eligibility (additional details on ECG assessments are in 
Section 8.3.4).
12. Has a history of alcoholism or drug dependency/abuse within the 5 years preceding
Screening.
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13. Based on clinical interview and responses on the C-SSRS, is at imminent risk of 
self-harm 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 or method (eg, 
positive response to item 4 or 5 in assessment of suicidal ideation on the C-SSRS) in the 
past 2 months or suicidal behavior in the past 6 months.
14. Has a known allergy or intolerance to the active or inert ingredients in MK-1942.
Prior/Concomitant Therapy
15. Has received any of the treatments listed in Table 1 more recently than the indicated 
period before Screening.
16. Anticipates receiving any of the treatments listed in Table 1 during the current study
Table 1
Prohibited Medications and Specified Washout Period
Prohibited Medications, Supplements, and Other Substances
Period Before 
Screening
Anti-amyloid agents (eg, tarenflurbil, tramiprosate)
3 months
Anti-amyloid antibodies (eg, bapineuzumab, aducanumab)
ever
CNS-penetrant anticholinergic medications
Regularly used (>2 doses/week) CNS-penetrant anticholinergic medications of moderate 
potency or greater (eg, benztropine, cyclobenzaprine, cyproheptadine, dicyclomine, 
diphenhydramine, promethazine, diphenoxylate with atropine, hydroxyzine, hyoscyamine, 
prochlorperazine,).
Exception: Daily use of anticholinergic medications for incontinence (eg, oxybutynin, 
tolterodine, darifenacin, solifenacin, trospium, fesoterodine), nasal spray for rhinorrhea 
(ipratropium) or inhalants for pulmonary disorders (eg, tiotropium) are acceptable if stable 
for ≥4 weeks before the first dose of study intervention.
4 weeks
Antidepressants
Antidepressants that are monoamine oxidase inhibitors or antidepressants with moderate or 
greater anticholinergic potency or cognitive side effects, including tricyclics (eg,
amoxapine, isocarboxazide, maprotiline, phenelzine, protriptyline, tranylcypromine, 
trimipramine).
4 weeks
Neuroleptics
Neuroleptics with moderate or greater anticholinergic potency (eg, chlorpromazine, 
fluphenazine, loxapine, perphenazine, thioridazine, thiothixene, trifluoperazine, clozapine)
4 weeks
Mood stabilizers and anticonvulsants (eg, lithium, valproic acid, levetiracetam, 
carbamazepine)
Exception: use of pregabalin and gabapentin for neuropathic pain is acceptable and must be 
stable dose for 4 weeks before first dose of study intervention.
4 weeks
General anesthetics 
3 months
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Prohibited Medications, Supplements, and Other Substances
Period Before 
Screening
Sedatives/benzodiazepines
Doses of lorazepam >3 mg/day or the equivalent dose of other benzodiazepines
Doses of the following partial benzodiazepine agonists: zolpidem >10 mg/day, zaleplon 
>20 mg/day, zopiclone >15 mg/day
Exception: For participants on an allowed dose of a benzodiazepine or partial 
benzodiazepine, the dose should be stable for ≥4 weeks before first dose of study 
intervention. For other medications in this category not specified here, please contact the 
Sponsor for guidance.
4 weeks
Analgesics/narcotics
Regularly used (>2 doses/week) narcotic analgesics (eg, codeine, morphine, 
hydromorphone, oxycodone, propoxyphene (Darvon) and its variations, and combination 
products that contain a narcotic).
Exception: short-term use (<4 weeks) more than 2 doses/week is acceptable for temporary 
conditions.
4 weeks
CYP2C19 inducers and substrates
Strong CYP2C19 inducers: carbamazepine (strong inducer), artemisinin, norethisterone, 
rifampin
CYP2C19 substrates: clopidogrel, propranolol, tolbutamide, warfarin, primidone, 
tapentadol, fluoxetine (doses >40 mg/day are prohibited), moclobemide, voriconazole
Note: Participants must discontinue CYP2C19 substrates at Screening or earlier.
4 weeks
Agents with glutamatergic activity (ketamine, esketamine, N-acetylcysteine, lamotrigine, 
riluzole).
Exception: use of memantine is acceptable and must be stable approved dose for at 
least 3 months before first dose of study intervention.
4 weeks
Anti-parkinsonian medications (eg, L-dopa, amantadine, bromocriptine, pergolide, 
selegiline, I-deprenyl/selegiline, rasagiline).
Exception: carbidopa/levodopa and dopamine agonists are allowed for treating restless leg 
syndrome and must be stable dose for ≥4 weeks before first dose of study intervention.
3 months
Stimulant medications (eg, amphetamine, methylphenidate, atomoxetine, modafinil)
4 weeks
Supplements with possible psychotropic effects (eg, kava-kava, melatonin, S-Adenosyl 
methionine [SAMe], St. John’s Wort, tryptophan, gingko, and valerian)
Exception: use of melatonin is acceptable and must be stable dose for at least 4 weeks 
before first dose of study intervention.
4 weeks
COVID-19 experimental therapies
Note: any licensed COVID 19 vaccine is allowed in the study and will be treated just as any 
other concomitant therapy.
4 weeks
NOTE: This is not a complete list of excluded medications. Contact the Sponsor if there is a question about a 
specific medication.
Prior/Concurrent Clinical Study Experience
17. Is currently participating in or has previously participated in an interventional clinical 
study within the 3 months before Screening.
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Diagnostic Assessments
18. Has MHIS >4 at Screening.
19. Has laboratory or clinical evidence of clinically significant hepatic conditions such as one 
or more of the following:
ALT ≥1.5 × ULN at Screening* or
AST ≥2 × ULN at Screening*
*Note: Participants may be retested 1 time at least 1 day after initial Screening
bloodwork.
20. Has liver disease, including but not limited to chronic viral hepatitis, nonviral hepatitis, 
cirrhosis, malignancies, autoimmune liver diseases (eg, autoimmune hepatitis, primary 
biliary cholangitis, or primary sclerosing cholangitis).
21. Has known renal disease or is experiencing renal insufficiency as defined by eGFR 
<30 mL/min/1.73 m2 (MDRD) at Screening).
22. Has an abnormal TSH value at Visit 1 (Screening). Exception: A participant with an 
abnormal TSH value and a normal FT4 value may be eligible if clinically stable and 
without signs of hypo- or hyperthyroidism, in the investigator’s judgment. Any thyroid 
treatment must be stable for ≥3 months before Visit 1 (Screening).
Other Exclusions
23. Resides in a nursing home or assisted care facility with need for direct continuous 
medical care and nursing supervision. Participant may reside in such facilities provided 
continuous direct medical care is not required and a qualified study partner is available 
for coparticipation and the participant is physically able to attend all required study visits.
24. Had major surgical procedure or donated or lost >1 unit of blood (approximately 500 mL) 
within the 4 weeks before Screening.
25. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, trial 
partner 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
Participants will refrain from consuming grapefruit juice, grapefruits, and grapefruit products 
from Screening through Visit 8 (EOT/DC Visit). Other types of fruit juice, fruits, and fruit 
products are permitted during the study. Sites should instruct participants to take study 
intervention with water.
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The participant should fast for at least 1 hour before and 1 hour after dosing with study 
intervention.
Evening dosing: Participants should take their evening dose of study intervention close to 
bedtime, at least 1 hour after the evening meal, and should continue to fast for at least 1 hour 
after dosing.
Morning dosing (days with no clinic visit and Visit 4, Visit 5, Visit 7, Visit 8): Participants 
should take their morning dose of study intervention at least 1 hour after a light breakfast, 
and should continue to fast for at least 1 hour after dosing.
Morning dosing (Visit 3 and Visit 6): participants must NOT take a morning dose of study 
intervention from the blister cards dispensed at the previous visit. A light breakfast (eg, a 
slice of toast with low fat spread, a cup of skim or 1% milk, a cup of nonfat yogurt, a packet 
of oatmeal made with water, or a piece of fruit [except grapefruit]) can be eaten at least 1
hour before dosing at these visits to minimize hunger. Participants should NOT eat a meal 
until at least 1 hour after taking study intervention from the new blister cards dispensed in the 
clinic.
For details of timing of visits, see Section 8.11.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
Participants will abstain from alcohol for 24 hours before each visit.
5.3.3
Activity Restrictions
Participants will be informed about the risk of dizziness with MK-1942 treatment and 
instructed not to drive or operate heavy machinery until they determine that study 
intervention, taken as directed, does not affect their ability to engage in these activities.
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 is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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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 will be packaged to support enrollment. 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 2. Country-specific 
differences are noted in Appendix.7.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Treatment 
Period
Use
IMP or
NIMP/
AxMP
Sourcing
MK-1942 
5 mg
Experimental
MK-1942
Drug
Capsule
5 mg
5 mg bid
Oral
Weeks 1-12
Test 
Product
IMP
Central
MK-1942 
15 mg
Experimental
MK-1942
Drug
Capsule
8 mg
8 mg bid
Oral
Week 1
Test 
Product
IMP
Central
MK-1942 
15 mg
Experimental
MK-1942
Drug
Capsule
15 mg 
15mg bid
Oral
Weeks 2-12
Test 
Product
IMP
Central
Placebo
Placebo 
Comparator
Placebo
Drug
Capsule
0 mg
0 mg bid
Oral
Weeks 1-12
Placebo
IMP
Central
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product.
The classification of IMP and NIMP/AxMP 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 and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 2 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.
Refer to Section 8.1.10 for details regarding administration of the study intervention.
6.1.1
Medical Devices
No medical devices are used in this study.
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
Intervention randomization will occur centrally using an IRT system. There are 3 study 
intervention arms. Participants will be assigned randomly in a 1:1:1 ratio to MK-1942 5 mg
bid, MK-1942 15 mg bid, or placebo bid, respectively.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
2. MMSE ≤16, ≥17
3. Region (US/Canada, LATAM, Japan/South Korea, Europe/Australia/NZ)
Note that no more than approximately 60% of participants are to be enrolled in each MMSE 
stratum.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-1942 and placebo will 
be packaged identically so that the blind is maintained. The participant, the investigator, and
Sponsor personnel or delegate(s) who are involved in 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 for >3 consecutive days 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, compliance with study 
intervention will be assessed at each visit. Study partners will be directed to bring all 
dispensed blister cards to each visit. Compliance will be assessed by direct questioning, 
review of Study Medication Guidance, and counting returned capsules in blister cards
during the site visits and documented in the source documents. Deviation(s) from the 
prescribed dosage regimen should be documented.
•
Participants and study partners will also be reminded that the participant must continue
their AD therapy.
•
A record of the number of tablets dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention 
start and stop dates, including dates for intervention delays and/or dose interruptions will 
also be recorded in the CRF according to data entry guidelines.
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6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study. If there is a clinical indication for any medications specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding this with the Sponsor Clinical Director. The final decision on any
supportive therapy rests with the investigator and/or the participant’s primary physician. 
However, the decision to continue the participant on study intervention requires the mutual 
agreement of the investigator, the Sponsor, and the participant.
•
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements or other specific categories of interest) that the 
participant is receiving at the time of enrollment or receives during the study must be 
recorded according to the data entry guidelines.
•
Concomitant use of memantine is allowed as long as the participant is on an approved 
and stable dose ≥3 months before first dose of study intervention and throughout the 
study.
•
Concomitant use of products including THC and CBD is allowed provided that it is not 
taken within 3 days before cognitive testing.
•
Concomitant use of atypical antipsychotics is allowed as long as the participant is on a 
stable dose ≥6 weeks before first dose of study intervention.
•
Concomitant use of long-term steroids (≥6 weeks) is allowed with doses of prednisone up 
to 10 mg/day or equivalent.
•
Concomitant use of short-term steroids at higher doses (<6 weeks) is allowed.
o
Note that local injections into joints or bursae; topical, inhaled or nasal use is 
permitted.
The Sponsor Clinical Director should be contacted if there are any questions regarding 
concomitant or prior therapy.
For country-specific requirements, see Appendix 7.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration)
As described in Section 4.1 and shown in Section 1.2, the dose of MK-1942 for participants 
in the 15-mg dose group will be up-titrated as follows: 8 mg bid (Visit 2/Day 1) and 15 mg 
bid (Visit 3/Week 1 to Visit 8/Week 12). The 5-mg dose of MK-1942 does not require 
titration. Participants in the placebo group will not receive treatment with MK-1942.
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If a participant experiences clinically relevant tolerability issues, one of the 2 daily doses
(morning or evening) can be held at the discretion of the investigator for a brief period (1-2 
days) as needed. Every effort should be made to return to bid dosing as soon as possible. The 
expectation is for the investigator to hold doses only when necessary, as achieving steady 
state is important for long-term tolerability and interpretation of the study results. The dose 
modification and reason for the dose modification is to be documented in source documents.
If a dose is held for an AE, then it is to be recorded as such and not recorded as a compliance 
issue. Compliance is described in Section 6.4.
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/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 8.1.15). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
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 
period will still continue to be monitored in the study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.11.4 unless the participant has 
withdrawn from the study (Section 7.2).
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.
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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, MSD 
subsidiary, or through the emergency unblinding call center.
•
The participant has a medical condition or personal circumstance, which, in the opinion 
of the investigator or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant’s study partner is no longer willing or able to participate in the study and 
a suitable replacement study partner cannot be identified within a reasonable period.
•
The participant is unable to tolerate study intervention after being up-titrated at Visit 3
(See Section 6.6).
•
The participant has an ALT ≥3 × ULN
•
The participant has an AST ≥3 × ULN with a total bilirubin ≥2 × ULN and ALP 
<2 × ULN
•
The participant has an AST ≥3 × ULN with ALT value >100 IU/L
Note 1: Such observed elevations in liver function tests should be confirmed by repeat 
testing within 48 hours of initial test results. If test results are unable to be confirmed 
within this timeframe, the study intervention should be withheld until test results are 
available. Study intervention should be discontinued if unable to repeat testing.
Note 2: If the investigator identifies a clear cause for the liver enzyme elevations 
unrelated to study intervention, then study intervention may be continued with approval 
by the Sponsor.
•
The participant meets either of the following criteria for QTcF interval at a visit 
(Note: ECGs will be performed in triplicate [Section 8.3.4]):
o
The average of the 3 QTcF intervals based on either the local ECG printout or 
subsequent central vendor overread is >500 msec.
o
The average of the 3 QTcF intervals based on either the local ECG printout or 
subsequent central vendor overread increased by >60 msec, relative to the central 
vendor overread average at Visit 2 (Day 1).
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•
The participant begins to use a prohibited medication/therapy/product or a prohibited 
dose of an allowed medication listed in Section 5.2 (Concomitant Medications, Table 1)
that presents a safety concern in the investigator’s judgment.
Note: Participants who are willing and able to safely (per the investigator) stop using the 
prohibited medication/therapy/product or reduce from a prohibited to an acceptable dose for 
an allowed medication through Visit 8 (Week 12) may continue study intervention at the 
investigator’s discretion.
•
The participant reports suicidal ideation with intent, with or without a plan or method 
through an AE or C-SSRS assessment (ie, a positive response to Items 4 or 5 in the 
assessment of suicidal ideation on the C-SSRS) or suicidal behavior. If the reported 
suicidal ideation is passive, and participant expressly denies any intent to act, and who, 
after evaluation, is not judged to be at serious risk for self-harm during the study, the 
participant may continue on study intervention. Refer to Section 8.3.6.1 on Clinical 
Assessments for Suicidal Ideation and Behavior Monitoring (for requirements pertaining 
to the evaluation of such events), and Section 8.4.7 for Events of Clinical Interest.
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
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.
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 8.1.14. 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.
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•
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.
•
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 approximate amount of blood collected from each participant over the duration of the 
study will be 128 ml (Appendix 2).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
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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. Documented 
consent from each participant’s study partner (referred to as study partner consent) will also 
be obtained by the investigator or qualified designee. If there are changes to the 
participant’s/study partner'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 trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion. Study partner consent 
will similarly be documented by the study partner’s dated signature on a consent form and 
the dated signature of the person conducting the consent discussion.
A copy of the signed and dated informed consent forms (participant and study partner 
consents) should be given to the participant (or their legally acceptable representative) and 
study partner before participation in the study.
The initial participant and study partner ICFs, any subsequent revised ICFs, and any written 
information provided to the participant/study partner must receive the IRB/IEC’s 
approval/favorable opinion in advance of use. The participant or his/her legally acceptable 
representative and the participant’s study partner should be informed in a timely manner if 
new information becomes available that may be relevant to the participant’s/study partner'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 or the study partner's dated signature.
Specifics about the study and the study population are to be included in the study informed
consent form.
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 
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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 ID 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
Active medical conditions, detailed neurological history, and other relevant medical history 
within the last 5 years will be obtained by the investigator or qualified designee.
Clinically significant findings in physical examination, laboratory tests, ECGs, and other 
physical evaluations during Screening are to be noted in the medical history. Clinically 
significant changes from the screening evaluation during the study should be captured as 
AEs.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medications for AD dementia taken 
by the participant within 1 year before Screening. Other prior medications taken by the 
participant within 3 months before Screening will also be recorded. The investigator or 
qualified designee will also review for history of anti-amyloid antibodies, as these have 
lifetime exclusions (Table 1).
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. Participants are to remain on their fixed/unchanged course of background 
AChEI therapy from Screening through Visit 9 as follows:

Donepezil 5 or 10 mg/day (capsule or tablet)

Donepezil 23 mg SR/day

Rivastigmine 6 or 12 mg/day (capsule or tablet)

Rivastigmine 9.5 mg or 13.3 mg/24 hours (patch)

Galantamine 16 or 24 mg/day (capsule or tablet)
Note that other approved formulations are acceptable as long as dose ranges are consistent 
with those noted in this protocol.
Participants taking memantine should also continue stable therapy at approved dose until 
Visit 9.
Prohibited medications/therapies/products and prohibited doses for allowed medications 
listed in Table 1 should not be administered from the indicated period before Screening to 
Visit 9 (Postdose Follow-up Visit).
The list of prohibited medications/therapies/products in Table 1 is not comprehensive. 
Investigators should use their medical judgment when a participant presents with a treatment 
that meets a prohibited category, but is not on the list or contact the Sponsor for clarification.
8.1.6
Diagnostic Assessment and External Verification of Diagnosis
Note that the investigator should take a comprehensive history and summarize in the DxV 
for the vendor. A Rater Training Vendor will be used to confirm that each participant 
randomized to study intervention meets entry criteria for probable AD dementia. To support 
confirmation of eligibility, the site will submit information for each participant to the Rater 
Training Vendor rater during the pretreatment period (Section 8.11.1.1). The required 
materials are specified in a diagnostic verification form.
A participant is not eligible for randomization until confirmation of eligibility is provided by 
the Rater Training Vendor who will approve randomization in IRT.
8.1.7
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.
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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 8.11.1.
8.1.8
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 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.
8.1.9
IRT Visit Registration, IRT Randomization, and Study Intervention 
Dispensing
The investigator (or designee) will register the participant in IRT at the visits specified in the 
SoA. Participants who satisfy all entry criteria will be assigned a randomization number via 
IRT at Visit 2 (Day 1). Participants who do not meet eligibility criteria will be entered into 
IRT as screen failures. IRT will also be used to identify the study intervention supplies that 
will be dispensed to participants at the visits specified in the SoA. Refer to the IRT user 
manual for details about the IRT system.
8.1.10
Study Intervention Administration
Blinded study intervention will be administered as oral capsules and packaged in blister 
cards. At Visit 2 (Day 1), participants and study partners will be educated by a trained 
member of the site staff on appropriate dosing and fasting instructions (see Section 5.3.1), 
package opening, and the requirement to return all blister cards at each visit. At Visit 2 
(Day 1). Sites will provide participants/study partners with a copy of the Study Medication 
Guidance and train participants on how to use the guide. Sites will be expected to review this 
guide during each treatment visit (Visit 3 to Visit 8) and provide retraining, as needed. 
Documentation of participant/study partner training will be filed with the participant’s source 
documents.
Details on appropriate handling, storage, and accountability of study intervention are 
provided in Section 6.2.2.
8.1.10.1
Timing of Dose Administration
The first dose of blinded study intervention will be witnessed (see Section 8.1.11) in the 
clinic at Visit 2 (Day 1) after all assessments and procedures as specified in the SoA are 
complete. The next dose of blinded study intervention will be taken at home with supervision 
from the study partner in the evening after Visit 2 (Day 1).
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For Visit 4, Visit 5, Visit 7, and Visit 8 during the treatment period, administration of study 
intervention will continue to occur at home with supervision by the study partner at 
approximately the same time in the morning and approximately the same time in evening.
On days with scheduled clinic visits during the titration period (Visit 3) and Visit 6, 
participants must not take a morning dose of study intervention from the blister cards 
dispensed at the previous visit. Participants will take their morning dose of study intervention 
in the clinic from the newly dispensed blister cards.
Dosing guidelines relative to meals are provided in Section 5.3.1. If a participant accidentally 
misses a dose of study intervention in the morning or evening, the missed dose should be 
taken as soon as possible. If more than 6 hours have passed since the participant’s normal 
morning or evening dosing time, then the missed dose should be skipped, and the next dose 
should be taken as normal. Participants should refer to the Study Medication Guidance for 
further information.
8.1.11
Witnessed Dose
Administration of study intervention will be witnessed by a trained member of the site staff 
at visits specified in the SoA. At Visit 6, the witnessed dose will occur after the first PK 
sample collection, but before assessments for the visit. For the other visits, each witnessed 
dose will be taken after assessments and procedures for the visit are complete. The time of 
dosing will be recorded for any witnessed dose and for the last 3 doses of study intervention 
before PK sample collection.
8.1.12
Study Intervention Accountability
Accounting for compliance and adherence with study intervention is described in Section 6.4.
8.1.13
Telephone Contacts (Site to Study Partner)
A telephone contact will be performed 2-4 days after Visits 2 and 3, by trained site personnel 
to monitor for AEs and compliance with study intervention and to encourage adherence with 
the fasting guidelines (Section 5.3.1). Additional telephone contacts/visits may be scheduled 
at the investigator’s discretion.
The investigator is responsible for ensuring that all telephone contacts are performed by 
trained site personnel (eg, a staff member who is a health care professional qualified to elicit 
a discussion with the study partner that will lead to a clinically meaningful disclosure on the 
participant’s well-being). Telephone contacts are to be documented in the source documents,
and the investigator must review the entry within 2 business days. However, if the study 
partner reports any clinically concerning events for the participant (eg, SAEs, ECIs) during a 
telephone call, then the investigator must be promptly notified. The investigator will contact 
the participant to determine whether a clinic visit is warranted.
If the study partner cannot be reached by telephone at the regularly scheduled time or misses 
a visit, the site should make at least 3 attempts (in addition to the initial phone call) to contact 
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the study partner within 48 hours of the missed scheduled time. All phone contacts and 
attempts should be recorded in source documents.
8.1.14
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.4.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the EOT/DC visit at the time of withdrawal. Any AEs that are present 
at the time of withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.14.1
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@MSD.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.
8.1.15
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 
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 a qualified physician should make reasonable attempts to enter the
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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.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be
used for emergency unblinding if this is required for participant safety.
8.1.16
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.
8.2
Efficacy/QoL/Screening Assessments
Rating scale assessments at clinic visits will be performed by site raters who meet the 
qualification and training requirements per scale. Rater qualifications, training, and 
applicable certification processes are established in a separate document. Each assessment 
scale may require different raters, but it is strongly encouraged that the same rater evaluates 
the same participant for the duration of the study. As a best practice, back-up raters should be 
identified for each participant to improve continuity and reliability of the ratings.
To avoid the influence of participant fatigue on the diagnostic and primary outcome data, the 
recommended order of assessments is to perform the MMSE as the first clinical assessment 
at Screening to assess eligibility. At baseline (Visit 2) and later visits, the ADAS-Cog is to be 
conducted first, followed by shorter tests, such as CERAD Verbal Fluency Test, COWAT, 
Trail Making Tests, Coding, and MMSE. The ADCS-CGIC is recommended as the last 
clinical efficacy assessment so that all relevant information can be reviewed when 
completing the ADCS-CGIC.
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Assessments will be performed at Screening for ADAS-Cog, CERAD Verbal Fluency Test, 
COWAT, Coding, and Trail Making Test to minimize practice effects before baseline
(Visit 2) assessments are conducted at Visit 2.
The following assessments may be audio recorded by sites for submission and review by a 
central rater vendor: MMSE, ADCS-ADL, ADCS-CGIC, ADAS-Cog13, NPI-Q, CERAD 
Verbal Fluency Test, COWAT, Trail Making Tests, and/or Coding. Some or all of the 
recorded interviews will be reviewed and scored by an external expert. The external expert
will provide feedback to the site raters on the quality of the site rater interviews and ratings to 
help develop and maintain good interrater reliability. Additionally, the external expert
feedback may be used to refine the scores entered by the site for an individual rating, at the 
discretion of the site rater.
While concerns have been raised that recording assessments via audiotaping or videotaping 
could theoretically compromise participant privacy, this issue must be balanced with the need 
to conduct methodologically adequate and scientifically rigorous trials that are capable of 
testing key hypotheses. Given that the key endpoints in this study involve subjective clinical 
judgments, monitoring the adequacy of participant interviews and ratings is essential and part 
of strong research methodology. Prior studies suggest that the failure to adequately monitor 
such ratings can substantially increase the risk of failed trials [Khan, A., et al 2013]. 
Recorded interviews will be encrypted using state-of-the-art methods to ensure privacy. 
Additional steps will be taken to ensure anonymity of specific private health information. 
Recordings will be reviewed only by approved study personnel for quality control purposes 
and will be destroyed in accordance with current retention requirements. Additional details 
are provided in a vendor operations manual.
8.2.1
Participant Assessed
8.2.1.1
MMSE
The MMSE is a brief 30-point questionnaire electronically administered and used to assess 
cognitive impairment with lower scores indicating greater impairment [Folstein, M. F., et al 
1975]. The MMSE assesses 11 categories of cognition including orientation to time, 
memory, attention, concentration, naming, repetition, comprehension, and the ability to 
create a sentence and to copy 2 intersecting polygons. These assessments will be used as an 
exploratory cognitive measure of clinical effect. The Screening MMSE will be used for 
purposes of determining participant enrollment.
8.2.1.2
Modified Hachinski Ischemia Scale
The MHIS, [Rosen, W. G., et al 1980] a tool to identify the possibility of a vascular etiology 
for the participant’s dementia, will be completed based on history obtained from the 
participant and study partner, physical and neurological examinations, and/or medical 
records. The MHIS will be completed electronically.
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8.2.1.3
ADAS-Cog
The ADAS-Cog11 [Rosen, W. G., et al 1984] is a structured scale that evaluates memory, 
orientation, attention, reasoning, language, and constructional praxis. Higher scores indicate 
greater impairment. These assessments will be used as the primary cognitive measure of 
clinical effect and will be electronically administered.
The ADAS-Cog11 includes Word Recall, Commands, Constructional Praxis, Naming 
Objects and Fingers, Ideational Praxis, Orientation, Word Recognition, Remembering Test 
Instructions, Spoken Language Ability, Word-Finding Difficulty, and Comprehension of 
Spoken Language.
The ADAS-Cog13 [Petersen, R. C., et al 2001], which includes the optional performance 
items of Delayed Word Recall and Number Cancellation as well as the traditional 11 items, 
will be administered to every participant; however, the ADAS-Cog11 will be used as the 
primary efficacy endpoint.
8.2.1.4
CERAD Verbal Fluency Test
The CERAD Verbal Fluency Test [Morris, J. C., et al 1989], a brief paper/pencil measure of 
semantic processing and executive functioning. This protocol will use animal naming only 
(test of semantic fluency).
8.2.1.5
Controlled Oral Word Association Test
The COWAT is a short, paper/pencil measure of phonemic fluency and executive 
functioning from the Multilingual Aphasia Examination [Schum, R., et al 1989].
8.2.1.6
Coding
The Coding subtest of the Wechsler Adult Intelligence Scale-IV is a brief paper/pencil task 
assessing attention, psychomotor speed and visuomotor coordination [Wechsler, D. 1981].
8.2.1.7
Trail Making Test
The Trail Making Test is a brief paper/pencil assessment of visual scanning (Part A) and 
visuomotor sequencing (Part B) [Reitan, R. M. 1955] [Reitan, R. M. and Wolfson, D. 1985].
8.2.2
ADCS-CGIC
The ADCS-CGIC [Becker, R. 1996] is a global scale assessing cognition and function based 
on structured interviews of both the participant and study partner. Two versions will be used
(baseline and follow-up) and administered electronically. The clinician makes a judgment as 
to whether the participant is improved or worsened as compared with baseline.
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8.2.3
Study Partner Assessed
8.2.3.1
ADCS-ADL
The ADCS-ADL [Galasko, D., et al 1997] assesses the competence of participants with AD
dementia in basic and instrumental activities of daily living (ADLs). It will be administered 
electronically to the participant’s study partner. All responses should relate to the 4 weeks 
before the time of rating. Each ADL item takes an ADL (eg, eating) and provide descriptions 
of level of competence with the rater selecting the most appropriate option (eg, ate without 
physical help and used a knife; used a fork or spoon, but not a knife; used fingers to eat; was 
usually or always fed by someone else).
8.2.3.2
Neuropsychiatric Inventory - Questionnaire (NPI-Q)
The NPI-Q is adapted from the NPI [Cummings, J. L., et al 1994] a validated informant-
based interview that assesses NPS over the previous month. It assesses the same 12 
behavioral symptoms as the NPI; however, the NPI-Q assesses only the severity of NPS and 
caregiver distress. These assessments will be used as a secondary behavioral measure of 
clinical effect and will be administered electronically.
This study uses the NPI version with 12 behavioral domains: delusions, hallucinations, 
agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, 
disinhibition, irritability/lability, motor disturbance, nighttime behaviors, and appetite/eating.
The NPI-Q provides symptom severity and distress ratings for each symptom reported, and 
total severity and distress scores reflecting the sum of individual domain scores. The severity 
scale has scores ranging from 1 to 3 points and the scale for assessing caregiver distress has 
scores ranging from 0 to 5 points. The total NPI-Q severity score is the sum of the individual 
severity scores for each symptom and ranges from 0 to 36, with higher scores indicating 
more severe behavioral impairment. The total NPI-Q distress score is the sum of the 
individual distress scores for each symptom and ranges from 0 to 60, with higher scores 
indicating greater distress.
8.2.3.3
EuroQol 5-Dimensional Health-Related Quality of Life Scale (EQ-5D-5L)
The EuroQol 5D-5L [Herdman, M., et al 2011] is a standardized instrument for use as a 
measure of health outcome. Mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression are each assessed on 5-point categorical scales ranging from “no 
problem” to “extreme problem.” Two different administrations of the EQ-5D-5L will be 
performed at time points according to the SoA. First, the caregiver will electronically provide 
a self-report of his or her own health status. Second, the participant’s caregiver will 
electronically provide a proxy-rating of the participant’s health status. In both situations, the 
EQ-5D-5L questionnaire will be completed by the participant’s caregiver.
8.3
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
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8.3.1
Physical Examination
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. The investigator (or 
qualified designee, consistent with local requirements) will perform the examinations of the 
following organ systems:

Head, eyes, ears, nose, and throat

Neck

Respiratory system

Cardiovascular system

Abdomen

Skin and extremities

General appearance
8.3.2
Neurological Examination
The general neurological examination includes all of the following:

Cranial nerve assessment

Motor system

Reflexes

Coordination and gait

Sensory system

Abnormal movements
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. Any medical conditions found during the physical and neurological examinations 
will be recorded in the Sponsor database.
8.3.3
Vital Signs, Height, and Weight
•
Vital signs will be measured in a semisupine position after 5 minutes’ rest and include 
temperature, systolic and diastolic blood pressure, pulse, and respiratory rate.
•
It is recommended that individual sites use the same method for measuring temperature 
(eg, oral, tympanic) in all participants throughout the study.
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•
For blood pressure readings, the correct size of the blood pressure cuff and correct 
positioning on the participant’s arm is essential for accurate measurements. It is 
recommended that individual sites use the same method (manual or automated) for 
measuring blood pressure and pulse throughout the study.
•
Height (cm/in) and body weight (kg/lbs) will be collected and recorded. Measurements 
should be recorded to the nearest centimeter/inch and kilogram/pound. Body weight data 
will be collected without shoes and with heavy clothing (such as coats) removed. The site 
should follow their local procedures to ensure the body weight scale is working properly.
8.3.4
Electrocardiograms
Twelve-lead ECGs will be performed when the participant is in the supine position after 5 to 
10 minutes of rest using a central ECG machine that automatically calculates heart rate and 
measures PR, QRS, QT, and QTcF intervals according to the instructions in a separate ECG 
instruction manual. Cardiologist overread will be provided by the central ECG vendor.
All scheduled ECGs will be performed in triplicate. ECG measurements should be obtained 
in close succession, ie, less than 2 minutes apart, with all 3 measurements completed in less 
than 4 minutes.
At Screening, the average of the 3 QTcF intervals based on the central vendor overread will 
be used to assess eligibility. At Visit 2 (Day 1), the average of the 3 QTcF intervals based on 
the local ECG printout will be used to assess eligibility (Section 5.2).
During the double-blind treatment period, participants will discontinue study intervention if 
the average of the 3 QTcF intervals at a visit is either >500 msec or increases by >60 msec 
relative to Visit 2 (Day 1). Details on discontinuation of study intervention due to QTcF 
results are in Section 7.1.
8.3.5
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 
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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 or 
through completion of Visit 9, whichever is late, 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.
8.3.6
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 specified time points, as 
indicated in the SoA, as well as at unscheduled visits as clinically indicated. 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, 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 (ie, a positive response to items 4 or 5 in the assessment of suicidal ideation on the 
C-SSRS) or suicidal behavior must be evaluated that day by a psychiatrist or other trained 
mental health professional who is a licensed psychologist, social worker, or mental health 
nurse practitioner (or comparable professional qualification in countries outside the United 
States). 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.
8.4
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 events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. 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
All AEs, SAEs, and other reportable safety events that occur after the participant provides
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment; 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, or a procedure.
From the time of intervention allocation/randomization through 14 days after cessation of 
study intervention, or through the completion of Visit 9, whichever is later, all AEs, SAEs, 
and other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside the 
period specified in the previous paragraph 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 the investigator 
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
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
- hepatic-related 
events listed in 
Section 8.4.7
- 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-hepatic-related 
events as listed in 
Section 8.4.7 (unless 
serious)
- do not require
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)
Overdose
Report if:
- receiving placebo run-in 
or other run-in medication 
Report all
Not required
Within 5 
calendar days of 
learning of event
ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse event.
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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.
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
There are no disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
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Events of clinical interest for this study include:
1. Elevated AST ≥3x ULN
2. Elevated ALT ≥2x ULN or twice the baseline value
3. Elevated total bilirubin ≥2x ULN with ALP <2x ULN
4. AEs of dizziness that are rated by the investigator as being moderate or severe in 
intensity
5. AEs related to gait disturbance (if not already captured in the narrative of AEs related to
moderate or severe dizziness)
6. AEs of falls (if not already captured in the narrative of AEs related to moderate or severe 
dizziness)
7. AEs of suicidal ideation and/or behavior or any self-injurious behavior
8. QTcF interval meeting either of the criteria specified for study intervention 
discontinuation (Section 7.1)
Note that the above AEs are classified as ECIs only after the first dose of study intervention 
is administered. An AE of fall or gait disturbance must be reported as an ECI unless
associated with moderate or severe dizziness and fully described in that ECI narrative. Sites 
should refer to the study ECI guidance document for details on assessment and follow-up
including follow-up on elevated liver function tests that met ECI criteria as assessed at 
Visit 9.
8.5
Treatment of Overdose
In this study, an overdose is defined as more than 3 capsules on a calendar day.
No specific information is available on the treatment of overdose of MK-1942.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
8.6
Pharmacokinetics
PK sampling information is displayed in Table 4.
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Table 4
PK Sampling Information
PK 
Sample #
PK sample name
PK Collection Day 
PK Collection
Time Window
1
MK-1942 PK 
sample/Placebo
Visit 2 (Day 1)
Any time before first dose
2
AChEI Plasma PK 
sample
Visit 2 (Day 1)
Any time before first dose
3
Memantine Plasma PK 
sample
Visit 2 (Day 1)
Any time before first dose
4
MK-1942 PK 
sample/Placebo
Visit 6 (Day 43)
Two PK samples to be drawn
1) predose and prescheduled assessments
2) postdose and post scheduled 
assessments (2-3 hours)
Note: at this visit the participant will be 
given a witnessed dose of study
medication after the first PK draw
5
AChEI Plasma PK 
sample
Visit 6 (Day 43)
After all scheduled assessments and at 
the time of postdose MK sample
6
Memantine Plasma PK 
sample
Visit 6 (Day 43)
After all scheduled assessments and at 
the time of postdose MK sample
7
MK-1942 PK 
sample/Placebo
Visit 8
After all cognitive assessments have 
been performed
8
AChEI Plasma PK 
sample
Visit 8
After all cognitive assessments have 
been performed
9
Memantine Plasma PK 
sample
Visit 8
After all cognitive assessments have 
been performed
PK=pharmacokinetic; V=visit
Note: sites to record the time of dose of MK-1942/Placebo for the last 3 doses before PK sample draw
PK collection is not required once the participant discontinues study intervention treatment. 
If a participant discontinues before Visit 8, then the last PK sample is collected at any time 
during the EOT visit. Blood samples collected may be stored and further analyses may be 
performed, if required.
8.6.1
Blood Collection for Plasma MK-1942
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Operations/Laboratory Manual.
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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 
•
Plasma for exploratory research
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample will be drawn for CYP2C19/APOE4 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 CYP2C19/APOE4. Leftover extracted DNA will be stored for 
FBR if the participant provides documented informed consent for FBR.
The planned genetic analysis sample should be obtained predose on Day 1 but may be 
collected at the next scheduled blood draw, if needed. Sample collection, storage, and 
shipment instructions for planned genetic analysis samples will be 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 plasma for exploratory research
8.10
Health Economics Medical Resource Utilization and Health Economics
Health Economics, Medical Resource Utilization and Health Economics are not evaluated in 
this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.1.
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Study Partner Specifics
The study partner:

Is not diagnosed with dementia.

Provides their own documented informed consent after the study has been explained 
to them.

Accompanies the participant to all study visits and participates in study telephone 
contacts.

Assesses side effects or corroborates any safety signals.

Assumes responsibility for study intervention procedures (eg, witnessing and/or 
helping to administer study medication, assessing compliance, review/completion of 
Study Medication Guidance).

Completes assessments specified in the protocol (eg, ADCS-ADL NPI-Q, EQ-5D-5L)
Every effort should be made to maintain the same study partner for the duration of the study. 
However, if the study partner is unable to continue with the study requirements, the study 
partner should discuss with the site whether a suitable replacement can be found. If a new 
study partner is identified, the new study partner will need to sign the study partner informed 
consent.
Scheduling Visits
It is preferable for visits to be scheduled at about the same time of day in the mornings for 
consistency, and for in-clinic visits, to minimize prolonged fasting durations (fasting 
guidance is provided in Section 5.3.1). Afternoon clinic visits are not preferred, but may be 
performed if morning visits are not feasible for participants. Participants with afternoon 
clinic visits should be scheduled at about the same time of day in the afternoon for 
consistency. See study operations manual for more information on afternoon clinic visits.
A visit should occur within the scheduling window shown in the SoA. Visits during the 
double-blind treatment period should be scheduled relative to Visit 2 (Day 1), regardless of 
the actual day the previous visit occurred on. If any visits deviate from the schedule, an 
attempt should be made to follow the original visit schedule for subsequent visits.
Visit Reminders
During the double-blind treatment period, it is recommended that site personnel contact 
participants/study partners on the day before each clinic visit to remind participants to (1) fast 
according to Section 5.3.1, (2) hold their morning doses of study intervention from the blister 
cards dispensed at the previous visit (up-titration visit [Visit 3] and Visit 6), (3) bring their 
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opened and unopened blister cards to the visit (not applicable at Visit 2 [Day 1]), and 
(4) bring their Study Medication Guidance (not applicable at Visit 2 [Day 1]).
8.11.1
Screening
Approximately 12 weeks before intervention randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5. 
Screening procedures may be repeated after consultation with the Sponsor.
Screening could take up to 12 weeks to complete the full assessment of the participant’s 
eligibility requirements (eg, MRI scan via central reader, MMSE review by Rater Training 
Vendor, prohibited medication washout). Assessments that are to be reviewed by the Rater 
Training Vendor, such as the MMSE, should be sent to the Rater Training Vendor as soon as 
possible (ie, same day that assessment was performed) so specific eligibility criteria can be 
determined, and the results can be sent back to the site in a timely manner. Once final 
eligibility is determined, the participant’s Visit 2 should be scheduled to occur as soon as 
possible.
For country-specific requirements, see Appendix 7.
Split Screening Visit Option
To reduce participant burden, Screening may be split into more than 1 day. If this screening 
option is chosen, it is required that documented informed consent for the main study is 
obtained (Section 8.1.1.1) and a screening number is assigned (Section 8.1.7) on the first day 
of Screening.
Prohibited medications will be discontinued in accordance with Table 1. If a participant
requires a washout for a prohibited medication, an abbreviated Screening may be performed 
(eg, obtain informed consent, review medical history, preliminary review of 
inclusion/exclusion criteria, review of prior and concomitant medications, assignment of a 
screening number). After the participant has completed the specified washout, the participant
will return to complete the remaining Screening procedures. Once the participant has fully 
completed Screening and eligibility has been confirmed, the participant may proceed to Visit 
2 per protocol.
Rescreening
In some circumstances, participants who are excluded may be rescreened once per 
investigator judgment. Consultation with the Sponsor or its designee should take place before
any additional rescreening. All rescreening should be documented, and rescreening will be 
reviewed on an individual basis. Note: Repeat MMSE is acceptable, but may not be 
completed for at least 6 months for participants whose score is above the upper range for 
inclusion.
Additional details on rescreening procedures and other reasons for rescreening are described 
in the study operations manual.
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Ordering of Procedures/Assessments:
Below is a recommended guide on the ordering of procedures/assessments (non-inclusive), 
when applicable, for Screening:

Administrative Procedures

Cognitive/clinical assessments

Physical and neurological examinations

Vital signs, ECGs, laboratory test results

MRI
Additional information regarding procedures for clinical and cognitive assessments, 
including the preferred order of administration for cognitive and clinical assessments will be 
specified in Rater Training Vendor documentation and training.
8.11.1.1
Rater Training Vendor Review of Participant Eligibility
This study will include a review by outside expert(s) associated with the Rater Training 
Vendor of each participant before randomization. Participants cannot be randomized without 
the approval of the Rater Training Vendor. This review may include all available medically 
relevant data, a narrative summary of the participant's history, and audiotapes of key clinical 
and cognitive assessments performed at the Screening Visit. These assessments may include 
the MMSE and/or the ADAS-Cog13 assessments.
The DxV is a questionnaire to ensure that participants are enrolled on the basis of objectively 
ascertained and well-documented diagnosis of probable AD dementia. The DxV is to be 
completed by the site investigator, requiring their review of the key study entry criteria at the 
Screening Visit. The DxV also collects additional information that supports the 
NINCDS-ADRDA (1984) criteria [McKhann, G., et al 1984] such as the clinical history, 
neuropsychological testing, other supportive diagnostic information, and facilitates timely 
review of the site-based assessments by site-independent clinicians.
The Rater Training Vendor will inform the site if a participant is eligible before Visit 2
(Day 1). Participants who do not meet eligibility criteria will be screen-failed.
8.11.1.2
MRI
To evaluate the eligibility criteria, each participant must have either: an MRI scan performed 
during the Screening period or a previous MRI performed within 18 months before the 
Screening Visit that is available for review by the blinded independent central reviewing
vendor. A head CT scan without contrast obtained at Screening or within 18 months before 
Screening may be accepted instead of MRI on a case-by-case basis, as approved by the 
Sponsor (eg, when MRI is contraindicated for the participant); if applicable, the CT scan 
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must also be available for blinded independent central review per Imaging Charter. If a new 
MRI needs to be performed for Screening, the scan should be scheduled to occur during the 
screening period after the participant has met all the inclusion and exclusion criteria that do 
not require an MRI.
8.11.2
Treatment Period
Each visit should be performed as specified in the SoA.
Participants who satisfy all entry criteria will be randomized (via IRT) to double-blind study 
intervention at Visit 2 (Day 1). Participants and study partners will be educated by a trained 
member of the site staff on appropriate dosing instructions (including missed doses, 
Section 8.1.10) and fasting guidance (Section 5.3.1). The first dose of study intervention will 
be witnessed by a member of the site staff in the clinic. Witnessed dosing will continue at the 
up-titration visit (Visit 3) and Visit 6.
A telephone contact will be performed 2-4 days after Visits 2 and 3, by trained site personnel
(Section 8.1.13) to monitor for AEs and compliance with study intervention and to encourage 
adherence with the fasting guidelines (Section 5.3.1). Additional telephone contacts/visits 
may be scheduled at the investigator’s discretion.
There may be instances where visit procedures are conducted over more than 1 day provided 
that they are completed within the allowed window (see SoA).
If there are extenuating circumstances where time does not enable an entire scheduled clinic 
visit, remote assessments for study partners only may be done, if allowed by local 
regulations, in accordance with Sponsor guidelines. In addition, the C-SSRS can be remotely 
completed with the participant. See Rater Training Vendor documentation and training for 
specific guidelines.
8.11.3
EOT/DC Visit
EOT/DC Visit procedures specified in the SoA will be performed at the end of the treatment 
period (Visit 8 [Week 12]). Additionally, participants who discontinue study intervention 
prematurely should have an EOT/DC Visit as soon as possible after the decision to 
discontinue study intervention is made and should also complete a 14-day postdose follow-up 
visit for laboratory assessments if possible. For participants who discontinue study 
intervention prematurely, prohibited medications/products/therapies (Table 1) can be started 
after the EOT/DC Visit.
8.11.4
Participants Discontinued From Study Intervention but Continuing to Be 
Monitored in the Study
Any participant who prematurely discontinues study intervention will be encouraged to 
continue their participation in the study off study intervention and be followed up for all 
remaining study visits (Section 7.1) as outlined in the SoA. The subsequent scheduled visit 
may be skipped if within 7 days of the DC visit. Note that PK samples will not be collected if 
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a participant discontinues study intervention. In addition, the postdose follow-up visit (Visit 
9) does not need to be conducted for participants who discontinue study intervention and are 
continuing to be monitored in the study, as long as safety follow-up has been completed 
through 14 days after last dose.
If a participant discontinues study intervention prematurely (before Visit 8) and continues 
with study visits off study intervention, an EOT/DC visit will still be completed as indicated 
in the SoA. If the participant subsequently discontinues the study (before Visit 8), a study DC 
visit will be conducted at that time with the same procedures as the EOT visit.
8.11.5
Postdose Follow-up Visit 
Visit procedures specified in the SoA will be performed at the Postdose Follow-up visit
(Visit 9). Participants will be off study intervention; therefore, there are no fasting 
requirements associated with this visit. If needed, instead of a site visit, Visit 9 laboratory 
assessments may be performed at a local laboratory and Visit 9 nonlaboratory assessments 
may be performed by TC.
8.11.6
Poststudy
Participants will not be followed up after completion of the postdose follow-up visit.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but before any unblinding/final database lock, changes are made to primary 
and/or key secondary hypotheses, or the statistical methods related to those hypotheses, then 
the protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or 
other nonconfirmatory analyses made after the protocol has been finalized, but before
unblinding/final database lock, will be documented in an sSAP and referenced in the CSR for 
the study. Post hoc exploratory analyses will be clearly identified in the CSR. Other planned 
analyses (ie, those specific to the analysis of PK data, patient-reported outcomes, and future 
biomedical research) will be documented in separate analysis plans.
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9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
A Phase 2a/2b Randomized, Placebo-Controlled Clinical Study to Evaluate 
the Safety and Efficacy of MK-1942 as Adjunctive Therapy in Participants 
with Mild to Moderate Alzheimer’s Disease Dementia
Treatment Assignment
The study will be conducted as a double-blind study under in-house blinding 
procedures. Treatment randomization will occur centrally using an IRT. 
Participants will be assigned randomly in a 1:1:1 ratio to one of the 2 MK-
1942 doses or the placebo. The randomization will be stratified by AD
dementia severity via baseline MMSE (≤16, ≥17) and geographic region 
(US/Canada, LATAM, Japan/South Korea, Europe/Australia/NZ).
Analysis Populations
Efficacy: FAS
Safety: APaT
PK: PP
Primary Endpoint(s)
The primary endpoint is the change from baseline in ADAS-Cog11 at Week 
12.
Key Secondary Endpoints
The key secondary endpoint is the ADCS-CGIC Overall score at Week 12.
Statistical Methods for 
Key Efficacy
The primary hypothesis will be evaluated by comparing each MK-1942 dose 
to placebo with respect to mean change from baseline in ADAS-Cog11 score 
at Week 12 using a longitudinal ANCOVA model. 
Statistical Methods for 
Key Safety Analyses
For overall safety endpoints, specific AEs and safety topics of special interest 
that meet predefined threshold rules, point estimates, and 95% CIs for the 
differences between treatment groups in the percentage of participants with 
events will be provided using the Miettinen and Nurminen method
[Miettinen, O. and Nurminen, M. 1985].
Interim Analyses
Two types of interim analyses may be performed in this study. Results will
be reviewed by an eDMC. These interim analyses are summarized below.
Additional details are provided in Section 9.7.
The first type of interim analysis will be for safety only and will be
conducted approximately every 4 to 6 months, with the frequency subject to
change per eDMC recommendation.
In addition, a nonbinding futility IA may be performed when the first 50% of 
randomized participants have had the opportunity to treat for 12 weeks (ie, 
the IA will be based on a data cutoff that is 12 weeks after the randomization 
of the 204th participant). Results will be reviewed by an eDMC.
Futility may be declared if the Bayesian predictive conditional probability for 
the primary hypothesis based on the CFB in ADAS-Cog11 at Week 12 is less 
than 15% for both between-treatment comparisons (MK-1942 5 mg vs 
placebo and MK-1942 15 mg vs placebo).
Details are provided in Section 9.7.
Multiplicity
The Type-I error rate over the multiple treatment comparisons will be 
controlled using a Bonferroni procedure (across dose comparisons with 
placebo), in conjunction with sequential testing over the multiple endpoints
(see Figure 2).
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Sample Size and Power
The planned sample size is 408 participants, with 136 participants per arm. 
The study has ~90% power to show at least 1 MK-1942 dose is superior to 
the placebo as measured by the CFB in ADAS-Cog11 at Week 12 under the 
primary assumptions as provided in Section 9.9.1, at an overall two-sided 5% 
alpha-level.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete. Participants are considered to have finished the study when they complete the last 
study-related telephone call or visit, withdraw from the study, or are lost to follow-up.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.3.1
Estimands
In the language of ICH E9 (R1) [Food and Drug Administration 2021] there are 3
“intercurrent events” of interest: IE1) discontinuation of MK-1942 or placebo, IE2) 
discontinuation of stable background AD treatment (list to be provided in the sSAP), and 
IE3) use of any non-AD treatment that has the potential to adversely affect cognition 
(hereafter, “adverse non-AD treatment”; list to be provided in the sSAP).
Primary Objective
Primary Estimand (based on ‘treatment policy strategy’ in ICH E9(R1))
To address the primary objective, an estimand based on the TPS will be used. This “TPS 
estimand” is intended to contrast the effect of MK-1942 (at a specified dose level), relative to 
placebo, when initiated with stable background AD treatment, regardless of how long any of 
these treatments or any adverse non-AD treatment are used during an envisioned 12-week 
follow-up period.
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The TPS estimand consists of the following attributes:

Target population: participants between the ages of 55 and 90 years (inclusive) with 
mild to moderate AD dementia

Endpoint: change from baseline in the ADAS-Cog11 Total score at Week 12

Treatment regimen: MK-1942 (at a specified dose level) or placebo initiated with 
stable background AD treatment, with potential discontinuation of any of these 
treatments or use of any adverse non-AD treatment during an envisioned 12-week 
follow-up period

Population-level summary: mean of the endpoint noted above, compared between 
treatment regimens
(Note: for estimating the TPS estimand, data collected after occurrence of IE1, IE2, or IE3 
will be used in the main analysis; see details in Section 9.6.1.)
Supplemental Estimand (based on ‘hypothetical strategy’ in ICH E9[R1])
A supplemental estimand based on the HS will be used. This “HS estimand” is intended to 
contrast the effect of MK-1942 (at a specified dose level), relative to placebo, when initiated 
with stable background AD treatment under a hypothetical scenario in which there is no 
discontinuation of the stable background AD treatment and no use of any adverse non-AD 
treatment during an envisioned 12-week follow-up period.
The HS estimand has the same target population, endpoint, and population-level summary as 
the TPS estimand, but differs in the treatment regimen attribute.
The HS estimand consists of the following attributes:

Target population: participants between the ages of 55 and 90 years (inclusive) with 
mild to moderate AD Dementia

Endpoint: change from baseline in the ADAS-Cog11 Total score at Week 12

Treatment regimen: MK-1942 (at a specified dose level) or placebo initiated with 
stable background AD treatment, without discontinuation of the latter and without use 
of any adverse non-AD treatment during an envisioned 12-week follow-up period

Population-level summary: mean of the endpoint noted above, compared between 
treatment regimens
(Note: for estimating the HS estimand, data collected after occurrence of IE2 or IE3, or after 
occurrence of IE1 followed by at least one of IE2 or IE3, will be discarded in the main 
analysis; see details in Section 9.6.1.)
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Secondary Objectives
Both TPS and HS estimands, as described for the primary efficacy endpoint, will be applied 
to the key secondary efficacy endpoint (ADCS-CGIC) and to the secondary endpoint 
(ADCS-ADL). For all other efficacy endpoints, where applicable, only the TPS estimand, as 
described for the primary efficacy endpoint, will be applied.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
9.4.1
Efficacy Endpoints
In general, if a baseline value (defined as the most recent measurement before the first dose) 
exists for a particular efficacy measure, then the change from baseline in that value will be 
evaluated. The primary efficacy evaluation period of this study is the 12-week double-blind 
treatment period.
Primary Endpoint
The ADAS-Cog11 is an 11-item assessment for cognition. The primary endpoint of this 
study is the change from baseline in the ADAS-Cog11 Total score at Week 12.
Key Secondary Endpoint
The ADCS-CGIC focuses on clinicians’ observations of change in the patient’s cognitive, 
functional, and behavioral performance since the beginning of the study. The ADCS-CGIC
Overall score at Week 12 is the key secondary endpoint.
Secondary Endpoints
The ADCS-ADL is an informant-based measure of the patient’s functional ability in 
activities of daily living. The change from baseline in total ADCS-ADL score at Week 12 is 
a secondary endpoint.
Tertiary/Exploratory Endpoints
The exploratory endpoints for this study will be detailed in the sSAP and include the 
following measurements at all planned postdose time points up to, and including, Week 12:

The change from baseline in total NPI-Q severity score 

The ADAS-Cog11 Total score

The ADAS-Cog13 Total score
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
The ADCS-CGIC scores (General Condition, Cognition, Behavior, Function, Overall) 

The COWAT Total score

The Coding Total score

The Trail Making Test Parts A and B scores, respectively

The CERAD Verbal Fluency Test score

The MMSE Total score

The EQ-5D-5L

Improvement in the ADCS-CGIC Overall score, with a score of 1, 2, or 3 indicating 
improvement

Composite score of Memory

Composite score of Executive Function

Composite score of Attention

Item response theory derived ADAS-Cog11 score
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory values, ECGs, and vital signs.
Responses on the C-SSRS are classified according to 11 prespecified categories (Ideation: 
Passive, Active-nonspecific, Active-method, Active-method and intent, and Active-method, 
intent and plan; Behavior: Preparatory actions or behaviors, Aborted attempt, Interrupted 
attempt, Suicide attempt, and Completed suicide; Non-suicidal Self-Injurious Behavior). The 
most severe treatment-emergent event within each of 3 broad categories (suicidal ideation, 
suicidal behavior, and non-suicidal self-injurious behavior) reported at a visit will be used for 
analysis and reporting. An event is considered treatment-emergent during the assessment 
phase if it is either newly emerged or is more severe than the most severe event reported to 
have occurred in the study-defined pretreatment reference period.
9.4.3
Pharmacokinetic Endpoints
The PK endpoint is MK-1942 plasma concentrations.
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The FAS population will serve as the primary population for the analysis of efficacy data in 
this study. The FAS population will be defined separately for each efficacy endpoint and 
consists of all randomized participants who:

Receive at least 1 dose of study intervention

Have a baseline measurement (for those analyses that require a baseline measurement) 
and at least 1 valid postrandomization observation for the analysis endpoint after at least 
one dose of study intervention
o
For analyses by time point, a valid postrandomization observation is an observation 
which 1) is collected within an analysis window and 2) does not occur after an 
intercurrent event (for those analyses in which such observations are to be excluded).
Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the FAS population.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of study intervention.

For analyses conducted by time point, participants must have a baseline measurement and 
at least 1 valid postrandomization observation for the analysis endpoint after at least one 
dose of study intervention.
o
For analyses by time point, a valid post-treatment observation is an observation which 
1) is collected within an analysis window and 2) does not occur after the relevant 
window pertaining to cessation of study intervention (for those analyses in which 
such observations are to be excluded).
Participants will be included in the treatment group corresponding to the study intervention
they actually received for the analysis of safety data using the APaT population. This will be 
the treatment group to which they are randomized except for participants who take incorrect 
study intervention for the entire treatment period; such participants will be included in the 
treatment group corresponding to the study intervention actually received.
9.5.3
Pharmacokinetic Analysis Populations
The PP Population consists of the set of data generated by the subset of participants who 
comply with the protocol sufficiently to ensure that generated data will be likely to show the 
effects of treatment. Compliance covers such considerations as exposure to treatment, 
availability of measurements, and absence of important protocol deviations. Important
protocol deviations will be identified to the extent possible. Any participants or data values
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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 will be included in the PP dataset. This population 
will be used for the PK analyses.
9.6
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 9.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type-1
error control strategy are described in Section 9.8. Nominal p-values and 95% CIs will be 
computed for other efficacy analyses but should be interpreted with caution due to potential 
issues of multiplicity, sample size, etc.
9.6.1
Statistical Methods for Efficacy Analysis
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
A separate modeling and simulation analysis plan will be used to describe methods used to 
evaluate the exploratory objective to assess the effect of MK-1942 on ADAS-Cog11 at the 
item-level over time.
Data from all 3 treatment groups through Week 12 will be used to contrast the treatment 
comparisons/time points of interest for the primary efficacy endpoints. The primary analysis 
is based on a longitudinal ANCOVA model including the change from baseline in 
ADAS-Cog11 Total score at each planned post-randomization visit up to Week 12. The 
longitudinal ANCOVA model will handle missing data assuming a missing-at-random 
missing data mechanism. This model will be used to generate confidence intervals and 
p-values (compared with placebo). This model assumes a different mean for each treatment 
at each of the repeated time points in the analysis. In this model, time (ie, week) is treated as 
a categorical variable so that no restriction is imposed on the trajectory of the means over 
time. The analysis model will include categorical terms for treatment, time, APOE4 status
(positive, negative), and geographic region (US/Canada, LATAM, Japan/South Korea, 
Europe/Australia/NZ) as well as continuous terms for baseline, baseline MMSE score, years 
since diagnosis, and age. In addition, the model will also include the interaction terms of 
time-by-treatment and time-by-baseline. The treatment difference in terms of the mean 
change from baseline in the ADAS-Cog11 Total score at a given time point will be 
estimated, and as appropriate, tested from the model. An unstructured covariance matrix will 
be used to model the correlation among repeated measurements. The Kenward-Roger 
approximation will be used to compute the degrees of freedom [Kenward, M. G. and Roger, 
J. H. 1997].
If the model fails to converge, the following respective steps will be taken until the model 
does converge: 1) geographic region will be collapsed from 4 levels to 2 levels (US/Canada 
and Rest of World), 2) APOE 4 status will be removed from the model, 3) geographic region 
will be removed from the model.
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The same analysis strategy and model used for the primary efficacy endpoint will also be 
used for the other continuous efficacy endpoints. It is noted that the ADCS-CGIC scores
essentially measure the change from baseline at each postdose visit and that no baseline value 
for the ADCS-CGIC scores exists. As such, the analysis of this measurement will model the 
postdose score (as opposed to the CFB score) and will not include terms for baseline and the 
interaction of time-by-baseline in the model. 
As outlined in Table 5, supportive analyses will be performed for the primary and secondary 
hypotheses to assess the robustness of the primary findings with respect to (1) the impact of 
intercurrent events; and (2) the handling of missing data. Details related to supportive
analyses will be provided in the sSAP.
Summary statistics will be computed for all efficacy endpoints over time. This minimally 
includes means and standard deviations for continuous endpoints and counts and percentages 
for categorical endpoints.
Table 5
Analysis of Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive Analysisa
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoints
CFB in ADAS-Cog11 Total 
score at Week 12
P
Longitudinal ANCOVAb with TPS
Estimand
FAS
Model-based
S
Longitudinal ANCOVAb with HS
Estimand
FAS
Model-based
S
Longitudinal ANCOVA with TPS
Estimand and CBMIb
FAS
CBMI
Secondary Endpoints
ADCS-CGIC Overall score
at Week 12
P
Longitudinal ANCOVAc with TPS
Estimand
FAS
Model-based
S
Longitudinal ANCOVAc with HS
Estimand
FAS
Model-based
S
Longitudinal ANCOVA with TPS
Estimand and CBMIc
FAS
CBMI
CFB in ADCS-ADL Total 
score at Week 12
P
Longitudinal ANCOVAb with TPS 
Estimand
FAS
Model-based
S
Longitudinal ANCOVAb with HS 
Estimand
FAS
Model-based
S
Longitudinal ANCOVA with TPS 
Estimand and CBMIb
FAS
CBMI
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Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive Analysisa
Statistical Method
Analysis 
Population
Missing Data 
Approach
ADAS-Cog11=Alzheimer’s Disease Assessment Scale-11-item cognitive subscale; ADCS=Alzheimer’s Disease 
Cooperative Study; ADL=activities of daily living; ANCOVA=analysis of covariance; APOE=apolipoprotein E;
CBMI=Control-Based Mean Imputation; CFB=change from baseline; CGIC=Clinical Global Impression of Change; 
FAS=full analysis set; HS=hypothetical strategy; MMSE=Mini-Mental State Examination; TPS=treatment policy strategy
  a
P=Primary approach, S=supportive approach
  b
Longitudinal ANCOVA model with categorical terms for treatment, time, APOE4 status, and region, as well as 
continuous terms for baseline, baseline MMSE score, years since diagnosis, and age. In addition, the model will 
include the interaction terms of time-by-treatment and time-by-baseline.
  c
Longitudinal ANCOVA model with categorical terms for treatment, time, APOE4 status, and region, as well as 
continuous terms for baseline MMSE score, years since diagnosis, and age. In addition, the model will also include 
the interaction term of time-by-treatment.
The strategy to address multiplicity issues regarding multiple treatment comparisons, 
multiple efficacy endpoints, and an interim analysis is described in Section 9.7 (Interim 
Analyses) and Section 9.8 (Multiplicity).
9.6.2
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of AEs and other relevant 
parameters including laboratory tests, vital signs, and ECG measurements.
9.6.2.1
Overall Safety Assessment
The overall safety evaluation will include a summary by treatment group of the number and 
percentage of participants with at least one AE, drug-related AE, serious AE, serious, 
drug-related AE; and a discontinuation from study intervention due to an AE. Point estimates 
and 95% CIs for the differences between treatment groups (ie, MK-1942 dose groups 
compared with placebo) in the percentages of participants with the event will be provided.
The number and percentage of participants with specific AEs will also be provided. Point 
estimates and 95% CIs for the differences between treatment groups (ie, MK-1942 dose 
groups compared with placebo) in the percentages of participants with specific AEs will be 
provided for AEs that occur in at least 4 participants in any treatment group. This threshold 
for the number of participants with AEs was chosen because the 95% CI for the 
between-group difference in percent incidence will always include zero when fewer 
participants per group have events and thus would add little to the interpretation of 
potentially meaningful differences. Similar information will be provided for each SOC.
CIs for between-treatment group differences will be provided using the M&N method (1985)
[Miettinen, O. and Nurminen, M. 1985]. None of the CIs that will be generated to evaluate 
safety endpoints will be adjusted for multiplicity. As such, these CIs should only be regarded 
as helpful descriptive measures for the review of the safety profile and not as a formal 
method for assessing statistical significance of between-group differences. Rainfall plots with 
point estimates and 95% CIs will be displayed for AEs that occur in at least 4 participants in 
any treatment group. Point estimates and 95% CIs will be provided for the percentage of 
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participants with safety parameters that meet predefined limits of change based on the same
threshold criteria described above for the specific AEs.
For continuous safety measures, such as change from baseline in laboratory, vital signs, and 
ECG parameters, summary statistics for baseline, on-treatment, and change from baseline 
values will be provided by treatment group.
9.6.2.2
Assessment of Safety Topics of Special Interest
The following are considered safety topics of special interest in this study (details pertaining 
to the exact AE terms considered as AEs of special interest will be included in the sSAP):

AEs of dizziness that are rated by the investigator as moderate or severe in intensity

AEs related to gait disturbance, independent of feelings of moderate or severe 
dizziness

AEs of falls, independent of feelings of moderate or severe dizziness

AEs of suicidal ideation

AEs of suicidal behavior

AEs of non-suicidal self-injurious behavior
The rationale for considering these as safety topics of special interest in this study is provided 
in Sections 2.2.2, 2.3, and 4.2.3. The safety topics of special interest will be summarized by 
the number and percentage of participants with an event. Point estimates and 95% CIs for 
between-group differences will be provided for these events using the M&N method
[Miettinen, O. and Nurminen, M. 1985].
Additionally, for the C-SSRS, the 11 prespecified categories of suicidal ideation and 
behavior will be summarized. Participant counts (and cumulative counts) for each category 
will be based on the most severe treatment-emergent event observed during the assessment 
period.
In constructing the treatment-emergent C-SSRS analyses, a pretreatment reference period is 
required, from which a baseline score for each of the 3 categories (ideation, behavior, non-
suicidal self-injury) is derived. For this study, the baseline score for each of the 3 categories 
will be taken as the maximum score arising from all predose C-SSRS administrations, within 
the relevant timeframe. The first predose administration references lifetime history. Each 
subsequent predose administration references the timeframe since the last predose 
administration.
It is noted that the first predose administration actually consists of 2 separate administrations; 
one using lifetime as the reference period and another using fixed-time intervals (6 months 
for behavior and 2 months for ideation).
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For this study, separate analyses will be conducted using 2 defined pretreatment reference 
periods:

Lifetime – Baseline score is the maximum score over all predose assessments.

Fixed-Time-Interval – Baseline score is the maximum score over all predose 
assessments, excluding the Lifetime History assessment.
Table 6 summarizes the analysis strategy for safety endpoints in this study.
Table 6
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
95% 
Between-
group CI
Graphical 
Display
Overall 
Safety 
Assessment
Any AE
X
X
Any serious AE
X
X
Any drug-related AE
X
X
Any serious drug-related AE
X
X
Discontinued study treatment due to AE 
X
X
Death due to AE
X
X
Specific AEs (incidence ≥4 participants in 
any treatment group)
X
X
X
SOCs, PDLCs (incidence ≥4 participants in 
any treatment group)
X
X
Specific AEs, SOCs or PDLCs (incidence <4 
participants in all treatment groups)
X
Change from Baseline Results (Laboratory test 
results, ECGs, Vital Signs)
X
Assessment 
of Safety 
Topics of 
Special 
Interest
Dizziness AEs of moderate or
severe intensity
Gait disturbance AEs (independent of feelings 
of dizziness)
AEs of falls (independent of feelings of 
dizziness)
AEs of suicidal ideation, suicidal behavior, or 
non-suicidal self-injurious behavior
11 prespecified categories of suicidal ideation 
and behavior (from C-SSRS)
X
X
X
X
X
X
X
X
X
AE=adverse event; CI=Confidence Interval; C-SSRS=Columbia Suicide Severity Rating Scale;
ECG=electrocardiogram; PDLC=Predefined Limit of Change; SOC=System Organ Class
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9.6.3
Statistical Methods for Pharmacokinetic Analysis
Plasma concentrations will be summarized by nominal time point using the following 
(non-model-based) descriptive statistics: N (number of participants with nonmissing data), 
arithmetic mean, standard deviation, arithmetic percent CV (calculated as 100 × standard 
deviation/arithmetic mean), median, minimum, maximum, GM, and geometric percent CV 
(calculated as 100 × sqrt (exp(s2) -1), where s2 is the observed variance on the natural log-
scale).
9.6.4
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables, baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
Two types of interim analyses may be performed in this study. Results will be reviewed by 
an eDMC.
The first type of interim analysis will be for safety only and will be conducted approximately 
every 4 to 6 months, with the frequency subject to change per eDMC recommendation.
In addition, a nonbinding interim futility analysis may be performed at the discretion of the 
Sponsor when approximately the first 50% of randomized participants have had the 
opportunity to receive study intervention for 12 weeks (ie, the IA will occur 12 weeks after 
the randomization of the 204th participant). The endpoints, timing, and purpose of the 
interim analysis are summarized in Table 7 below.
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Table 7
Summary of Interim Analysis Strategy
Key Endpoints for Interim 
Analysis
Timing of Interim Analysis
Purpose of Interim Analysis
Safety endpoints as requested by
eDMC
Interim safety analyses will be
reviewed initially every 
4-6 months (approximately) by 
the eDMC. The eDMC may 
change the frequency of these 
analyses based on the results of
these analyses.
Safety
Change from baseline at Week 12
in ADAS-Cog11 score (MK-1942 
5 mg versus placebo)
At the discretion of the 
Sponsor, after the first 50% of 
randomized participants have 
had the opportunity to treat for 
12 weeks (ie, the IA will be 
based on a data cutoff that is 12 
weeks after the randomization 
of the 204th participant). 
Assess futility
Change from baseline at Week 12 
in ADAS-Cog11 score (MK-1942 
15 mg versus placebo)
ADAS-Cog11=Alzheimer’s Disease Assessment Scale-11-item cognitive subscale; eDMC=external Data 
Monitoring Committee, IA=interim analysis
Study enrollment is likely to be ongoing at the time of any interim analyses. Blinding to 
treatment assignment will be maintained at all investigational sites. The results of interim 
analyses will not be shared with the investigators before the completion of the study. 
Participant-level unblinding will be restricted to an external unblinded statistician and 
scientific programmer performing the interim analysis, who will have no responsibilities 
associated with the conduct or design of the study.
An eDMC will serve as the primary reviewer of the results of the interim analyses of the 
study and will make recommendations for discontinuation of the study or protocol 
modifications to an executive committee of the Sponsor. If the eDMC recommends 
modifications to the design of the protocol or discontinuation of the study, this executive 
committee (and potentially other limited Sponsor personnel) may be unblinded to results at 
the treatment level to act on these recommendations. The extent to which individuals are 
unblinded with respect to results of interim analyses will be documented by the unblinded 
statistician. Additional logistical details will be provided in the eDMC Charter. 
Treatment-level results from the interim analysis will be provided to the eDMC by the
unblinded statistician. Before final study unblinding, the unblinded statistician will not be 
involved in any discussions regarding modifications to the protocol, statistical methods, 
identification of protocol deviations, or data validation efforts after the interim analyses.
If the study is stopped early, the CSR will include all available data up to and including the 
close-out visits. This approach to include all available information is in line with the ICH-E9 
guideline, the ITT principle and the CHMP guideline on adaptive designs.
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Should the futility IA be conducted, then the decision of whether to terminate the study for 
futility will be based on the Bayesian predictive conditional probability, ie, the likelihood of 
correctly detecting a treatment difference at the end of the study given the results at the 
interim, corresponding to the primary hypotheses. The Bayesian predictive conditional 
probabilities will be computed assuming that the observed trend at the interim will continue 
to the end of the study. Details pertaining to the computation of the Bayesian predictive 
conditional probabilities are included in the sSAP. The interim analysis will include data for 
participants who completed the study or dropped out, as well as the partial data of ongoing 
participants. Additional details regarding the calculation of the Bayesian predictive 
conditional probability will be described in the sSAP.
Traditional conditional power [Lan, K. K. G. 1988] computes the probability of success by 
fixing the portion of data already observed and by assuming the distribution of the remaining
data, with this assumption typically rooted in what has been observed in the study thus far 
(ie, assuming the “current trend”). The first step in calculating the Bayesian predictive 
conditional probability is to replace the assumption of the “current trend” used to calculate 
the conditional power, with an assumption that is centered around the “current trend.” This is 
accomplished by replacing the observed model-based mean and variance with a randomly 
sampled normal variate (generated using the observed model-based mean and variance). This 
process is repeated 500 times, and the Bayesian predictive conditional probability is taken as 
the average of these computed conditional powers. The resultant Bayesian predictive 
conditional probability is less prone to extreme values (ie, conditional powers <0.01 or 
>0.99). If the Bayesian predictive conditional probability is <15% for both primary 
hypotheses, the study may be stopped for futility.
The operating characteristics of the interim futility analysis (calculated via simulation) are 
provided in Table 8. The probability that the study will meet futility criteria if both null 
hypotheses are true (ie, the true mean CFB treatment difference (MK-placebo) of both doses
is equal to 0) is approximately 70%. The probability that the study will meet futility criteria if 
the true mean CFB treatment difference (MK-placebo) for both doses is equal to 0.5 (a 
difference thought not to be clinical meaningful) is approximately 47%.
Table 8
Operating Characteristics of the Interim Futility Analysis
Assumed Week 12 CFB Trt. vs. Pbo (8 mg, 30 mg)
P (Stop at IA)a
(0.0, 0.0)
69.7
(0.5, 0.5)
47.4
(2.0, 2.0)
2.1
CFB=change from baseline; IA=interim analysis; P=probability; Pbo=placebo; Trt=treatment
Based on 5000 simulations conducted under the same assumptions and design parameters (dropout rate, 
assumed variances, α) as were used to simulate the power calculations corresponding to the primary 
hypotheses.
a P (Stop at IA) is equal to the probability that both doses have a Bayesian predictive conditional probability
less than 15% at the time of the IA. 
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9.8
Multiplicity
The overall Type-I error among the 2 dose comparisons to placebo for the primary and key 
secondary endpoints will be controlled at the two-sided 5% significance level by utilizing a
Bonferroni (Step-down) Procedure in conjunction with a closed testing sequential approach
as shown in Figure 2.
Specifically, a separate hypothesis family will be created for each of the MK-1942 5-mg and 
MK-1942 15-mg doses. Each family will be comprised of 1 hypothesis for the primary 
endpoint and 1 hypothesis for the key secondary endpoint.
No multiplicity adjustments will be made for other endpoints.
Figure 2
Formal Hypothesis Testing Strategy
9.9
Sample Size and Power Calculations
9.9.1
Efficacy Parameter Estimates
Variance estimates were based on data from MK-7622 P012 (restricted to exclude MMSE 
values outside the range of MK-1942 P008), which was a similarly designed study in a mild
to moderate AD population. Simple summary statistics were computed (variance at each time
point, correlation matrix across all time points). The upper bound of a 90% CI for the 
variance was used to represent the variance at each time point in constructing the power 
simulations. Though not directly used in the simulations, the corresponding assumed 
variance for the Week 12 CFB standard deviation can be computed using these upper bounds 
and the computed correlations. This information is found in Table 9.
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The assumed dropout rate (20%) was determined using data from MK-7622 P012 in 
conjunction with a wide range of literature references [Fullerton, T., et al 2018], [Gault, L. 
M., et al 2015], [Gault, L. M., et al 2016], [Haig, G. M., et al 2014], [Atri, A., et al 2018], 
[Olin, J. T. 2002], [Rockwood, K., et al 2001], [Wilkinson, D. 2001] while also factoring in 
the potentially higher dropout due to the COVID-19 pandemic.
The assumed CFB mean treatment difference for ADAS-Cog11 Total score is not based on 
prior MK-1942 data, but rather on what treatment difference is considered clinically 
meaningful. Similarly, the assumed mean treatment difference for CGIC score is not based 
on prior MK-1942 data, but rather on what effect size is considered clinically meaningful.
Table 9
Assumed Variances and Correlations Used in the Power Simulations
Endpoint
Baseline 
SD
Week 12 
SD
UB of 90% CI for 
Baseline SD
UB of 90% CI 
for Week 12 SD
Corr (Baseline, 
Week 12)
Week 12 CFB 
SD Using UB of 
90% CI
ADAS-
Cog11
7.76
8.25
8.47
9.12
0.844
4.95
CGICa
NA
0.91
NA
1.00
NA
NA
ADAS-Cog11=Alzheimer’s Disease Assessment Scale-Cognitive Subscale (11);CFB=change from baseline;
CGIC=Clinical Global Impression of Change; CI=confidence interval; Corr=correlation; NA=not applicable; 
SD=standard deviation; UB=upper bound.
a Since the CGIC is intrinsically captured as a change score, no baseline or CFB values exist.
9.9.2
Sample Size and Power for Efficacy Analyses
The sample size of 136 per arm was selected to provide approximately 90% power for 
success for at least one of the MK-1942 dose comparisons (vs placebo) pertaining to the 
primary hypothesis (Table 10).
Table 10
Power Calculations for ADAS-Cog11 Total Score and CGIC
Endpoint
Assumed Mean CFB. Trt. 
Diff vs. Pbo (8 mg, 30 mg)
Assumed Week 12 
CFB SD
P (Success for at 
least one dose)
P (Success at a given 
dose)
ADAS-Cog11a
(2.0, 2.0)
4.95
89.7
77.7
CGICb
(0.3, 0.3)
1.00
NC
48.9
ADAS-Cog11=Alzheimer’s Disease Assessment Scale-Cognitive Subscale (11); CFB=change from baseline; 
NC=not computed (since only the marginal power was computed); Pbo=placebo; SD=standard deviation; Trt=treatment
136 randomized participants per arm
All calculations/simulations assume a 20% dropout rate at Week 12.
a Computed using 5000 simulations, according to the prespecified multiplicity strategy (see Section 9.8) at an overall
two-sided α=0.05 level.
b Marginal power was calculated (not simulated) absent regard to the multiplicity approach using α=0.025. The formal 
power is lower than that presented in the table, as success on ADAS-Cog11 is required within a given dose family in 
order for testing to proceed. Since the CGIC is intrinsically captured as a change score, the assumed means and SDs 
presented are not CFB.
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9.9.3
Sample Size and Power for Safety Analyses
The probability of observing at least one event for any safety endpoint in this study depends 
on the number of participants treated and the underlying percentage of participants with a
specific AE in the study population. If the underlying incidence of one event on a safety 
endpoint is 0.8% (1 of every 136 participants receiving the study intervention), there is a 
66.5% chance of observing at least one AE among 136 participants in the study intervention 
group. If no such AEs are observed among the 136 participants in a treatment group, this 
study will provide 95% confidence that the underlying percentage of participants with that 
AE is <3% in the treatment group.
9.10
Subgroup Analyses
To assess whether the treatment effect with respect to the primary and key secondary 
endpoints is consistent across various subgroups of the study population, the
between-treatment group effect (with a nominal 95% CI) will be estimated and plotted 
(Forest plot) within each subgroup of the following classification variables.

Age group (<65, 65-74, 75-90)

Gender (female; male)

Race (white; other)

Geographic Region (US/Canada, Europe/Australia/NZ, Rest of World)

Years since diagnosis (<median; ≥median score)

Baseline MMSE total score (MMSE score ≤19; MMSE score ≥20)

Baseline BMI (<median; ≥median value)

APOE4 status (positive, negative)

Memantine use at baseline (yes, no)
The consistency of the treatment effect will be assessed in the context of the primary (or key 
secondary, as appropriate) efficacy analysis model using only the data for a specific 
subgroup. CIs will only be produced for a subgroup if both treatment groups (MK-1942 dose 
group and placebo) have at least 15 participants (approximately 10%) within the subgroup; 
summary statistics for subgroups will be provided regardless of sample size.
In addition to conducting the subgroup analyses above (which are all based on 
pre-randomization characteristics), an additional subgroup analysis will be conducted on a 
post-randomization factor: low PK versus normal PK. The criteria for inclusion in the “low 
PK” group will be defined separately for each treatment arm, noting that all participants
randomized to the placebo arm will belong to the “normal PK” arm. The criteria for inclusion 
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in the 2 respective groups will be defined in the sSAP. For further information regarding PK 
variability, refer to Section 6 of the IB.
These subgroups will be interpreted with caution, as inclusion in the subgroups themselves 
may be subject to the effect of the drug in ways that cannot be measured or perceived, 
rendering between-treatment comparisons within these subgroup levels as suspect.
9.11
Compliance (Medication Adherence)
In this study, as part of the routine recording of the amount of study treatment taken by each 
participant, the number of capsules remaining in study packaging will be counted, reviewed, 
and recorded at regular intervals. Study intervention records will be used to calculate 
participant compliance.
A day within the study will be considered an “On-Therapy” day if the participant takes the 
intended number of capsules.
For a participant who is followed for the entire study period, the “Number of Days Should be 
on Therapy” is the total number of days from randomization to the last scheduled day for 
treatment administration for that participant. For a participant who discontinued from the 
study permanently, the “Number of Days Should be on Therapy” is the total number of days 
from randomization to the date of the last dose of study intervention.
For each participant, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance by treatment group for the FAS 
population.
9.12
Extent of Exposure
The extent of exposure to study treatment will be evaluated by summary statistics (N, mean, 
median, SD). Additionally, the total number of days each participant took a particular total 
daily dose of study intervention will be identified and summarized (as participant counts and 
percentages) within duration categories).
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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
Committees Structure
10.1.4.1
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 Interim 
Analyses) and recommend to the EOC whether the study should continue in accordance with
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.2
Scientific Advisory Committee
This study was developed in collaboration with a SAC. The SAC comprises both Sponsor 
and non-Sponsor scientific experts who provide scientific and strategic guidance on various 
aspects of the clinical trial and/or development, which may include study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.4.3
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
10.1.5
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.
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Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
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.
10.1.7
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.
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 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
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 
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.
10.1.9
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 
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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.
10.1.10
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 11 will be performed by the central laboratory.
•
Local laboratory results are only required if the central laboratory results are not available 
in time for either study intervention administration and/or response evaluation. Screening 
laboratory test results can also be repeated locally if a laboratory error is suspected. If a 
local sample is required, it is important that the sample for central analysis is obtained at 
the same time. For Visit 9, if a participant cannot attend the in-person site visit, scheduled 
safety laboratory assessments may be performed at a local laboratory, and other 
nonlaboratory assessments will be performed by TC. 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.
•
Screening laboratory tests should NOT to be repeated if the initial results are 
exclusionary, except where repeat tests are allowed in the eligibility criteria (Section 5.2). 
Rescreening may be performed after a participant’s laboratory abnormality initially 
leading to exclusion resolves (information on rescreening is provided in Section 8.11.1). 
Laboratory criteria for study intervention discontinuation are in Section 7.1 and below.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and 5.2 of the protocol.
•
The approximate amount of blood collected from each participant over the duration of the 
study is 128 ml.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
All laboratory tests should be performed after all efficacy assessments are completed at 
each visit, except for Visit 6, where laboratory tests will be done with first PK draw and 
before efficacy assessments.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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Table 11
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
WBC
WBC count with differential (absolute, percentage):

Neutrophils

Lymphocytes

Monocytes

Eosinophils

Basophils
Platelets
RBC 
Morphology, MCV, RDW
Hemoglobin
MCH, MCHC
Hematocrit
Chemistry
Creatinine 
(includes eGFR 
calculation)
Phosphorus
Calcium
CK
Sodium
Potassium
Chloride
CO2 or bicarbonate
AST (SGOT)
ALT (SGPT)
Albumin
Total protein
Alkaline phosphatase
Lactate Dehydrogenase
Gamma-Glutamyl 
Transpeptidase
Globulin
Urea Nitrogen
Uric Acid
Total bilirubin
Indirect bilirubin
Direct bilirubin
Glucose
Urinalysis
Color and clarity
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase
Microscopic examination (reported if detected), includes bacteria, casts, crystals, 
epithelial cells, RBC, WBC, yeast, oval fat bodies, fat, mucous, sperm, trichomonas
Other Tests
INR at Visit 2 (randomization) only
TSH with reflex FT4 
FSH – female only, if applicable
Biomarkers
Genotyping for CYP2C19/APOE4
Serology (HIV antibody, HbsAg, and hepatitis B, C virus antibody)
•
Serologies are at the discretion of the investigator (except for country-specific 
requirements [Appendix 7])
Serum vitamin B12, folate, homocysteine, methylmalonic acid
ALT=alanine aminotransferase, AST=aspartate aminotransferase, CK=creatine kinase, eGFR=estimated glomerular 
filtration rate, FSH=follicle-stimulating hormone, FT4=free thyroxine T4, HbsAg=hepatitis B surface antigen, 
HDL=high density lipoprotein, INR=international normalized ratio, LDL=low density lipoprotein, MCH=Mean 
corpuscular (or cell) hemoglobin, MCHC=mean corpuscular hemoglobin concentration, MCV=mean corpuscular 
volume, RBC=red blood cell, RDW=red blood cell distribution width, SGOT=serum glutamic-oxaloacetic transaminase, 
SGPT=serum glutamate-pyruvate transaminase, TSH=thyroid-stimulating hormone, WBC=white blood cell 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
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.
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•
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.
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.
10.3.3
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.
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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, 
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.
10.3.4
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
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10.3.5
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 
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 /toxicity
•
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?
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•
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 
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.
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(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?
•
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.
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•
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.
10.3.6
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).
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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 Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
•
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 must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Women of Childbearing Potential (WOCBP) Nonparticipant Only
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
•
Women in the following categories are not considered WOCBP:
-
Premenarchal
-
Premenopausal female with 1 of the following:
-
Hysterectomy
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-
Bilateral salpingectomy
-
Bilateral oophorectomy
-
Permanent infertility due to an alternate medical cause other than the above (eg, 
Mullerian agenesis, androgen insensitivity.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
10.5.2
Contraception Requirements
As WOCBP are not eligible to participate in this study, there are no contraceptive 
requirements for female participants in this study. Contraceptive use by men is described in 
Section 5.1.
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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 Research3, 4
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 Research3, 4
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 Research3, 4
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 Usage3, 4
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 Research3, 4
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@MSD.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 Specimens3, 4
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 Security3, 4
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 Participants3, 4
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 Population3, 4
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 Research3, 4
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@MSD.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
Argentina-specific Requirements
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
United Kingdom-specific Requirements
Section 6.5 Concomitant Therapy 
Listed below are specific concomitant therapies or vaccinations that are prohibited during the 
study (exceptions noted):
•
Live vaccines must not be administered for 90 days after the last dose of study 
intervention. Refer to Section 5.2 for information on COVID-19 vaccines.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-incompetent 
adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other 
concomitant therapy.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ACC
American College of Cardiology
AChEIs
acetylcholinesterase inhibitors
ADAS-Cog11
Alzheimer’s Disease Assessment Scale-11-item cognitive subscale
ADAS-Cog13
Alzheimer’s Disease Assessment Scale-13-item cognitive subscale
ADCS-ADL
Alzheimer’s Disease Cooperative Study Activities of Daily Living
ADCS-CGIC
Alzheimer’s Disease Cooperative Study Clinical Global Impression of 
Change
ADL
activities of daily living 
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event 
AHA
American Heart Association
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APaT
All-Participants-as-Treated
APOE
apolipoprotein E
AR
adverse reaction
AST
aspartate aminotransferase
AUC
area under the curve
bid
twice daily
BLA
Biologics License Application
BMI
body mass index
BP
blood pressure
CERAD
Consortium to Establish a Registry for Alzheimer’s Disease
CFB
change from baseline
CG
Cockcroft-Gault
CHMP
Committee for Medicinal Products for Human Use
CI
confidence interval
CL
clearance
Cmax
maximum plasma concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus disease caused by severe acute respiratory syndrome
coronavirus 2
COWAT
Controlled Oral Word Association Test
CRF
Case Report Form 
C-SSRS
Columbia Suicide Severity Rating Scale 
CSR
clinical study report
CT
computed tomography
CYP
cytochrome P450
CYP2C19
cytochrome P450 2C19
DC
discontinuation
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Abbreviation
Expanded Term
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DxV
diagnostic verification form
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EEA
European Economic Area
eDMC
External Data Monitoring Committee
eGFR
estimated glomerular filtration rate
EM
exposure margin
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EOT 
End of Treatment
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone 
FSR
first site ready
FT4
Free T4 test
GCP
Good Clinical Practice 
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
HS
hypothetical strategy
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
IE1
Intercurrent Event 1
IE2
Intercurrent Event 2
IE3
Intercurrent Event 3
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IND
Investigational New Drug 
IRB
Institutional Review Board
IRT
interactive response technology
IV
intravenous
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PRODUCT:  MK-1942  
122
PROTOCOL/AMENDMENT NO.:  008-00  
MK-1942-008-00 FINAL PROTOCOL
07-JUL-2022
11
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