A Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Assess the Safety, Tolerability, and Pharmacokinetics of MK-1167 Administered to Patients With Alzheimer's Disease Receiving Stable Donepezil Treatment
Phase: PHASE1
Conditions: Alzheimer's Disease
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:                NCT06285240
Document Date:            14-Jun-2024
A Randomized, Double-Blind, Placebo-
Controlled Clinical Trial to Assess the Safety, 
Tolerability, and Pharmacokinetics of MK-1167
Administered to Patients with Alzheimer’s
Disease Receiving Stable Donepezil Treatment

PROTOCOL IDENTIFIER: MK-1167
1
STUDY NUMBER: 007-02
MK-1167-007-02 FINAL PROTOCOL
14-JUN-2024
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 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Assess 
the Safety, Tolerability, and Pharmacokinetics of MK-1167 Administered to Patients with 
Alzheimer’s Disease Receiving Stable Donepezil Treatment
Study Number: 007-02
Compound Code(s): MK-1167
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):
NCT
N/A
EU CT
N/A
EudraCT
N/A
jRCT
N/A
WHO/UTN
N/A
IND
164154
Approval Date: 14 June 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 2
14-JUN-2024
Addition of Panel B 
Amendment 1
23-FEB-2024
Update Exclusion Criteria
Original Protocol
05-JAN-2024
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendment:
The primary rationale for Amendment 02 is to add an additional panel (Panel B) where 
participants will receive multiple doses of 6 mg MK-1167/placebo.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
1.3 Schedule of 
Activities and 
Throughout
A second SoA table was added to reflect the 
addition of Panel B where participants will 
receive 6 mg of MK-1167/placebo. 
To address the addition of a panel in order to 
study a higher dose.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Throughout
Minor administrative, formatting, grammatical, 
and/or typographical changes were made 
throughout the document.
To ensure clarity and accurate interpretation of 
the intent of the protocol.
1.1 Synopsis:
Estimated 
Duration of Study
Updated estimated duration of study from 4 to 
5 months. 
Addition of Panel B necessitates update to 
estimated timelines for study conduct.
1.1 Synopsis: 
Intervention 
Groups and 
Durations
For Panel B added arm name, intervention 
name, unit dose strength(s), dosage level(s), 
route of administration, regimen/treatment 
period/vaccination regimen, and use.
Addition of Panel B necessitates updates to 
intervention groups and duration for study 
conduct.
1.1 Total Number 
of Intervention 
Groups/Arms
Updated text (‘2 arm’) to include the following 
detail: ‘There will be 2 panels (A and B) with 
approximately 16 participants each.’
Addition of Panel B necessitates inclusion of the 
number of participants for Panel B for study 
conduct.
1.1 Synopsis: 
Duration of 
Participation
Added 16-week time frame for Panel B.
Addition of Panel B necessitates addition of 16-
week timeframe for study conduct.
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Section Number 
and Name
Description of Change
Brief Rationale
1.2 Schema
Updated Table 1 Study Design to included 
schema for Panel B. Added Figure 2 Study 
Schema for Panel B to reflect schema for Panel 
B.
Addition of Panel B necessitates update to Table 
1 Study Design and addition of Figure 2 Study 
Schema for Panel B for study conduct. 
2.2.1
Pharmaceutical 
and Therapeutic 
Background
Added information about preliminary safety 
data from Panel A of this study. 
Addition of information about preliminary safety 
data for Panel A of this study supports addition 
of Panel B.
2.2.2 Preclinical 
and Clinical 
Studies
Updated to include new safety data from 
clinically completed Phase 1 studies, including 
MK-1167 PN003, PN004, and PN006. Updated 
to include preliminary PK data from 1167 
PN006. 
Several Phase 1 studies have completed clinical 
investigation since publication of initial protocol.
2.2.3 Ongoing 
Clinical Studies
Updated to include new safety data from 
ongoing Phase 1 study MK-1167 PN007.
One Phase 1 study has additional data since 
publication of initial protocol.
4.1 Overall 
Design
Updated to include addition of Panel B to the 
study design. 
Addition of Panel B necessitates update to the 
overall design for study conduct.
4.2 Scientific 
Rationale for 
Study Design
Updated to include addition of dosing and 
dosing duration for Panel B. 
Addition of Panel B necessitates update to 
scientific rationale for study design for study 
conduct. 
4.2.1.1 Safety 
Endpoints
Updated to include safety data from Phase I 
studies, including MK-1167 PN001, PN002, 
PN004, PN006, and PN007 Panel A. 
Several Phase I studies have additional data 
since publication of initial protocol. 
4.3 Justification 
of Dose
Updated to provide PK projections for Panel B 
based on MK-1167 PN001, PN002, and PN004 
Panel A PK data to inform justification of dose 
for Panel B. Updated to include information 
about MK-1167 PN003 to support dose of Panel 
B. Updated Table 2 to reflect addition of PN004 
Panel A data used to inform exposure 
projections. 
Addition of Panel B necessitates update to 
justification of dose for study conduct. 
4.3.1 Rationale 
for Dose Interval 
and Study Design
Updated to include rationale for Panel B dose 
interval and study design 
Addition of Panel B necessitates update to 
rationale for dose interval and study design for 
study conduct. 
5.2 Exclusion 
Criteria
The first sentence of Exclusion Criterion 5 
correctly states the estimated eGFR value of 
≤60 mL/min/1.73 m2. The final sentence in the 
same section incorrectly states “80 mL/min” for 
CrCl and “80 mL/min/1.73m2” for eGFR. The 
correct value is indeed 60 mL/min” for CrCl 
and “60 mL/min/1.73m2” for eGFR.
The values in this section were inconsistent due 
to a typographical error.
5.3.1.1 Diet 
Restrictions
Updated to include full PK sampling days for 
Panel B. 
Addition of Panel B necessitates update to diet 
restrictions for study conduct. 
5.3.1.2 Fruit Juice 
Restrictions
Updated to include full PK sampling days for 
Panel B. 
Addition of Panel B necessitates update to fruit
juice restrictions for study conduct. 
5.3.2.1 Caffeine 
Restrictions
Updated to include full PK sampling days for 
Panel B.
Addition of Panel B necessitates update to 
caffeine restrictions for study conduct. 
6.1 Study 
Intervention(s) 
Administered –
Table 3
Updated to include intervention information for 
Panel B. Updated to include donepezil 5 mg as 
medication for potential dechallenge for Panels 
A and B. 
Addition of Panel B necessitates update to Table 
3. Potential need to down titrate donepezil dose 
necessitates update to Table 3. 
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Section Number 
and Name
Description of Change
Brief Rationale
6.3.1 Intervention 
Assignment
Added Table 5 to illustrate the allocation of 
participants to treatment for Panel B.
Addition of Panel B necessitates addition of 
Table 5 for study conduct. 
8.1.8.1 Timing of 
Dose 
Administration
Updated to include donepezil dosing 
information for Panel B.
Addition of Panel B necessitates update to 
timing of dose administration for study conduct. 
8.1.11 
Domiciling
Updated timing of participant reporting to CRU 
to the evening on Day -4
This change was made to address erroneous text 
in this section
8.3.2.2 
Orthostatic Vital 
Signs
When considering repeating orthostatic vital 
signs (VS) measurements, Section 8.3.2.2 
should be followed, including the instructions 
that participants should be semi recumbent for 
at least 10 minutes and then stand upright for 
approximately 2 minutes before measurement 
of orthostatic VS. 
The process for repeat measurements for 
orthostatic vital signs was erroneously omitted in 
this section.
8.4.7 Events of 
Clinical Interest
Updated the location/bulleting of the study-
specific ECIs
This change was made to enhance how the text 
is presented in this section
8.10.5 Critical 
Procedures Based 
on Study 
Objectives: 
Timing of 
Procedure
Updated study intervention administration for 
Panel B. Updated Table 7
 
. 
Addition of Panel B necessitates update to
timing of procedures for study conduct. 
 
 
 
9.5.1 Statistical 
Methods for 
Pharmacokinetic 
Analyses
Updated to include model-based PK and C24 
estimation information for Panel B.
Addition of Panel B necessitates update to 
statistical methods for PK analyses for study 
conduct. 
10.1.3 Appendix 
1: Data 
Protection
Added the following language: The Sponsor has 
EU-approved Binding Corporate Rules since 
2017, covering all aspects of its Global Privacy 
Program (Corporate Policy 20), and is 
self-certified pursuant to the EU-US Data 
Privacy Framework.
This change was made to reflect an update to the 
Data Protection language.
10.8 Appendix 8: 
Blood Volume 
Table
Updated donepezil sampling in the blood 
volume table for Panel A. Added blood volume 
table for Panel B.
This change was made to address the addition of 
Panel B.
10.13 Appendix 
13: List of 
Abbreviations
Addition of ‘COVID-19’ and ‘DBL’ per use in 
Sec. 2.2.2 and ‘EU’ per use in updated Data 
Protection.
Addition to Preclinical and Clinical Studies data 
and Data Protection warrants update. 
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................21
2
INTRODUCTION..........................................................................................................32
2.1
Study Rationale....................................................................................................32
2.2
Background ..........................................................................................................32
2.2.1
Pharmaceutical and Therapeutic Background .............................................32
2.2.2
Preclinical and Clinical Studies ...................................................................34
2.2.3
Ongoing Clinical Studies.............................................................................38
2.2.4
Information on Other Study-related Therapy: Donepezil Hydrocholoride..38
2.3
Benefit/Risk Assessment......................................................................................39
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................40
4
STUDY DESIGN............................................................................................................41
4.1
Overall Design......................................................................................................41
4.2
Scientific Rationale for Study Design.................................................................41
4.2.1
Rationale for Endpoints ...............................................................................42
4.2.1.1
Safety Endpoints................................................................................42
4.2.1.2
Pharmacokinetic Endpoints ...............................................................43
4.2.1.3
Pharmacodynamic Endpoints.............................................................43
4.2.1.4
Planned Exploratory Biomarker Research.........................................44
4.2.1.4.1
Planned Genetic Analysis ........................................................44
4.2.1.5
Future Biomedical Research..............................................................44
4.2.2
Rationale for the Use of Comparator/Placebo .............................................44
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................45
4.3
Justification for Dose...........................................................................................45
4.3.1
Rationale for Dose Interval and Study Design ............................................48
4.4
Beginning and End-of-Study Definition ............................................................49
4.4.1
Clinical Criteria for Early Study Termination .............................................49
5
STUDY POPULATION ................................................................................................50
5.1
Inclusion Criteria.................................................................................................50
5.2
Exclusion Criteria................................................................................................53
5.3
Lifestyle Considerations......................................................................................55
5.3.1
Meals and Dietary Restrictions....................................................................55
5.3.1.1
Diet Restrictions.................................................................................55
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5.3.1.2
Fruit Juice Restrictions ......................................................................56
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................56
5.3.2.1
Caffeine Restrictions..........................................................................56
5.3.2.2
Alcohol Restrictions...........................................................................57
5.3.2.3
Tobacco Restrictions..........................................................................57
5.3.3
Activity Restrictions ....................................................................................57
5.3.4
...........................................................................57
5.4
Screen Failures.....................................................................................................57
5.5
Participant Replacement Strategy......................................................................58
6
STUDY INTERVENTION............................................................................................59
6.1
Study Intervention(s) Administered...................................................................59
6.2
Preparation/Handling/Storage/Accountability .................................................61
6.2.1
Dose Preparation..........................................................................................61
6.2.2
Handling, Storage, and Accountability........................................................61
6.3
Measures to Minimize Bias: Randomization and Blinding..............................62
6.3.1
Intervention Assignment..............................................................................62
6.3.2
Stratification.................................................................................................62
6.3.3
Blinding........................................................................................................62
6.4
Study Intervention Compliance..........................................................................63
6.5
Concomitant Therapy..........................................................................................63
6.5.1
Rescue Medications and Supportive Care ...................................................65
6.6
Dose Modification/Escalation/Other..................................................................65
6.6.1
Stopping Rules.............................................................................................65
6.7
Intervention After the End of the Study............................................................66
6.8
Clinical Supplies Disclosure................................................................................66
6.9
Standard Policies..................................................................................................66
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................67
7.1
Discontinuation of Study Intervention...............................................................67
7.2
Participant Withdrawal From the Study...........................................................68
7.3
Lost to Follow-up .................................................................................................68
8
STUDY ASSESSMENTS AND PROCEDURES........................................................69
8.1
Administrative and General Procedures ...........................................................69
8.1.1
Informed Consent.........................................................................................69
8.1.1.1
General Informed Consent.................................................................70
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................70
8.1.2
Inclusion/Exclusion Criteria ........................................................................70
8.1.3
Participant Identification Card.....................................................................70
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8.1.4
Medical History ...........................................................................................71
8.1.5
Prior and Concomitant Medications Review...............................................71
8.1.5.1
Prior Medications...............................................................................71
8.1.5.2
Concomitant Medications..................................................................71
8.1.6
Assignment of Screening Number...............................................................71
8.1.7
Assignment of Randomization Number.......................................................71
8.1.8
Study Intervention Administration ..............................................................72
8.1.8.1
Timing of Dose Administration.........................................................72
8.1.9
Discontinuation and Withdrawal .................................................................72
8.1.9.1
Withdrawal From Future Biomedical Research ................................72
8.1.10
Participant Blinding/Unblinding..................................................................73
8.1.11
Domiciling ...................................................................................................73
8.1.12
Calibration of Equipment.............................................................................74
8.2
Efficacy Assessments ...........................................................................................74
8.3
Safety Assessments...............................................................................................74
8.3.1
Physical Examinations.................................................................................75
8.3.2
Vital Signs....................................................................................................75
8.3.2.1
Resting Vital Signs ............................................................................75
8.3.2.2
Orthostatic Vital Signs.......................................................................76
8.3.3
Electrocardiograms ......................................................................................76
8.3.4
Clinical Safety Laboratory Assessments .....................................................77
8.3.5
Neurological Exam ......................................................................................78
8.3.6
Mini-Mental State Examination...................................................................78
8.3.7
WAIS-IV Digit Symbol Substitution Test...................................................78
8.3.8
Suicidal Ideation and Behavior Monitoring.................................................78
8.3.8.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................78
8.3.9
Photograph of Rash......................................................................................79
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................79
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................80
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......82
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...82
8.4.4
Regulatory Reporting Requirements for SAE .............................................82
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................83
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................83
8.4.7
Events of Clinical Interest............................................................................83
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8.5
Treatment of Overdose........................................................................................84
8.6
Pharmacokinetics.................................................................................................84
8.6.1
Blood Collection for Plasma MK-1167 .......................................................84
8.7
Pharmacodynamics..............................................................................................84
8.8
Biomarkers ...........................................................................................................85
8.8.1
Planned Genetic Analysis Sample Collection..............................................85
8.9
Future Biomedical Research Sample Collection...............................................85
8.10
Visit Requirements...............................................................................................85
8.10.1
Screening......................................................................................................85
8.10.2
Treatment Period/Vaccination Visit ............................................................86
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................86
8.10.4
Poststudy......................................................................................................86
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......86
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................88
9
KEY STATISTICAL CONSIDERATIONS ...............................................................89
9.1
Responsibility for Analyses.................................................................................89
9.2
Hypotheses/Estimation ........................................................................................89
9.3
Analysis Endpoints...............................................................................................89
9.3.1
Primary Endpoints .......................................................................................89
9.3.2
Secondary Endpoints ...................................................................................89
9.3.3
Exploratory Endpoints .................................................................................89
9.4
Analysis Populations............................................................................................89
9.4.1
All Participants As Treated Population........................................................89
9.4.2
Per-Protocol (PP) Population.......................................................................89
9.5
Statistical Methods...............................................................................................90
9.5.1
Statistical Methods for Pharmacokinetic Analyses......................................90
9.5.2
Statistical Methods for Pharmacodynamic Analyses...................................91
9.5.3
Statistical Methods for Safety Analyses ......................................................91
9.6
Interim Analyses ..................................................................................................92
9.7
Multiplicity ...........................................................................................................92
9.8
Sample Size and Power Calculations .................................................................92
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................93
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........93
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................93
10.1.2
Financial Disclosure.....................................................................................96
10.1.3
Data Protection.............................................................................................97
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10.1.3.1
Confidentiality of Data ......................................................................97
10.1.3.2
Confidentiality of Participant Records...............................................97
10.1.3.3
Confidentiality of IRB/IEC Information............................................98
10.1.4
Publication Policy........................................................................................98
10.1.5
Compliance with Study Registration and Results Posting Requirements ...98
10.1.6
Compliance with Law, Audit, and Debarment ............................................99
10.1.7
Data Quality Assurance ...............................................................................99
10.1.8
Source Documents .....................................................................................100
10.1.9
Study and Site Closure...............................................................................101
10.2
Appendix 2: Clinical Laboratory Tests............................................................102
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................103
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................103
10.3.2
Definition of AE ........................................................................................103
10.3.3
Definition of SAE ......................................................................................104
10.3.4
Additional Events Reported.......................................................................105
10.3.5
Recording AE and SAE .............................................................................106
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................109
10.4
Appendix 4: Drug–Device Combination Products/Combination Medicinal 
Products: Complaints, 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
Contraceptive Requirements......................................................................113
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................114
10.7
Appendix 7: Country-specific Requirements..................................................118
10.8
Appendix 8: Blood Volume Tables...................................................................119
10.9
Appendix 9: 12-Lead Electrocardiogram Evaluation Criteria......................120
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...122
10.11 Appendix 11: The National Institute of Neurological and Communicative 
Diseases and Stroke/Alzheimer’s Disease and Related Disorders 
Association (NINCDS-ADRDA) Criteria for Probable AD...........................123
10.12 Appendix 12: General and Targeted Neurological Examinations ................125
10.12.1
The General Neurological Examination ....................................................125
10.12.1.1
Module 1 – Mental Status Examination...........................................125
10.12.1.2
Module 2 – Cranial Nerve Assessment............................................125
10.12.1.3
Module 3 – Motor System ...............................................................126
10.12.1.4
Module 4 – Reflexes ........................................................................127
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10.12.1.5
Module 5 – Coordination and Gait ..................................................127
10.12.1.6
Module 6 – Sensory .........................................................................128
10.12.2
The Targeted Neurological Examination...................................................128
10.12.2.1
Module 1 – Mental Status Examination...........................................128
10.12.2.2
Module 2 – Cranial Nerve Assessment............................................129
10.12.2.3
Module 3 – Motor System ...............................................................129
10.12.2.4
Module 5 – Coordination and Gait ..................................................129
10.12.2.5
Module 6 – Sensory .........................................................................129
10.13 Appendix 13: Abbreviations .............................................................................130
11
REFERENCES.............................................................................................................135
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LIST OF TABLES
Table 1
Study Design....................................................................................................18
Table 2
.......46
Table 3
..........................................................................................60
Table 4
Allocation of Participants to Treatment For Panel A.......................................62
Table 5
Allocation of Participants to Treatment For Panel B.......................................62
Table 6
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................81
Table 7
...............................................87
Table 8
Protocol-required Safety Laboratory Assessments........................................102
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LIST OF FIGURES
Figure 1
...............................................................................19
Figure 2
...............................................................................20
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Assess 
the Safety, Tolerability, and Pharmacokinetics of MK-1167 Administered to Patients with 
Alzheimer’s Disease Receiving Stable Donepezil Treatment
Short Title: Clinical Trial to Evaluate MK-1167 in AD Patients Taking Donepezil
Acronym: N/A
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The study population consists of patients with mild to moderate AD, 50 to 90 years of age.
Primary Objective
Primary Endpoint
Evaluate the safety and tolerability of 
MK-1167 when administered to patients 
with mild to moderate Alzheimer’s Disease
on stable doses of oral donepezil 10 mg 
daily
Adverse events, discontinuation due to 
Adverse events
Secondary Objectives
Secondary Endpoints
Evaluate the pharmacokinetic profile of 
MK-1167 when administered to patients 
with mild to moderate Alzheimer’s Disease
on stable doses of oral donepezil 10 mg 
daily
Estimation:
 
AUC0-24, Cmax, C24, Tmax, CL/F, Vz/F, 
t1/2
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Dementia Alzheimer's type
Population
Patients with mild to moderate cognitive 
impairment associated with Alzheimer’s 
Disease
Study Type
Interventional
Intervention Model
Sequential
This is a multi site study
Type of Control
Placebo
Study Blinding
Double-blind
Blinding Roles
Participants or Subjects, Investigator, and 
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 5 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:
For Panel A, approximately 16 participants will be allocated/randomized such that 12
evaluable participants complete the study as described in Section 9.8. For Panel B, 
approximately 12 participants will be allocated/randomized as described in Section 9.8.
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Panel A 
MK-1167
5 MG, 
1 MG
6 MG
Oral
 
loading doses
QD 
Days 1 to 7
Test Product
Panel A
MK-1167
1 MG
3 MG
Oral
 
maintenance 
doses QD
Days 8 to 21
Test Product
Panel A
Donepezil
10 MG
10 MG
Oral
QD dosing
during entire 
treatment 
period
Comparator
Panel A
Placebo to 
MK1167
0 MG
All 
Dosage 
Levels
Oral
 
QD 
Days 1 to 21
Placebo
Panel B
MK-1167
5 MG, 
1 MG
6 mg
Oral
 
QD 
Days 1 to 31
Test Product
Panel B
Donepezil
10 MG
10 mg
Oral
QD dosing 
during entire 
treatment 
period
Comparator
Panel B
Placebo to 
MK-1167
0 MG
All 
Dosage 
Levels
Oral
 
QD 
Days 1 to 31
Placebo
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Total Number of Intervention Groups/Arms
There will be 2 panels (A and B). Panel A 
will have approximately 16 participants, and 
Panel B will have approximately 12 
participants.
Duration of Participation
Each participant will participate in the study 
for approximately 11 weeks for Panel A and 
12 weeks for Panel B from the time the 
participant provides documented informed 
consent through the final protocol-specified 
contact. After a screening period of up to 4
weeks, each participant will be receiving 
assigned study intervention for 
approximately 21 days for Panel A and 
31 days for Panel B.
 
Study Governance Committees:
Executive Oversight Committee
No
External Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 13.
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1.2
Schema
The study design is depicted in Table 1, and the study schema in Figure 1 and Figure 2.
Table 1
Study Design
Panel A a,b,c (n≤16)
 
Panel B a,c,d (n≤12)
 
Loading Dose
MK-1167/Placebo
6 mg QD
Days 1 to 7
Maintenance Doses
MK-1167/Placebo
3 mg QD
Days 8 to 21
All Doses
MK-1167/Placebo
6 mg QD
Days 1 to 31
Donepezil 10 mg QD throughout treatment 
period
Donepezil 10 mg QD 
throughout treatment period
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Figure 1
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Figure 2
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1.3
Schedule of Activities
Panel A
Study Period
Screeninga
Poststudyb
Notes
Study Day
Administrative/Study Procedures
Informed Consent
X
Sections 5.1, 8.1.1.1
Informed Consent for FBR
X
Sections 5.1, 8.1.1.2
Participant ID Card
X
Section 8.1.3
Inclusion/Exclusion Criteria
X
X
X
Reviewed at Screening, Day -1, and 
after completion of Day 1 predose 
procedures. 
Sections 5.1, 5.2, 8.1.2
Medical History
X
Includes medical history of illicit 
drugs, alcohol, tobacco, and caffeine 
use. 
Section 8.1.4
Prior/Concomitant Medication 
Review
X -------------------------------------------------------------------------------------------------------------X
Sections 5.2, 6.5, 8.1.5
Assignment of Screening 
Number
X
Section 8.1.6
Assignment of 
Treatment/Randomization 
Number
X
Sections 5.5, 8.1.7
MK-1167/Placebo 
Administration
X
X
X
X
X
Section 8.1.8, 8.10.5
Donepezil Administrationc
X ------------------------------------------------------------------------------------------------------------- X
Section 8.1.8, 8.10.5
Standard Mealsd
X
X
X
X
X
X
X
X
X
Meals and snacks will be provided. 
Section 5.3.1
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Panel A
Study Period
Screeninga
Poststudyb
Notes
Study Day
Domiciling
X
X
X
X
X
X
X
X
X
Participants will report to the CRU 
in the evening of Day -4.
 
 
 At the discretion of the 
investigator, participants may be 
requested to remain in the CRU 
longer.
Section 8.1.11 
Safety Procedures
Full Physical Examination
X
Xe
X
X
Screening: anytime.
Section 8.3.1.
Full Neurological 
Examination
X
X
Section 8.3.5, Appendix 12
Targeted Neurological 
Examination
Xe
X
X
Section 8.3.5, Appendix 12
Height
X
Section 8.3.1.
Weight
X
Xe
X
BMI to be taken only at Screening.
Day 1: predose.
Section 8.3.1.
Resting VS (Semi
Recumbent): Heart Rate
and Blood Pressure
X
X
X
X
X
Screening and Poststudy visits: 
anytime.
 
Section 8.3.2.1.
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Panel A
Study Period
Screeninga
Poststudyb
Notes
Study Day
Orthostatic VS: Heart Rate 
and Blood Pressure
X
X
X
X
X
Screening and Poststudy visits: 
anytime.
 
Section 8.3.2.2.
VS: Respiratory Rate and 
Body Temperature
X
X
X
X
X
Screening and Poststudy visits: 
anytime.
 
Section 8.3.2.
12-lead ECGg
X
X
Xh
X
X
Xi
Xi, j
Screening: anytime.
 
 
 
Section 8.3.3, Appendix 9
Serum FSH (PONCBP only)
X
Appendices 2, 5, 8
Urine or Serum Pregnancy 
Test (POCBP only)
X
X
Urine test will be collected. Serum 
test will be collected in the event 
that urine test is positive or cannot 
be confirmed.
Section 5.1, Appendix 2
HIV, Hepatitis B and C 
Screen (per site SOP)
X
Section 5.2, Appendices 2, 8
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Panel A
Study Period
Screeninga
Poststudyb
Notes
Study Day
UDS/BDS (per site SOP)
X
Xe
Drug screen is mandatory at 
Screening; any additional drug 
screen(s) is/are conducted per site 
SOP.
Section 8.3.4, Appendix 2
Alcohol Screen
X
X
Breathing test. 
Section 5.2, Appendix 2
Clinical Safety Assessment 
(Hematology, Urinalysis, and 
Chemistry)
X
X
X
X
X
X
Screening, Day -3, and Poststudy 
visits: anytime.
 
Section 8.3.4, Appendices 2, 8
AE/SAE Review
X ------------------------------------------------------------------------------------------------------------ X
Section 8.4, Appendix 3
MMSE-2
X
Xk
X
Sections 5.1, 5.2, 8.3.6
DSSTl
X
X
Xh
Xm
X
X
Sections 4.2.1.3, 8.3.7, 8.7
C-SSRS Baselinen
X
Sections 4.2.3, 5.2, 8.3.8
C-SSRS Since Last 
Assessmentn
X
X
X
X
Sections 4.2.3, 8.3.8
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Panel A
Study Period
Screeninga
Poststudyb
Notes
Study Day
Pharmacokinetics
Blood for Plasma MK-1167 
and Metabolites Assaying
X
X
X
X
X
Xi
Xi
Xi
Xi
Xi
Xi, j
 
 
 
 
 
 
 
                                   
Blood for Plasma Donepezil 
Assayingo
X
X
X
X
Day 
: 24 hours postdosef.
Day 
: 0.5, 1, 2, 3, 4, 6, 8, 12, and 
24 hours postdosef
Day 
: predose and 0.5, 1, 2, 3, 4, 
6, 8, 12, 24 hours postdose
Section 8.10.5, Appendix 8.
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Panel A
Study Period
Screeninga
Poststudyb
Notes
Study Day
Biomarkers
Blood for Genetic Analysis
X
Predose from enrolled participants 
only.
Section 8.8, Appendix 8.
X
Sections 8.8, 8.10.1, and Appendix 
8.
AE=adverse event; BDS=blood drug screen; BMI=body mass index; C-SSRS=Columbia-Suicide Severity Rating Scale; CYP=cytochrome P450; DSST=Digit Symbol Substitution 
Test; ECG=electrocardiogram; FBR=future biomedical research; FSH=follicle-stimulating hormone; HIV=human immunodeficiency virus; ID=identification; MMSE-2=Mini-
Mental State Examination Edition 2; PK=pharmacokinetic(s); POCBP=participant of childbearing potential; PONCBP=participant of nonchildbearing potential; SAE=serious 
adverse event; SOP=standard operating procedure; UDS=urine drug screen; VS=vital signs.
a
Screening should occur within 4 weeks prior to Day 1. 
b
The Poststudy Visit will occur at approximately 
 days after last dose. 
c
Donepezil will be administered in the mornings at approximately the same time as MK-1167/placebo. If participants do not usually take their donepezil in the mornings, they 
should be instructed to start taking it in the morning starting on Day -7 until Day -4. 
d
Standardized meals/snacks to be provided on all days during domiciling at ~ 2 (breakfast), ~ 4 (lunch), ~ 7 (snack), ~ 10 (dinner), and ~ 13 (snack) hours postdose or 
equivalent (Section 5.3.1).
e
Can be conducted within 24 hours prior to first dose.
f
24-hour timepoint will be collected at predose when dosing occurs on the day of collection.
g
ECG measurements to be obtained in triplicate and performed before any blood sample for each timepoint. 
h
Day 2 only.
i
Participants will return to the clinic for collection of MK-1167 plasma samples and ECG recordings at the hours/days specified in the Schedule of Activities. 
j
 will be collected before any Poststudy Visit procedures. 
k
Give within 12 hours of morning dose.
l
A practice assessment will be administered at Screening. The assessment given on Day -1 will provide the baseline value. On Days 
, assessments should be 
given within 4 hours after the morning dose. See Study Operation’s Manual for specific instructions on test administration.
m
Days 17 to 20 only.
n
C-SSRS Baseline version to be used at Screening Visit, and all other visits use the C-SSRS Since Last Assessment version.
o
Donepezil 24-hour postdose samples
 will be analyzed; remaining donepezil blood samples will be archived.
p
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Panel B
Study Period
Screeninga
Poststudyb
Notes
Study Day
Administrative/Study Procedures
Informed Consent
X
Sections 5.1, 8.1.1.1
Informed Consent for FBR
X
Sections 5.1, 8.1.1.2
Participant ID Card
X
Section 8.1.3
Inclusion/Exclusion Criteria
X
X
X
Reviewed at Screening, Day -1, and after 
completion of Day 1 predose procedures. 
Sections 5.1, 5.2, 8.1.2
Medical History
X
Includes medical history of illicit drugs, 
alcohol, tobacco, and caffeine use. 
Section 8.1.4
Prior/Concomitant Medication 
Review
X -------------------------------------------------------------------------------------------------------X
Sections 5.2, 6.5, 8.1.5
Assignment of Screening 
Number
X
Section 8.1.6
Assignment of 
Treatment/Randomization 
Number
X
Sections 5.5, 8.1.7
MK-1167/Placebo 
Administration
X ------------------------------------------- X
Section 8.1.8, 8.10.5
Donepezil Administrationc
X ------------------------------------------------------------------------------------------------- X
Section 8.1.8, 8.10.5
Standard Mealsd
X ------------------------------------------------------------------ X
Meals and snacks will be provided during 
domiciling. 
Section 5.3.1
Domiciling
X ------------------------------------------------------------------ X
Domiciling for Panel B is optional. Participants 
may choose to travel to and from the CRU or 
they can choose to domicile at the CRU.  
Section 8.1.11 
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Panel B
Study Period
Screeninga
Poststudyb
Notes
Study Day
Safety Procedures
Full Physical Examination
X
Xf
X
Xe
X
X
Screening: anytime.
Section 8.3.1.
Full Neurological Examination
X
X Section 8.3.5, Appendix 12
Targeted Neurological 
Examination
Xf
X
Xe
X
X
Section 8.3.5, Appendix 12
Height
X
Section 8.3.1.
Weight
X
Xf
X BMI to be taken only at Screening.
Section 8.3.1.
Resting VS (Semi
Recumbent): Heart Rate
and Blood Pressure
X
X
Xr
X
Xs
X
X
X
Screening and Poststudy visits: anytime.
 
Section 8.3.2.1.
Orthostatic VS: Heart Rate 
and Blood Pressure
X
X
Xr
X
Xs
X
X
X
Screening and Poststudy visits: anytime.
 
Section 8.3.2.2.
VS: Respiratory Rate and 
Body Temperature
X
X
X
X
X
X
X
Screening and Poststudy visits: anytime.
Section 8.3.2.
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Panel B
Study Period
Screeninga
Poststudyb
Notes
Study Day
12-lead ECGh
X
X
Xi
X
X
X
Xj
Xj,k
Screening: anytime.
 
 
 
Section 8.3.3, Appendix 9
Serum FSH (PONCBP only)
X
Appendices 2, 5, 8
Urine or Serum Pregnancy 
Test (POCBP only)
X
X
Urine test will be collected. Serum test will be 
collected in the event that urine test is positive 
or cannot be confirmed.
Section 5.1, Appendix 2
HIV, Hepatitis B and C Screen 
(per site SOP)
X
Section 5.2, Appendices 2, 8
UDS/BDS (per site SOP)
X
Xf
Drug screen is mandatory at Screening; any 
additional drug screen(s) is/are conducted per 
site SOP.
Section 8.3.4, Appendix 2
Alcohol Screen
X
X
Breathing test. 
Section 5.2, Appendix 2
Clinical Safety Assessment 
(Hematology, Urinalysis, and 
Chemistry)
X
X
X
X
X
X
X
Screening, Day -3, and Poststudy visits: 
anytime.
 
Section 8.3.4, Appendices 2 and 8
AE/SAE Review
X ------------------------------------------------------------------------------------------------------ X
Section 8.4, Appendix 3
MMSE-2
X
Xl
X Sections 5.1, 5.2, 8.3.6
DSSTm
X
X
Xi
X
X
Xn
X
X Sections 4.2.1.3, 8.3.7, 8.7
C-SSRS Baselineo
X
Sections 4.2.3, 5.2, 8.3.8
C-SSRS Since Last 
Assessmento
X
X
Xe
X
X
X
X Sections 4.2.3, 8.3.8
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Panel B
Study Period
Screeninga
Poststudyb
Notes
Study Day
Pharmacokinetics
Blood for Plasma MK-1167 
and Metabolites Assaying
X
X
X
X
X
X
X
X
X
Xj
Xj
Xj
Xj
Xj
Xj,k
 
 
 
 
 
 
 
Sections 8.6.1, 8.10.5, Appendix 8                       
Blood for Plasma Donepezil 
Assayingp
X
X
X
X
Day 
: 24 hours postdoseg.
Day 
: 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours 
postdoseg.
Day 
: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 
hours postdose.
Section 8.10.5, Appendix 8
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Panel B
Study Period
Screeninga
Poststudyb
Notes
Study Day
Biomarkers
Blood for Genetic Analysis
X
Predose from enrolled participants only.
Section 8.8, Appendix 8.
X
Sections 8.8, 8.10.1, and Appendix 8
AE=adverse event; BDS=blood drug screen; BMI=body mass index; CRU=Clinical Research Unit; C-SSRS=Columbia-Suicide Severity Rating Scale; CYP=cytochrome P450; 
DSST=Digit Symbol Substitution Test; ECG=electrocardiogram; FBR=future biomedical research; FSH=follicle-stimulating hormone; HIV=human immunodeficiency virus; 
ID=identification; MMSE-2=Mini-Mental State Examination Edition 2; PK=pharmacokinetic(s); POCBP=participant of childbearing potential; PONCBP=participant of 
nonchildbearing potential; SAE=serious adverse event; SOP=standard operating procedure; UDS=urine drug screen; VS=vital signs.
a
Screening should occur within 4 weeks prior to Day 1. 
b
The Poststudy Visit will occur at approximately 
 days after last dose. 
c
Donepezil will be administered in the mornings at approximately the same time as MK-1167/placebo. If participants do not usually take their donepezil in the mornings, they 
should be instructed to start taking it in the morning starting on Day -7 until Day -4. On Days
, donepezil will be dispensed and administered by site staff.
d
Standardized meals/snacks will be provided on all days during domiciling at ~ 2 (breakfast), ~ 4 (lunch), ~ 7 (snack), ~ 10 (dinner), and ~ 13 (snack) hours postdose or 
equivalent (Section 5.3.1).
e
Day 16 only.
f
Can be conducted within 24 hours prior to first dose.
g
24-hour timepoint will be collected at predose when dosing occurs on the day of collection.
h
ECG measurements to be obtained in triplicate and performed before any blood sample for each timepoint. 
i 
Day 2 only.
j
Participants will return to the clinic for collection of MK-1167 plasma samples and ECG recordings at the hours/days specified in the Schedule of Activities. 
k
Day 
 scheduled study procedures 
will be collected before any Poststudy Visit procedures. 
l
Within 12 hours of morning dose.
m
A practice assessment will be administered at Screening. The assessment given on Day -1 will provide the baseline value. On Days 
 assessments 
should be given within 4 hours after the morning dose. See Study Operation’s Manual for specific instructions on test administration.
n
 
o
C-SSRS Baseline version to be used at Screening Visit, and all other visits use the C-SSRS Since Last Assessment version.
p
Donepezil 24-hour postdose samples (Days 
 will be analyzed; remaining donepezil blood samples will be archived.
q
r
Day 4 only.
s
On both Days 12 and 16.
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2
INTRODUCTION
2.1
Study Rationale
This study investigates MK-1167 
 
MK-1167 is a PAM of the α7 nAChR and is not considered a compound with high potential 
for risk of harm to participants [European Medicines Agency 2017]. MK-1167 is not a 
biological molecule, does not exhibit species-specific action, and is not directed towards 
immune system targets. 
 
 
 
 
 
 
 
 
 
 
 
The purpose of this study is to evaluate the safety and tolerability, and effect of multiple 
doses of donepezil on the multiple dose PK of MK-1167 in patients with AD. Donepezil is an 
AChEI, and 10 mg daily is the standard of care for patients with mild to moderate AD. 
 
 
 
 
 
2.2
Background
Refer to the IB for detailed background information on MK-1167.
2.2.1
Pharmaceutical and Therapeutic Background
MK-1167 is a PAM of the α7 nAChR. The compound is being developed for the treatment of 
cognitive deficits associated with CNS disorders, with a primary focus on AD. 
AD is the leading cause of dementia in elderly people and affects an estimated 35 million 
individuals worldwide, several which is escalating because of increased lifespan. AD is a 
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progressive neurodegenerative disorder in which cognitive deficits gradually worsen over 
time. Characteristics of the disease include degeneration of cholinergic neurons in the basal 
forebrain and reduction of cholinergic innervation of the cerebral cortex, hippocampus, and 
other regions of the brain. 
It has been hypothesized that cholinergic hypofunction contributes to the cognitive deficits of 
patients suffering from AD. This hypothesis is supported by the fact that AChEIs, which 
inhibit hydrolysis of ACh, provide symptomatic benefit and have been approved for the 
treatment of the cognitive impairments in AD. However, AChEIs produce only modest 
efficacy so a treatment that significantly improves cognition as an adjunctive therapy would 
represent an important advance.
The α7 nAChR is a ligand-gated ion channel that is highly expressed in brain regions 
associated with cognitive function. The expression level of α7 nAChRs can be affected by 
several pathological conditions, including AD. In addition, genetic evidence supports the 
involvement of the α7 nAChR in cognitive function since both large deletions to 
Chromosome 15q13.3, as well as smaller deletions to the gene for the α7 nAChR, CHRNA7, 
frequently produce cognitive deficits in addition to other phenotypes. Positive clinical data in 
AD patients with α7 nAChR agonists further support the rationale that drugs that enhance α7 
nAChR activity have therapeutic potential. Most notably, an α7 nAChR partial agonist, 
encenicline (Forum Pharmaceuticals, Inc), produced significant effects in a Phase 2 AD study 
but was discontinued during Phase 3 due to profound GI side effects. These side effects are 
believed to be due to off-target activity, namely serotonin 5-HT3 receptor antagonism. 
Furthermore, encenicline, as well as other α7 agonists, cause desensitization of the α7 
receptor and produce an inverted U-shaped dose-effect function in a variety of preclinical 
assays. This profile is thought to limit the efficacy of α7 nAChR agonists and/or require 
exposures to be in a very specific range to produce efficacy.
PAMs of the α7 nAChR are hypothesized to exhibit an improved clinical profile in 
comparison to α7 nAChR agonists and be devoid of the tolerability issues that halted 
encenicline. In contrast to α7 nAChR agonists, PAMs do not promote receptor 
desensitization. Furthermore, α7 nAChR PAMs demonstrate efficacy over a much wider 
range of concentrations in several assays (no inverted U) and maintain efficacy upon 
repeated dosing. Additionally, α7 nAChR PAMs exhibit improved selectivity over related 
channel targets, presumably through binding to a nonconserved region of the α7 nAChR.
 
 
 
 
 
 
 
 
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2.2.2
Preclinical and Clinical Studies
Refer to the IB for detailed preclinical studies for MK-1167.
 
 
MK-1167-001 (PN001)
Study MK-1167-001 was a randomized, placebo-controlled, double-blind, single ascending 
dose study to evaluate the safety, tolerability, and PK of MK-1167 in healthy male 
participants. The study consisted of 4 alternating panels (A, B, C, and D) consisting of 
8 participants, each of whom were administered single-oral doses of MK-1167 or placebo 
(3:1 ratio as an on-site formulation (oral suspension). A total of 32 participants were enrolled, 
of whom 30 received single-oral doses of MK-1167 (3 to 100 mg). Overall, single-oral doses 
of MK-1167 up to 76 mg were generally well tolerated in healthy male participants. Of the 
32 participants, 28 (87.5%) experienced 1 or more AEs during the study: n=25 (83.3%) on 
MK-1167 and n=8 (57.1%) on placebo. The most frequently reported AEs (>1 participants) 
after MK-1167 intervention were headache (11), dizziness (7), fatigue (5), diarrhea, sunburn 
(4 each), back pain, postural dizziness, gastrointestinal pain, oropharyngeal pain (3 each), 
dyspepsia, hematoma, skin irritation, and vomiting (2 each). Most AEs were mild to 
moderate in intensity.
 
 
Decreases in orthostatic BP persisted for approximately 
5-hours postdose and then resolved spontaneously. No changes to resting BP or HR were 
observed in this participant, or in any other study participant in semirecumbent testing at any 
dose. Subsequent doses in the study were adapted such that doses ≥100 mg were not 
administered to study participants following the observation of this AE.
There were no serious AEs, ECIs or deaths reported in the study and no participant 
discontinued from the study due to an AE. There were no clinically meaningful trends 
observed as a function of study intervention for laboratory safety tests, VS, or ECGs.
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MK-1167-002 (PN002)
Study MK-1167-002 was a randomized, placebo-controlled, single site, double-blind study of 
MK-1167 in healthy participants to assess the safety, tolerability, and PK of multiple doses of 
MK-1167. This study completed 4 sequential panels (A, B, C, and D) with 8 healthy 
participants in each panel who received multiple doses of MK-1167 (n=6) or placebo (n=2) 
in a randomized, blinded fashion. In Panel A, participants received a 4-mg loading dose of 
MK-1167 or placebo on Day 1 followed by 1 mg maintenance doses every other day on 
Days 3, 5, 7 and 9. In Panel B, participants received a 20-mg loading dose of MK-1167 or 
placebo on Day 1 followed by 2 mg QD (maintenance dose) for 9 consecutive days (Days 2 
to 10). In Panel C, participants received a 40-mg loading dose of MK-1167 or placebo on 
Day 1 followed by 4 mg qd (maintenance dose) for 9 consecutive days (Days 2 to 10). In 
Panel D, participants received a 22-mg loading dose of MK-1167 or placebo qd for Days 1 to 
4 followed by 8 mg qd (maintenance dose) starting on Day 5 and for 6 consecutive days.
Based on unblinded data from PN002, single oral loading doses of MK-1167 up to 40 mg 
and multiple oral doses of MK-1167 (1 to 8 mg) were generally well tolerated in healthy 
male participants. Of the 32 participants included in the study analysis set, 12 (37.5%) 
experienced 1 or more AEs during the study: n=10 (41.7%) on MK-1167 and n=2 (25.0%) on 
placebo. The most frequently reported AE (>1 participant) after MK-1167 intervention was 
abdominal discomfort (n=3). After placebo intervention, there were no AEs reported by 
>1 participant. All AEs were mild to moderate in severity, limited in duration, and all 
resolved without intervention. There were no clinically meaningful trends in laboratory 
safety measurements, vital signs, physical and neurological examinations, C-SSRS or ECGs. 
No participant was discontinued or withdrew participation due to an AE.
MK-1167-003 (PN003)
Study MK-1167-003 was a single-blind, placebo-controlled, 2-period, fixed sequence 
investigation of the ability of a single, oral dose of MK-1167 to modify glutamatergic 
neurotransmission in the prefrontal cortex of healthy adult males using selPOCE-13C-MRS 
to measure MK-1167 induced changes in the FE of 13C-glutamate (13C-glu) and 13C-
glutamine (13C-gln) relative to placebo (baseline) treatment. This study is clinically complete 
and DBL was achieved on 09-MAY-2024. A total of 26 participants were enrolled in this 
study, of whom 11 received single doses of MK-1167 1 mg and 15 received single doses of 
MK-1167 6 mg. Overall, single doses of MK-1167 1 mg and 6 mg were generally well 
tolerated in healthy male participants. Of the 15 participants who received single doses of 
MK-1167 6 mg, 9 (58%) experienced 1 or more AEs during the study. The most frequently 
reported AEs (>1 participants) after MK-1167 6 mg intervention were catheter site or 
venipuncture pain (3) and panic attack (2). The episodes of panic attack were attributed to 
study-specific procedures in PN003, specifically the requirement in this study to participate 
in MRS imaging without movement for an extended period of time. All AEs were mild to 
moderate in intensity and resolved without intervention.
There were no serious AEs, ECIs or deaths reported in the study and no participant 
discontinued from the study due to an AE. There were no clinically meaningful trends 
observed as a function of study intervention for laboratory safety tests, VS, or ECGs.
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MK-1167-004 (PN004)
Study MK-1167-004 was a randomized, placebo-controlled, single-site, double-blind study 
of MK-1167 in 2 panels of healthy elderly male and female participants, conducted in 
conformance with GCP. The primary objective of the study was to assess the safety, 
tolerability, and to characterize the PK of multiple doses of MK-1167 in healthy elderly 
study participants before administration in patients with AD in later studies. In this study, 
approximately 8 participants received single-day oral loading doses of MK-1167 10 mg/PBO
following by maintenance doses of oral doses of MK-1167 1 mg/PBO daily for 16 days
(Panel A), and approximately 8 participants received multiple-day oral loading doses of MK-
1167 10 mg/PBO for 3 days following by maintenance doses of oral doses of MK-1167 
3 mg/ PBO daily for 13 days (Panel B). This study is clinically complete, but DBL has not 
yet been achieved. A total of 16 participants were enrolled in this study, all of whom received 
multiple oral doses of MK-1167/PBO. Preliminary data indicate that the multiple-dose 
administration of MK-1167/PBO was generally well tolerated in healthy male and female 
elderly study participants. Of the 8 participants in Panel A, 5 (62.5%) experienced 1 or more 
AEs during the study. The most frequently reported AE (>1 participants) after 
MK-1167/PBO intervention in Panel A was headache (2).
 
 
 
 
All AEs for 
both panels were mild to moderate in intensity.
There were no serious AEs, ECIs or deaths reported in the study and no participant 
discontinued from the study due to an AE. There were no clinically meaningful trends 
observed as a function of study intervention for laboratory safety tests, VS, or ECGs.
MK-1167-006 (PN006)
Study MK-1167-006 was an open-label, fixed-sequence, 2-period study to evaluate the 
safety, tolerability, and PK profile of a single oral dose of MK-1167 coadministered with 
diltiazem, a calcium channel blocker that has been extensively characterized as an inhibitor 
of CYP3A4 and frequently used as a perpetrator in DDI studies. The study was performed to 
assess the effect of MK-1167 on safety, PK, and interaction with CYP3A4 inhibitors in 
healthy male and female (of non-childbearing potential) study participants prior to 
introducing the treatment in patients with AD. This study is clinically complete and DBL was 
achieved on 27-FEB-2024. On Day 1 of Period 1, a single dose of MK-1167 3 mg was 
administered. PK sampling was performed predose and up to 600 hours postdose. There was 
a washout of at least 35 days between dosing in Period 1 and the first dose in Period 2. In 
Period 2, diltiazem was administered QD for 49 consecutive days with a single dose of MK-
1167 3 mg coadministered on Day 3. PK sampling for MK-1167 was performed predose and 
up to 1128 hours post MK-1167 dosing. Predose blood samples were also collected for 
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diltiazem PK. Safety was monitored throughout the study by repeated clinical and laboratory 
evaluations.
A total of 16 participants were enrolled in this study, of whom 14 completed the study and 
received 2 single doses of MK-1167. These participants received a single dose of MK-1167
3 mg alone on Day 1 of Period 1 and a single dose of MK-1167 3 mg coadministered with 
diltiazem on Day 3 of Period 2. Two participants were discontinued from the study due to 
AEs (positive COVID-19) on Day -1 of Period 2; these 2 participants received 1 single dose 
of MK-1167 3 mg alone on Day 1 of Period 1. Overall, single doses of MK-1167 3 mg were 
generally well tolerated in healthy study participants when administered alone or with 
diltiazem. Of the 16 study participants, 6 (38%) experienced 1 or more AEs during the study. 
The most frequently reported AEs (≥2 participants) after MK-1167 intervention were dry 
mouth, COVID-19, and headache, each reported by 2 (13%) participants. All AEs were mild 
to moderate in intensity.
There were no serious AEs, ECIs or deaths reported in the study. There were no clinically 
meaningful trends observed as a function of study intervention for laboratory safety tests, 
VS, or ECGs.
MK-1167-001, and MK-1167-002 were conducted in Belgium (PN001, PN002) and MK-
1167-003 was conducted in the Netherlands (PN003). MK-1167-004 and MK-1167-006 were
conducted in the US (PN004, PN006) under the MK-1167 IND.
PK
The PK of MK-1167 in plasma and blood were determined following single oral doses in 
healthy adult male participants of
 
 
 
 
 
 Given that 
the t1/2 estimates were generally equivalent in plasma and blood, these results suggest that 
the partitioning between the blood and plasma is rapid and reversible. In a comparison of fed 
and fasted participants following administration of 12-mg MK-1167, the PK exposures in 
plasma and whole blood were equivalent to one another indicating no relevant food effect on 
MK-1167 PK.
 
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Additional safety and PK information is available in the IB.
2.2.3
Ongoing Clinical Studies
As of 28-MAY-2024, one Phase 1 study including oral doses of MK-1167 is ongoing in 
addition to MK-1167-007.
MK-1167-005 (PN005)
Study MK-1167-005 is a 2-part, randomized, placebo-controlled, single-site, double-blind 
study to evaluate the safety, tolerability, and PK of single and multiple doses of MK-1167 in 
healthy Japanese participants. As of 28-MAY-2024, the study is ongoing, but no clinical data 
are available. MK-1167-005 is being conducted in Japan.
MK-1167-007 (PN007)
2.2.4
Information on Other Study-related Therapy: Donepezil Hydrocholoride 
Donepezil HCl is an AChEI that is indicated for symptomatic treatment of mild-to-moderate 
AD. Standard dosing is donepezil HCl 10 mg, 1 tablet PO daily. The most common AE of 
donepezil HCl, defined as those occurring at a frequency of at least 5% in patients receiving 
10 mg/day and twice the placebo rate, are largely predicted by the cholinomimetic effects of 
donepezil HCl, including nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue and 
anorexia. These AEs are typically of mild intensity and transient, resolving during continued 
donepezil HCl treatment without the need for dose modification [Jack, C. R. Jr., et al 2018]. 
Less commonly observed AEs include depression and sleep disturbances (eg, abnormal 
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dreams and somnolence). Donepezil HCl is ~ 96% bound to human plasma proteins, mainly 
to albumins (~ 75%) and alpha-1 acid glycoprotein (about 21%) over the concentration range 
of 2 to 1000 ng/mL. Donepezil HCl is both excreted in the urine intact and extensively 
metabolized to 4 major metabolites, 2 of which are known to be active, and a number of 
minor metabolites, not all of which have been identified. Donepezil HCl is metabolized by 
CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. Donepezil HCl has a 
Tmax of ~ 3 to 4 hours and t1/2 ~ 70 hours.
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.
 
 
 
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.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The study population consists of patients with mild to moderate AD, 50 to 90 years of age.
Primary Objective
Primary Endpoint
Evaluate the safety and tolerability of 
MK-1167 when administered to patients 
with mild to moderate Alzheimer’s Disease
on stable doses of oral donepezil 10 mg 
daily
Adverse events, discontinuation due to 
Adverse events
Secondary Objectives
Secondary Endpoints
Evaluate the pharmacokinetic profile of 
MK-1167 when administered to patients 
with mild to moderate Alzheimer’s Disease
on stable doses of oral donepezil 10 mg 
daily
Estimation: 
 
AUC0-24, Cmax, C24, Tmax, CL/F, Vz/F, 
t1/2
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
Evaluate the changes in cognitive function 
of Alzheimer’s Disease patients by 
comparing the Mini Mental State 
Examination and Digit Symbol Substitution 
Test scores obtained at baseline with those 
from the last day of dosing.
Mini Mental State Examination scores
Digit Symbol Substitution Test scores
 
Germline genetic variation
Explore the relationships between genetic 
variation, response to the treatment(s) 
administered, and mechanisms of disease. 
Variation across the human genome may be 
analyzed for association with clinical data 
collected in the study.
Germline genetic variation
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, double-blind, placebo-controlled, multisite study to evaluate the safety, 
tolerability, and PK of multiple doses of MK-1167 in participants with Alzheimer’s disease
maintained on baseline AChEI treatment with donepezil 10 mg PO daily.
 
 
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.
 
 
 
 
 
 
In Panel A, participants will receive a loading dose of MK-1167 6 mg or matching PBO on 
Days 1 to 7 followed by QD dosing of MK-1167 3 mg or matching PBO for 14 consecutive 
days (Days 8 to 21). In Panel B, participants will receive QD dosing of MK-1167 6 mg or 
matching PBO for Days 1 to 31.
 
 
 
 
4.2
Scientific Rationale for Study Design
 
 
 
 
 
 
 
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4.2.1
Rationale for Endpoints
4.2.1.1
Safety Endpoints
Safety and tolerability of MK-1167 in male and female participants with AD will be 
evaluated as the primary objective for this study. 
 
 
 
 
 
A cholinergic-related AE term has been defined and is composed of the following individual 
component AEs: nausea, vomiting, diarrhea, and abdominal pain.
Prospective assessment of suicidal ideation and behavior will be performed in this study
using the C-SSRS.
Based on data from the preclinical toxicology and safety studies as well as clinical safety 
data from PN001, PN002, PN004, PN006 and PN007 Panel A (Section 2.2.3), it is expected 
that multiple-day administration of MK-1167 up to 6 mg daily for 31 days will be well
tolerated in study participants with AD maintained on a stable dose of donepezil 10 mg daily. 
No specific target organ toxicities have been identified in preclinical studies conducted with 
MK-1167 to date. In PN001 and PN002, single-dose administration of MK-1167 up to 76 mg 
and multiple-dose administration up to 8 mg daily was generally well tolerated in healthy 
younger adult study participants. In PN004, multiple-day oral loading doses of MK-1167 
10 mg/PBO for 3 days following by maintenance doses of oral doses of MK-1167/PBO 3 mg 
daily for 13 days were generally well tolerated in healthy elderly study participants (Section 
2.2.2). In PN007 Panel A, multiple-day oral loading doses of MK-1167/PBO 6 mg for 7 days 
following by maintenance doses of oral doses of MK-1167/PBO 3 mg daily for 14 days were 
generally well-tolerated in participants with AD maintained on a stable baseline dose of 
donepezil 10 mg (Section 2.2.3).
 
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4.2.1.2
Pharmacokinetic Endpoints
A secondary objective of this study is to evaluate the plasma PK profile of MK-1167 
following multiple doses in male and female participants with AD. To characterize the PK of 
MK-1167, plasma AUC0-24, Cmax, and C24 will be determined. Other PK endpoints to be 
evaluated include Tmax, apparent terminal t1/2, apparent CL/F, and apparent Vz/F.
4.2.1.3
Pharmacodynamic Endpoints
Digit Symbol Substitution Test
The DSST, which assess processing speed and working memory, will be used in this study to 
measure potential effects of MK-1167 on cognition. The DSST is a rapid assessment of 
cognitive function that will be included in the current study on an exploratory basis to 
characterize potential effects of MK-1167 on cognition state 
 
.
The DSST is one of the oldest and best-established neuropsychological tests and is found in a 
wide variety of intelligence scales. The test participant is required to associate certain symbols 
(usually digits) with other non-alpha-numeric symbols, and the speed and accuracy with which 
the task is performed serve as measures of executive function, specifically attention and 
processing speed. The task can be administered and performed quickly and because there are 
several versions of the test, the possibility of learning bias is reduced. 
The DSST has been demonstrated to be sensitive to a wide variety of organic brain diseases
including AD and has been used previously to demonstrate a treatment effect of encenicline a 
selective α7 nicotinic acetylcholine receptor partial agonist developed by Forum 
Pharmaceuticals for cognitive impairment in AD and schizophrenia [Barbier, A. J., et al 
2015]. 
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4.2.1.4
Planned Exploratory Biomarker Research
4.2.1.4.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME, mechanism of action of the drug, disease etiology, and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC allow, a 
sample will be collected for DNA analysis from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
 
 
 
 
 
4.2.1.5
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
Placebo will be used in this study to allow for an appropriate assessment of the safety data of 
MK-1167 and to maintain study blinding to reduce bias.
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4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring
Prospective assessment of suicidal ideation and behavior will be performed in this study 
using the C-SSRS. This assessment is being conducted in compliance with the 2012 FDA 
guidance requiring prospective assessment in clinical studies conducted under IND 
applications and studies that are intended for submission in a NDA to the Neurology or 
Psychiatry Divisions of the FDA or BLA, as well as assessment in studies that fall within the 
guidance for other reasons (eg, CNS active/penetrant compounds, and known mechanisms or 
indications for which suicidal ideation/behavior has been previously identified as a potential 
concern).
4.3
Justification for Dose
 
As this is a Phase 1 assessment of MK-1167 in humans, and the PK, pharmacodynamic and 
safety profiles of the compound are still being evaluated, modifications to the dose or dosing 
regimen may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants. Details of allowed 
modifications are provided in Section 8.10.6.
For the highest dose of MK-1167 to be tested in this study (Panel B), a dose of MK-1167 6 
mg will be administered for approximately 31 days to achieve plasma concentrations that are 
sufficient to provide data on safety and tolerability over a range of potential doses that may 
be investigated for efficacy in AD patients in later studies, accounting for both inter-
individual PK variability as well as potential DDI effects when MK-1167 is coadministered 
with CYP3A4 moderate inhibitors.
Preclinical investigations of MK-1167 indicate that participant age should not significantly 
affect the absorption, distribution, metabolism, or elimination profiles of MK-1167. As a 
result, PK data from doses previously investigated in healthy young adult participants in 
PN001 and PN002 as well as healthy elderly participants in PN004 Panel A have been used 
to anticipate exposures and concentrations for elderly participants in Panels A and B for the 
present study and are summarized in
 
 
 
 
 
 
 
 
 
 
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Table 2
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Based on the overall GLP toxicity study findings in the rat and the dog, the dog is considered
to be the more sensitive species. For more detailed information regarding results from the rat
and dog toxicological studies, please refer to the IB for MK-1167.
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.3.1
Rationale for Dose Interval and Study Design
MK-1167, an α7 nAChR PAM, is not considered a compound with higher potential for risk 
of harm to volunteers according to the publication "Guideline on Strategies to Identify and 
Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products" 
(European Medicine Agency guidance released July 2007). It is not a biological molecule, 
does not exhibit highly species-specific action, nor is it directed towards immune system 
targets. Safety assessment toxicity trials and ancillary pharmacology trials with MK-1167 
provide no contraindications to the initiation of clinical study in people with this compound 
via the oral route. 
 
 
 
 
 
 and to reach steady state within the duration of the 
planned treatment in this study, Panel A participants received a loading dose of MK-1167 
6 mg or placebo for Days 1 to 7 followed by QD maintenance dosing of MK-1167 3 mg or 
placebo for Days 8 to 21. This dosing schedule is similar to the multiple-dose administration 
paradigm previously implemented in healthy young adult participants in PN002 and healthy 
elderly participants in PN004.
 
 
 The loading and daily maintenance doses 
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and the corresponding projected exposures in a given panel of healthy elderly participants 
will not exceed the highest multiple dosage/exposures previously obtained in healthy young 
adult participants in PN002.
 
 
 
 
 
 
 
 
 
 
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
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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
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Be in good health based on medical history, physical examination, VS measurements, 
and ECGs performed before randomization.
a.
Participants with chronic medical conditions, including but not limited to 
hypertension, hyperlipidemia, diabetes (Type 1 or 2) or hypothyroidism, which 
have been well-controlled on a stable dose of medication for the past 2 months 
and who are not receiving any proscribed medications for treatment may be 
enrolled if clinically acceptable to the investigator and Sponsor.
Appendix 9 provides a table of the 12-Lead Electrocardiogram Evaluation Criteria.
2. Be in good health based on laboratory safety tests obtained at the Screening Visit. 
Appendix 2 provides a table of laboratory safety tests to be performed. Appendix 10 
provides an algorithm for the assessment of out-of-range laboratory values.
3. BMI between 18 and 35 kg/m2, inclusive. See Section 8.3.1 for criteria on rounding to the 
nearest whole number. BMI = weight (kg)/height (m)2.
4. Report a history of cognitive and functional decline with gradual onset and slow 
progression for at least 1 year before Screening, that is either corroborated by an 
informant who knows the subject well or is documented in medical records. 
5. Meet the criteria for a diagnosis of probable AD based on NINCDS-ADRDA criteria for 
probable AD (Appendix 11).
6. Have a MMSE-2 score between 14 and 28, inclusive, at Screening as confirmed by the 
investigator. The MMSE-2 should be administered by a certified practitioner alternating 
the colors (red, blue) of the exam for a given subject to avoid learning effects with 
repeated administration. 
7. Be receiving donepezil 10 mg daily for symptomatic treatment of cognitive impairment 
associated with AD. The dose level must be stable for at least 2 months prior to 
Screening. If receiving donepezil via a transdermal system (ie, patch), it should be a
10-mg/day dose and should switch prescription to a 10-mg oral daily dose, before 
enrollment. 
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8. Have a reliable and competent trial partner/caregiver who has a close relationship with 
the participant, has face-to-face contact at least 3 days a week for a minimum of 6 waking 
hours a week, and is willing to accompany the participant, if desired, to study visits. 
Overnight stays at the clinic for the partner/caregiver are not required but may be 
requested at the discretion of investigator after consultation with the Sponsor. The study
partner/caregiver should understand the nature of the study and adhere to study
requirements (eg, dosing, visit schedules, and nature and number of evaluations).
Demographics
9. Is an individual of any sex/gender, from 50 years to 90 years of age inclusive, at the time 
of providing the informed consent or assent, as applicable.
Assigned Male Sex at Birth
10. If capable of producing sperm, the participant agrees to the following during the 
intervention period and for at least the time needed to eliminate the study intervention 
after the last dose of study intervention. 
 

Abstains from penile-vaginal intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agrees to remain abstinent.
OR

Uses contraception as detailed below 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) as detailed below:
o
Uses a penile/external condom when having penile-vaginal intercourse 
with a nonparticipant of childbearing potential who is not currently 
pregnant and should also be advised of the benefit for that partner to use 
an additional method of contraception as a condom may break or leak.
Note: Participants capable of producing ejaculate whose partner is 
pregnant or breastfeeding must agree to use penile/external condom during 
each episode of sexual activity in which the partner is at risk of drug 
exposure via ejaculate.
o
Contraceptive use by participant capable of producing sperm should be 
consistent with local regulations regarding the methods of contraception 
for those participating in clinical studies. If the contraception requirements 
in the local label for any of the study interventions are more stringent than 
the requirements above, the local label requirements are to be followed. 
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Assigned Female Sex at Birth
11. A participant assigned female sex at birth is eligible to participate if not pregnant or
breastfeeding, and at least one of the following conditions apply:

Is not a POCBP
OR

Is a POCBP and:
o
Uses a contraceptive method that is highly effective (with a failure rate of 
<1% per year), with low user dependency, or is abstinent from penile-
vaginal intercourse as their preferred and usual lifestyle (abstinent on a 
long-term and persistent basis), during the intervention period and for at 
least the time needed to eliminate the study intervention after the last dose 
of study intervention. 
 
o
The investigator should evaluate the potential for contraceptive method 
failure (ie, noncompliance, recently initiated) in relationship to the first 
dose of study intervention. Contraceptive use by POCBPs should be 
consistent with local regulations regarding the methods of contraception 
for those participating in clinical studies. If the contraception requirements 
in the local label for any of the study interventions are more stringent than 
the requirements above, the local label requirements are to be followed.
o
Has a negative highly sensitive pregnancy test (urine or serum) as required 
by local regulations within 24 hours (for urine test) or 72 hours (for serum 
test) before the first dose of study intervention. If a urine test cannot be 
confirmed as negative (eg, an ambiguous result), a serum pregnancy test is 
required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
o
 
o
Medical history, menstrual history, and recent sexual activity has been 
reviewed by the investigator to decrease the risk for inclusion of a POCBP 
with an early undetected pregnancy.
Informed Consent
12. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
13. The reliable and competent trial partner/caregiver who has a close relationship with the 
participant has provided documented informed consent/assent for the study.
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Additional Categories
14. Willing to comply with the study restrictions (see Section 5.3 for a complete summary of 
study restrictions).
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. 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 5 years or suicidal behavior in their lifetime.
2. History of clinically significant endocrine, gastrointestinal, cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary, or major 
neurological (including stroke and chronic seizures) abnormalities or diseases that are not 
under medical control over the past 2 months. Participants with a remote history of 
uncomplicated medical events (eg, uncomplicated kidney stones, as defined as 
spontaneous passage and no recurrence in the last 5 years, or childhood asthma) may be 
enrolled in the study at the discretion of the investigator.
3. Has evidence of a clinically relevant or unstable psychiatric disorder, based on DSM-5 
criteria, including schizophrenia or other psychotic disorder, bipolar disorder, or delirium 
at the time of the pre-study (screening) visit, or has a history of clinically significant 
psychiatric disorder of the last 5 years. Candidates may be excluded if they currently 
manifest neuropsychiatric symptoms of dementia, specifically episodes of aggression, 
emotional outbursts or agitation. Following consultation between the Investigator and the 
Sponsor, a history of major depressive disorder, generalized anxiety disorder, and/or 
insomnia under good control for ≥ 2 months on stable medical therapy may not be 
exclusionary.
4. History of cancer (malignancy). 
a.
Participants with adequately treated disease deemed as “cured,” or who, in the 
opinion of the study investigator, are highly unlikely to sustain a recurrence for 
the duration of the study, may be enrolled at the discretion of the investigator and 
Sponsor.
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5. Estimated eGFR ≤60 mL/min/1.73 m2 based on the 2021 CKD-EPI.
CKD-EPI Equation (2021):
Where Scr is serum creatinine, K is 0.7 for females and 0.9 for males, α is -0.241 for females 
and -0.302 for males, min indicates the minimum of Scr/K or 1, max indicates the maximum
of Scr/K or 1.
At the discretion of the investigator a measured CrCl, as determined by a 24-hour urine 
collection, may be used in place of, or in conjunction with, the estimate of the eGFR.
Participants who have an eGFR or measured CrCl of up to10% below of either 60 mL/min 
(for CrCl) or 60 mL/min/1.73 m2 (for eGFR) may be enrolled in the study at the discretion of 
the investigator.
6. History of significant multiple and/or severe allergies (eg, food, drug, latex allergy), or 
has had an anaphylactic reaction or significant intolerability (ie, systemic allergic 
reaction) to prescription or nonprescription drugs or food.
7. Positive test(s) for HBsAg, hepatitis C antibodies or HIV at the screening visit.
8. The participant had a major surgery and/or donated or lost 1 unit of blood (approximately 
500 mL) within 4 weeks prior to the prestudy (screening) visit.
Prior/Concomitant Therapy
9. Unable to refrain from or anticipates the use of any medication, including prescription 
and nonprescription drugs or herbal remedies beginning approximately 2 weeks (or 
5 half-lives) prior to administration of the initial dose of study intervention, throughout 
the study, until the poststudy visit. There may be certain medications that are permitted 
(see Section 6.5).
a.
Exception: participants on a stable dose of memantine (at least 2 months prior to 
Screening) may be included in the study. 
 
 
Prior/Concurrent Clinical Study Experience
11. Participated in another investigational study within 4 weeks (or 5 half-lives, whichever is 
greater) prior to the prestudy (screening) visit. The window will be derived from the date 
of the last visit in the previous study.
eGFRcr = 142 × min(Scr/K,1)α × max(Scr/K, 1)-1.200 × 0.994Age × 1.012 [if female]
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Diagnostic Assessments
12. Has a QTc interval ≥470 msec (for males) or ≥480 msec (for females) at the screening 
visit or Day -1/pre-dose visit. has a history of risk factors for Torsades de Pointes (eg, 
heart failure/cardiomyopathy or family history of long QT syndrome), has uncorrected 
hypokalemia or hypomagnesemia, is taking concomitant medications that prolong the 
QT/QTc interval.
 
Other Exclusions
14. Under the age of legal consent.
15. The participant is a smoker and/or has used nicotine or nicotine-containing products (eg, 
nicotine patch and electronic cigarette) within 3 months of screening.
16. Consumes greater than 3 servings of alcoholic beverages (1 serving is approximately 
equivalent to: beer <354 mL/12 ounces>, wine <118 mL/4 ounces>, or distilled spirits 
<29.5 mL/1 ounce>) per day. Participants who consume 4 servings of alcoholic 
beverages per day may be enrolled at the discretion of the investigator.
17. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or 
other caffeinated beverages per day.
18. The participant is a regular user of cannabis, any illicit drugs or has a history of drug 
(including alcohol) abuse within approximately 2 years. Participants must have a negative 
drug screen prior to randomization.
19. The investigator has any concern regarding safe participation in the study or for any other 
reason the investigator considers the participant inappropriate for participation in the 
study.
20. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
 
 Participants will fast from all food and drinks, 
except water, between study intervention administration and the first scheduled meal. Meals 
and snack(s) will be provided by the investigator at time points indicated in the SoA. 
Participants will fast from all food and drinks, except water, between meals and snacks. 
Meals do not have to be identical; however, the caloric content and composition of meals will 
be the same on each full PK sampling day in each panel. The meal content should be 
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consistent within a given clinical site.
 
Approximately 240 mL of water will be provided during study intervention 
administration. Additional water may be provided in 50-mL increments if required. Water 
will be restricted 1 hour before and 1 hour after study intervention administration.
On all other days, participants will fast from all food and drinks, except water, for at least 
8 hours before study intervention administration. Participants will remain fasted between 
study drug administration and the first scheduled meal. Meals and snacks will be provided by 
the investigator at time points indicated in the SoA. Meals and snacks will be unrestricted in 
caloric content, composition, and timing. Each study intervention administration will need to 
be taken with approximately 240 mL of water. Additional water may be provided in 50-mL 
increments if required. Water will be restricted 1 hour before and 1 hour after study 
intervention administration.
5.3.1.2
Fruit Juice Restrictions
 
 
 
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants are advised to refrain from consumption of caffeinated beverages or xanthine-
containing products from 12 hours prior to the Screening Visit. A recheck may be needed if 
participants did not refrain from consuming caffeinated beverages or xanthine-containing 
products 12 hours prior to the Screening Visit.
 
 
On all other days, caffeinated beverages or xanthine-containing products will be limited to no 
more than 6 units per day (1 unit = 120 mg of caffeine).
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5.3.2.2
Alcohol Restrictions
Participants are advised to refrain from consumption of alcohol 24 hours prior to the 
Screening Visit and 24 hours prior to initial domiciling on Day -3. A recheck may be needed 
if participations did not refrain from consuming alcohol 24 hours prior to the Screening Visit. 
Participants will refrain from consumption of alcohol during their entire sequester in the 
CRU. At all other times, alcohol consumption is limited to no more than approximately 
3 alcoholic beverages or equivalent servings (1 serving is approximately equivalent to: beer 
[354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day.
5.3.2.3
Tobacco Restrictions
Smoking (and/or the use of nicotine/nicotine-containing products) is not permitted during the 
study.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weightlifting, running, 
bicycling, etc) from the prestudy (screening) visit until administration of the initial dose of 
study intervention, throughout the study (including washout intervals between treatment 
periods), and until the poststudy visit.
5.3.4
Since this study intervention may make participants more likely to get sunburn, they will be 
required to protect their skin from sunlight exposure.
 
 
 
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. A minimal set of screen failure information 
may be included, as outlined in the eCRF entry guidelines. Minimal information may include 
demography, screen failure details, eligibility criteria, and any AEs or SAEs meeting 
reporting requirements.
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5.5
Participant Replacement Strategy
If a participant discontinues from study intervention or withdraws from the study, a 
replacement participant may be enrolled if deemed appropriate by the investigator and 
Sponsor. The replacement participant will generally receive the same intervention or 
intervention sequence (as appropriate) as the participant being replaced. The replacement 
participant will be assigned a unique treatment/randomization number.
The replacement participant may begin dosing at the subsequent dose level for that panel, 
based on investigator and Sponsor review and discussion.
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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 provided by the Sponsor will be packaged to support enrollment and 
replacement participants as required. When a replacement participant is required, the Sponsor 
or designee needs to be contacted before dosing the replacement participant. Clinical supplies 
will be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 3.
Country-specific requirements are noted in Appendix 7.
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All supplies indicated in
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 (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3. 
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants will be assigned randomly according to a computer-generated allocation 
schedule.
The sample allocation tables are provided below in Table 4 and Table 5. 
Table 4
Allocation of Participants to Treatment For Panel A
Number of Participants
Days 1 to 7
Days 8 to 21
Treatment
Treatment
n=12
6-mg MK-1167 QD + 
donepezil
3-mg MK-1167 QD + donepezil
n=4
Placebo to MK-1167
+ donepezil
Placebo to MK-1167
+ donepezil
n=number of participants in a subset of the study; QD=once daily.
The suggested doses may be adjusted downward based on evaluation of safety, tolerability and/or pharmacokinetic 
data observed in previous treatment periods/panels.
Note: Female participants will be assigned the low allocation range and male participants will be assigned the upper
allocation range
Table 5
Allocation of Participants to Treatment For Panel B
Number of Participants
Days 1 to 31
Treatment
n=9
6-mg MK-1167 QD + donepezil
n=3
Placebo to MK-1167
+ donepezil
n=number of participants in a subset of the study; QD=once daily.
The suggested doses may be adjusted downward based on evaluation of safety, tolerability and/or pharmacokinetic 
data observed in previous treatment periods/panels.
Note: Female participants will be assigned the low allocation range and male participants will be assigned the upper 
allocation range
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
A double-blinding technique will be used. MK-1167 and placebo will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or qualified study-site personnel. 
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.
Donepezil administration will be conducted as open label; therefore, the Sponsor, 
investigator, and participant will know the intervention administered. 
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See Section 8.1.10 for the description of unblinding if a medical emergency occurs during the 
study.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study-site staff.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant ID will be confirmed at the time of 
dosing by a member of the study-site staff other than the person administering the study 
intervention. Study-site personnel will examine each participant’s mouth to ensure that the 
study intervention was ingested.
6.5
Concomitant Therapy
If a participant does not discontinue all prior medications within 14 days or 5 half-lives of
the first dose of study intervention, they may be included in the study if the investigator can 
rationalize that the specific use of a prior medication is not clinically relevant within the 
context of the study.
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination, 
during the ongoing study (ie, after randomization or intervention allocation) must first be 
discussed between the investigator and Sponsor before administration, unless appropriate 
medical care necessitates that therapy or vaccination should begin before the investigator and 
Sponsor can consult. The participant will be allowed to continue in the study if both the 
Sponsor and the investigator agree.
In addition, the following are specifically restricted from concomitant use during the study:

 
 
 
 
 
 
 
 
 
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
 
 
 
 
 

All AChEIs other than donepezil (physostigmine, neostigmine, echothiophate, 
pyridostigmine, rivastigmine, galantamine, tacrine, edrophonium, succinylcholine, etc.).

All cholinergic agonist medications (pilocarpine, cevimeline, carbachol, bethanecol, 
etc.).

All medications with anticholinergic effects (amantadine, atropine, benztropine, 
cyclobenzaprine, darifenacin, dicyclomine, diphenoxylate with atropine, hydroxyzine, 
fesoterodine, glycopyrrolate, hydroxyzine, hyoscyamine, ipratropium, oxybutynin, 
phenothiazine, prochlorperazine, promethazine, quinidine, scopolamine, tolterodine, 
tropicamide, trospium, trimethobenzamide, trihexyphenidyl, tricyclic antidepressants 
[amitriptyline, monoamine oxidase inhibitors], as well as antihistamines cyproheptadine, 
promethazine, desloratadine, loratadine, diphenhydramine, etc.).

 
 

Mood stabilizers, anticonvulsants, and typical or atypical antipsychotic medications (eg, 
lithium, valproic acid, phenytoin, levetiracetam, carbamazepine) Exception: use of 
pregabalin and gabapentin for neuropathic pain is acceptable.

Sedatives/benzodiazepines (eg, chlordiazepoxide, clonazepam, diazepam, flurazepam, 
meprobamate, triazolam). Use of the following non-benzodiazepine medications for 
sleep may be acceptable if stable for at least 2 months before the Screening Visit, 
following review by the investigator and Sponsor: trazodone, mirtazapine, zaleplon, 
zopiclone, eszopiclone, and zolpidem.

Narcotic analgesics (eg, codeine, morphine, hydromorphone, oxycodone, propoxyphene 
and combination products that contain a narcotic).

Stimulant medications (eg, amphetamine, methylphenidate, atomoxetine, modafinil)
Paracetamol/acetaminophen may be used for minor ailments without prior consultation with 
the Sponsor.
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In addition, the following concomitant medications/vaccinations are permitted:

 

Female participants: Hormonal replacement therapy. The participant must be on a stable 
treatment regimen for at least 6 months prior to screening.

Cetirizine and montelukast sodium may be permitted for allergies following consultation 
with the Sponsor.

 
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/Other
Refer to Section 4.3.1 for a discussion on the dose planned for this study. 
For both Panels A and B, safety and tolerability of at least 8 participants through at least 24 
hours post-last dose will be evaluated to determine if study objectives continue to be met.
6.6.1
Stopping Rules
The following stopping rules will be used during the conduct of this study.
These stopping rules apply to study intervention which refers to relationship to
MK-1167/placebo administration. 
If any of the below stopping rules are met, the study will be stopped, and no further dosing 
will occur until the Sponsor has reviewed the totality of data available. Continuation of the 
study would require an amendment.

An individual participant reports an SAE, unless clearly not related to study 
intervention by the investigator.

Two (2) or more participants within a Panel (at the same dose level) report Severe 
Nonserious AEs unless clearly not related to study intervention by the investigator.
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If any of the stopping rules are met, subsequent doses of treatment for remaining participants
may be adjusted (maintained at the same level, decreased or halted) based on joint agreement 
of the Sponsor and investigator after an amendment is implemented.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention allocation/randomization
schedule for the study to unblind participants and to unmask study intervention identity. The 
emergency unblinding call center should only be used in cases of emergency (see
Section 8.1.10). The Sponsor will not provide random code/disclosure envelopes or lists with 
the clinical supplies.
This study is blinded, but supplies are provided open label; therefore, an unblinded 
pharmacist or qualified study-site personnel will be used to blind supplies. Study intervention 
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are provided.
6.9
Standard Policies
Not applicable.
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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 participate in the study as specified in Section 1.3 and Section 8.1.9, or  
a PCL (only applicable if not all procedures should be done per Section 1.3).
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study, for any of the following reasons:
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
The participant’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.
The participant interrupts study intervention administration for more than 1 consecutive days 
or has 1 cumulative missed doses.
The participant has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
The participant has a confirmed positive serum pregnancy test.
The participant has a positive drug screen at any time during the course of the study. The 
drug screen can be confirmed by a recheck at the discretion of the investigator after 
discussion with the Sponsor.
For a participant who are discontinued from study intervention, all applicable discontinuation 
activities will be performed according to Section 8.1.9, or if available, a protocol clarification 
letter.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention.
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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.
Participants may withdraw from the study at any time for any reason. If a participant 
withdraws from the study, they will no longer receive study intervention or be followed at 
scheduled protocol visits.
A participant must be withdrawn from the study if:

The participant or participant’s legally acceptable representative withdraws consent from 
the study.

Participant is lost to follow-up.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of maintaining 
the protocol-specified visit schedule.
The investigator or designee must make every effort to regain contact with the participant at 
each missed visit (eg, telephone calls and/or a certified letter to the participant’s last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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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 (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
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 providing documented informed consent or assent, when 
applicable, may be used for screening or baseline purposes provided the procedures meet 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 or assent, when applicable, be obtained from the 
participant. In these cases, such evaluations/testing will be performed in accordance with 
those regulations.
The maximum amount of blood collected from each participant over the duration of the study 
will not exceed the volume mentioned in Appendix 8.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. The ICF, any subsequent revised ICF, and any written information 
provided to the participant must receive the IRB/IEC’s approval/favorable opinion in 
advance of use.
Informed consent given by the participant (or their legally acceptable representative) must be 
documented on a consent form. The form must include the study protocol number, study 
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protocol title, dated signature, and agreement of the participant (or their legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated ICF should be given to the participant (or their legally 
acceptable representative) before participation in the study.
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Specifics about the study and the study population are to be included in the ICF.
The participant (or their legally acceptable representative) should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the study. The communication of this information 
will be provided and documented via a revised consent form or addendum to the original 
consent form that captures the participant’s or the participant’s legally acceptable 
representative’s dated signature.
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 their questions, 
and obtain documented informed consent , before performing any procedure related to FBR. 
A copy of the informed consent , will be given to the participant before performing any 
procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
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The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review before medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 4 weeks or 5 half-lives before screening.
 
 Participants will be stably 
maintained on donepezil (10 mg) for at least 2 months prior to Screening. 
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. Participants will be stably maintained on donepezil (10-mg) for at least 2 
months prior to screening.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1. Pre-trial screening logs may be collected for review by 
the Sponsor. If applicable, any information that would make the participant identifiable will 
be removed.
8.1.7
Assignment of Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
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8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or an appropriately 
qualified designee.
Study intervention should begin on the day of treatment allocation/randomization or as close 
as possible to that day.
8.1.8.1
Timing of Dose Administration
The first oral doses of MK-1167/placebo will be administered in the morning at 
approximately the same time every day. After all pre-dose procedures are completed on the 
morning of Day 1, either MK-1167 or placebo will be administered, with the time of 
administration constituting Time “0”. All capsules will be distributed and consumed within 
10 minutes of the recorded administration time. 
 
 
 
 
 
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study and/or intervention. If a participant discontinues for 
any reason at any time during the course of the study and/or intervention, the participant may 
be asked to return to the clinic (or be contacted) for a poststudy visit as per the number of 
days described in Section 8.10.4 to have the applicable procedures conducted. However, the 
investigator may decide to perform the poststudy procedures at the time of discontinuation or 
as soon as possible after discontinuation. If the poststudy visit occurs prior to the safety 
follow-up time frame as specified in Section 8.4.1, the investigator should perform a 
follow-up telephone call at the end of the follow-up period (Section 8.4.1) to confirm if any 
AEs have occurred since the poststudy clinic visit. Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@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 
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already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, they will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. The emergency unblinding call center will 
provide the investigator or medically qualified designee the requested information promptly 
and report unblinding to the Sponsor. Before contacting the emergency unblinding call center 
to request unblinding of a participant’s intervention assignment, the investigator who is 
qualified physician should make reasonable attempts to enter the intensity of the AEs 
observed, the relation to study intervention, the reason thereof, etc, in the medical record. If it 
is not possible to record this assessment in the medical record before the unblinding, the 
unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
8.1.11
Domiciling
Panel A:
Participants will report to the CRU in the evening on Day −4 before the scheduled day of 
study intervention administration on Day  and remain in the unit until all post-dose 
procedures have been performed on Day 
 for Panel A. 
 
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site. At the discretion of the 
investigator, participants may be requested to remain in the CRU longer.  
Participants may be permitted to leave the unit, for emergency situations only, during the 
domiciling period at the discretion of the investigator after discussion with the Sponsor. The 
decision how to monitor the participant will be at the discretion of the investigator after 
discussion with the Sponsor.
Panel B:
Domiciling for Panel B is optional. If participants choose to travel to and from the CRU on 
select days, they will need to report to the CRU in the evening on Day −4 before the 
scheduled day of study intervention administration on Day and remain in the unit until all 
post-dose procedures have been performed on Day  per the SoA. On Days 3-31 participants 
will be required to attend the CRU daily to receive study intervention and complete all 
activities per the SoA. Participants may also domicile at the CRU on Days 23 and 31, if 
deemed necessary by the investigator. At the discretion of the investigator, participants may 
be requested to remain in the CRU longer. 
If participants choose to domicile at the CRU for the duration of the study intervention 
period, participants will report to the CRU in the evening on Day −4 before the scheduled 
day of study intervention administration on Day 1 and remain in the unit until all post-dose 
procedures have been performed on 31 for Panel B. Participants can stay in the CRU through 
32 for Panel B, if deemed necessary by the investigator. At the discretion of the investigator, 
participants may be requested to remain in the CRU longer.
 
8.1.12
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 Assessments
There are no direct efficacy assessments in this study; surrogate markers of efficacy are 
outlined in Section 8.7.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
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(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Appendix 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard at prespecified 
timepoints noted in the SoA (Section 1.3). Height and weight will also be measured and 
recorded.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Body Mass Index 
BMI equals a person’s weight in kilograms divided by height in meters squared 
(BMI=kg/m2). BMI will be rounded to the nearest whole number according to the standard
convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.2
Vital Signs
Oral, tympanic, or temporal body temperature, PR, RR, and BP will be assessed.
BP and pulse measurements will be assessed in the semi-recumbent and/or standing position 
with a completely automated device. Manual techniques will be used only if an automated 
device is not available.
BP and pulse measurements should be preceded by at least 10 minutes of rest for the 
participant in a quiet setting without distractions.
8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a quiet setting without distractions in a semirecumbent 
position for at least 10 minutes before having VS measurements obtained. Semirecumbent 
VS will include HR, systolic and diastolic BP, RR, and body temperature at timepoints 
indicated in the SoA. The correct size of the BP cuff and the correct positioning on the 
participant’s arm is essential to increase the accuracy of BP measurements.
The predose (baseline) HR and BP will be triplicate measurements, obtained at least 1 to 
2 minutes apart within 3 hours of dosing MK-1167/placebo. The mean of these 
measurements will be used as the baseline to calculate change from baseline for safety 
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evaluations (and for rechecks, if needed). On all other days indicated in the SoA (See Section 
1.3) predose HR and BP will be single measurements. Postdose VS measurements will be 
single measurements unless there is an out-of-range reading. In this case, at least 3 measures 
of VS (either resting or orthostatic HR, BP) will be taken within a 15-minute period, or until 
readings fall into normal range.
Participants will continue to rest semirecumbent from dosing until 2 hours postdose except to 
stand for the measurement of orthostatic VS (if needed) or other study-related procedure.
Body Temperature
Body temperature will be measured. The same method must be used for all measurements for 
each individual participant and should be the same for all participants.
8.3.2.2
Orthostatic Vital Signs
Orthostatic VS (HR and systolic and diastolic BP) will also be obtained. Participants should 
be semirecumbent for at least 10 minutes and then stand upright for approximately 2 minutes 
before measurement of orthostatic VS. When there is an out-of-range reading, additional 
measurements should be taken until readings fall into normal range. Participants should be 
semirecumbent for at least 10 minutes and then stand upright for approximately 2 minutes 
before measurement of orthostatic VS.
8.3.3
Electrocardiograms
Triplicate 12-lead ECG will be obtained and reviewed by an investigator or medically 
qualified designee (consistent with local requirements) as outlined in the SoA using an ECG 
machine that automatically calculates the HR and measures PR, QRS, QT, and QTc intervals. 
Refer to Appendix 9 for evaluation and potentially significant findings.
At each time point when triplicate ECG are required, 3 individual ECG tracings should be 
obtained at least 1 minute apart. The full set of triplicates should be completed in no more 
than 6 minutes.
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry before lead placement. Participants may need to be shaved to ensure proper 
lead placement. Participants may need to remove interfering garments.
Participants should be resting in the semirecumbent position for at least 10 minutes before 
each ECG measurement.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin-marker pen to ensure reproducible electrode placement.
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Predose ECGs will be obtained in triplicate at least 1 minute apart within 3 hours before 
dosing MK-1167. The mean of these measurements will be used as the baseline to calculate 
change from baseline for safety evaluations (and for rechecks, if needed).
During each treatment period, if a participant demonstrates a mean increase in QTc interval 
≥60 msec compared to the mean predose baseline measurement, the participant will continue 
to be monitored by at least single repeat 12-lead ECGs every 15 minutes for at least 1 hour or 
until the QTc interval is within 60 msec of baseline. If prolongation of the QTc interval 
≥60 msec persists, a consultation with a cardiologist may be appropriate and the Sponsor 
should be notified.
Postdose ECG measurements will be triplicate measurements.
During each treatment period, if the mean QTc interval is ≥500 msec for postdose 
measurements, the Sponsor should be notified, and the ECGs should be reviewed by a 
cardiologist. The participant should be telemetry monitored (until the QTc interval is 
<500 msec) or should be considered for transfer to a location where closer monitoring and 
definitive care (eg, a CCU or ICU) is available.
If the mean QRS interval from any postdose ECG is 20% greater than the mean baseline 
QRS interval and is >120 msec (and change is not considered rate related or pacing induced) 
or there appears to be new onset intermittent bundle branch block, the participant will 
continue to be monitored by repeat 12-lead ECGs every 15 minutes for at least 1 hour or until 
the QRS interval is within 20% of baseline. If a >20% prolongation of the QRS interval 
persists, a consultation with a cardiologist may be appropriate and the Sponsor should be 
notified.
If at any time the QRS interval is prolonged ≥200 msec (and change is not considered rate 
related or pacing induced), then the Sponsor should be notified. The ECGs should be 
reviewed by a cardiologist and the participant should be considered for transfer to a location 
where closer monitoring and definitive care (eg, a CCU or ICU) is available.
If the participant has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted, the participant should be immediately transferred to an acute care setting for definitive 
therapy.
If prolongation of the QTc interval is noted, concomitant medications that prolong QTc 
interval should be held until the QTc interval is within 60 msec of baseline and the QTc 
interval is <500 msec.
A cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant abnormalities.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
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The investigator or medically qualified designee (consistent with local requirements) must 
review the laboratory report, document this review, and record any clinically relevant 
changes occurring during the study in the AE section of the CRF. The laboratory reports 
must be filed with the source documents. Clinically significant abnormal laboratory findings 
are those which are not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose modification), 
then the results must be recorded in the appropriate CRF (eg, SLAB).
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 20 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.5
Neurological Exam
The full neurological exam monitors aspects of mental status, cranial nerve function, motor 
system function, reflexes, coordination and gait and sensory function (Appendix 12) and will 
be administered at screening and the post-study exam. The targeted neurological exam 
contains Modules 1, 2 and 5 of the general examination, focusing on arousal, cranial nerve 
function, and gait.
8.3.6
Mini-Mental State Examination
The MMSE-2 will be administered to the participant in paper form, scored and recorded by 
the principal investigator or trained designee according to the instructions in the operations 
manual.
8.3.7
WAIS-IV Digit Symbol Substitution Test
The DSST will be administered to the participant in paper form and scored and recorded by 
the principal investigator or trained designee according to the instructions in the operations 
manual.
8.3.8
Suicidal Ideation and Behavior Monitoring
8.3.8.1
Clinical Assessments for Suicidal Ideation and Behavior Monitoring
Suicidal ideation and behavior will be prospectively assessed during this study using the 
C-SSRS. The C-SSRS should be administered by trained raters at the time points indicated in 
the SoA. In addition, C-SSRS will be administered at any unscheduled visit where safety 
assessments are performed. The C-SSRS will not be routinely administered at visits with a 
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sole purpose of PK sampling and/or witnessed study intervention administration. Site staff 
should review the contents of the C-SSRS for completeness.
If the C-SSRS is administered by someone other than the investigator, consider providing the 
completed C-SSRS to the investigator for review, before their assessment of the participant 
and to further inform their evaluation.
The C-SSRS is not explicit about whether the participant specifically has ideation at the time 
of screening. If a participant reports a prior history of ideation/behavior at screening, the 
assessor should also inquire and document if this is also present at the time of the Screening 
Visit.
Participants who at any time during this study report suicidal ideation or behavior that is 
considered to be an AE, either between visits or during visit interviews, must be assessed by 
the investigator. Participants who report suicidal ideation with intent, with or without a plan 
or method (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.
8.3.9
Photograph of Rash
Photographs of the rash are highly recommended to be taken immediately, along with any 
additional information that may assist the investigator to evaluate the skin reaction, skin 
eruption, or rash occurrence in determining etiology and study intervention relationship. See 
Investigator Site Binder for additional guidance.
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.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
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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
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 under any of the following circumstances:
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,
if it is the result of a protocol-specified intervention, including, but not limited to washout or 
discontinuation of usual therapy, diet, placebo, or a procedure.
From the time of intervention randomization through 14 days after cessation of intervention, 
all AEs, SAEs, and other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator any time outside the period 
specified in the previous paragraph also must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and 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 6.
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 6
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
through Protocol-
specified Follow-
up Period
Reporting 
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 (requiring
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– requiring
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (does not require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
through Protocol-
specified Follow-
up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
serious)
Overdose
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. 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). The investigator will also make every attempt to 
follow 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 toward 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 SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
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8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
A cholinergic-related AE term has been defined and is composed of the following individual 
component AEs: nausea, vomiting, diarrhea, and abdominal pain.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:


o
o
o
o

An overdose of Sponsor’s product, as defined in Section 8.5.

Potential DILI events defined as an elevated AST or ALT laboratory value that is 
greater than or equal to 3× the ULN and an elevated total bilirubin laboratory value 
that is greater than or equal to 2× the ULN and, at the same time, an alkaline 
phosphatase laboratory value that is less than 2× the ULN, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.*
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*Note: These criteria are based on available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The study-site guidance 
for assessment and follow-up of these criteria can be found in the Investigator Study 
File Binder (or equivalent). It may also be appropriate to conduct additional 
evaluation for an underlying etiology in the setting of abnormalities of liver blood 
tests including AST, ALT, bilirubin, and alkaline phosphatase that do not meet the 
criteria noted above. In these cases, the decision to proceed with additional evaluation 
will be made through consultation between the study investigators and the Sponsor 
Clinical Director. However, abnormalities of liver blood tests that do not meet the 
criteria noted above are not ECIs for this study.
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any study intervention 
administered that exceeds the dose prescribed by the protocol. It is up to the investigator or 
the reporting physician to decide whether a non-study intervention dose (eg, rescue or 
concomitant medication) is to be considered an overdose, in consultation with the Sponsor.
Sponsor does not recommend specific treatment for any overdose. 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
The decision as to which plasma and/or urine samples collected will be measured for 
evaluation of PK/pharmacodynamics will be collaboratively determined by the Sponsor (eg, 
samples at lower doses may not be measured if samples at higher doses reveal undetectable 
drug concentrations). If indicated, these samples may also be measured and/or pooled for 
assay in an exploratory manner for metabolites and/or additional pharmacodynamic markers.
8.6.1
Blood Collection for Plasma MK-1167
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Operations Manual.
8.7
Pharmacodynamics
Tools for cognitive assessment, such as the DSST (processing speed and working memory), 
may be useful to assess effects on cognition. The DSST is a rapid assessment of cognitive 
function that will be included in the current study
 
 
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8.8
Biomarkers
 
 

Blood for Genetic Analysis

8.8.1
Planned Genetic Analysis Sample Collection
 
 
 
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 pre-dose on Day 1 but may be 
collected at the next scheduled visit, 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
All sample collections for study-specific assessments shown in the SoA are described within
the main Informed Consent.
If the participant has provided documented informed consent for FBR, leftover samples will 
be used for FBR. The following specimens will be included for FBR:
Leftover samples listed in Section 8.8.
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Within approximately 4 weeks; before intervention randomization, potential participants will 
be evaluated to determine that they fulfill the entry requirements as set forth in Section 5.
Rescreening is defined as a separate screening period and be initiated as needed, by the 
investigator after consultation with the Sponsor, including for screen failures (Section 5.4).
Participants may be rescreened after consultation with the Sponsor. Rescreening is to include 
all screening procedures listed in the SoA (Section 1.3), including consent review.
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Rescreen procedures cannot be conducted the day prior to intervention randomization if there 
are Day −1 procedures planned per protocol.
8.10.2
Treatment Period/Vaccination Visit
Refer to the SoA (Section 1.3) and Administrative and General Procedures (Section 8.1).
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, all of study procedures specified in the SoA may be completed at the discretion of the 
investigator and with Sponsor agreement. The subset of study procedures completed will be 
communicated in a PCL. 
8.10.4
Poststudy
 
 
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the blood sample for MK-1167 is the critical procedure.
At any postdose time point, the blood sample for MK-1167 needs to be collected as close to 
the exact time point as possible. All other procedures should be completed as close to the 
prescribed/scheduled time as possible. Study procedures can be performed before or after the 
prescribed/scheduled time.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted.
PK Collection as outlined in 
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Table 7
Study Intervention Administration:
Panel A and Panel B - Predose and Postdose Procedures:
Predose standard safety evaluations: VS and ECG within 3 hours; laboratory safety tests and 
physical examination within 24 hours
Panel A - Postdose standard safety evaluations: VS, ECG, laboratory safety tests, 
physical/neurological examination, and C-SSRS.
-
Prior to 24-hours postdose may be obtained within 30 minutes of the theoretical sampling 
time
-
Between 24-hours and 48-hours postdose may be obtained within 1 hour of the 
theoretical sampling time
-
 postdose may be obtained within 4 hours of the theoretical 
sampling time
-
 may be obtained within 30 hours.
Panel B - Postdose standard safety evaluations: VS, ECG, laboratory safety tests, 
physical/neurological examination, and C-SSRS.
-
Prior to 24-hours postdose may be obtained within 30 minutes of the theoretical sampling 
time
-
24-hours postdose may be obtained within 1 hour of the theoretical sampling time
-
 may be obtained within 24 hours of the theoretical sampling time
-
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8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-1167 in humans, and the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is written with some 
flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Modifications to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.

Repeat of or decrease in the dose of the study intervention administered in any given 
period/panel

Interchange of doses between panels

Entire period(s) or panel(s) may be omitted

Decrease in the duration of study intervention administration (eg, number of days)

Adjustment of the dosing interval (eg, divided doses qd to bid, tid, or vice versa)

Addition of PK pause

Instructions to take study intervention with or without food or drink may also be modified 
based on newly available data

Modification of the PK/pharmacodynamic sample processing and shipping details based 
on newly available data
The PK sampling scheme currently outlined in the protocol may be modified during the study 
based on newly available PK data (eg, to obtain data closer to the time of peak plasma 
concentrations). If indicated, these collected samples may also be assayed in an exploratory 
manner for metabolites and/or additional pharmacodynamic markers.
Up to additional 50 mL of blood may be drawn for safety, PK, analyses. The total blood 
volume withdrawn from any single participant will not exceed the maximum allowable 
volume during their participation in the entire study (Appendix 8).
The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, etc) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during their participation in the entire study.
It is understood that the current study may use some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
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9
KEY STATISTICAL CONSIDERATIONS
This section details the principal statistical analysis strategy and procedures for the study. If, 
after the study has begun, changes are made to the statistical analysis plan stated below, then 
these deviations to the plan will be listed, along with an explanation as to why they occurred, 
in the Clinical Study Report.
9.1
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Quantitative Pharmacology and Pharmacometrics Department and Translational 
Medicine Department of the Sponsor.
9.2
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3 of the protocol.
9.3
Analysis Endpoints
9.3.1
Primary Endpoints
Safety: Primary safety endpoints will include all types of adverse events and discontinuation 
of study intervention due to adverse event(s), in addition to laboratory safety tests, ECGs, C-
SSRS and vital signs. Baseline is defined as measurements obtained pre-dose Day 1.
9.3.2
Secondary Endpoints
Pharmacokinetics: The pharmacokinetic variable(s) of plasma MK-1167 [AUC0-24, Cmax, 
C24, Tmax, CL/F, Vz/F, t1/2] are of secondary interest.
9.3.3
Exploratory Endpoints
MMSE-2, DSST.
9.4
Analysis Populations
The following populations are defined for the analysis and reporting of data. All participants 
will be reported, and their data analyzed, according to the treatment(s) they actually received.
9.4.1
All Participants As Treated Population
The All Participants as Treated Population consists of all participants who received at least 
one dose of treatment. This population will be used for assessments of safety and tolerability.
9.4.2
Per-Protocol (PP) Population
The Per-Protocol Population consists of the set of data generated by the subset of participants 
who comply with the protocol sufficiently to ensure that these data will be likely to exhibit 
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the effects of treatment, according to the underlying scientific model. 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 prior to unblinding by individuals responsible for data collection/compliance, and its 
analysis and interpretation. Any participants or data values excluded from analysis will be 
identified, along with their reason for exclusion, in the CSR. At the end of the study, all 
participants who are compliant with the study procedure as aforementioned and have 
available data from at least one treatment will be included in the Per-Protocol dataset. This 
population will be used for the pharmacokinetics and pharmacodynamic analyses.
9.5
Statistical Methods
9.5.1
Statistical Methods for Pharmacokinetic Analyses
Model-based PK summary
 
Kenward and Roger’s adjustment to the degrees of freedom will be employed. Ninety-five 
percent confidence intervals for the least squares means by day will be constructed on the 
natural log scale and will reference a t-distribution. Exponentiating the least-squares means 
and lower and upper limits of these confidence intervals will yield estimates for the 
population geometric means and confidence intervals about the geometric means on the 
original scale. A sample code is as follows:
proc mixed data=adpp;
class day usubjid;
model lnpk=day /ddfm=kr;
random usubjid;
lsmeans day /alpha=0.05 cl;
run;
To assess the accumulation of MK-1167 relative to the loading dose, the least squares mean
differences 
 and 90% confidence intervals from this model 
will be back transformed to obtain the geometric mean accumulation ratios (Day 8/Day 1 and 
Day 21/Day 1) and 90% confidence intervals for 
 
 
Kenward and Roger’s adjustment to the degrees of freedom will be employed. 
Ninety-five percent confidence intervals for the least squares means by day will be 
constructed on the natural log scale and will reference a t-distribution. Exponentiating the 
least-squares means and lower and upper limits of these confidence intervals will yield 
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estimates for the population geometric means and confidence intervals about the geometric 
means on the original scale. A sample code is as follows:
proc mixed data=adpp;
class day usubjid;
model lnpk=day /ddfm=kr;
random usubjid;
lsmeans day /alpha=0.05 cl;
run;
 
 
Descriptive Statistics
Individual values will be listed for each PK parameter by treatment, and the following (non-
model-based) descriptive statistics will be provided: N (number of participants with non-
missing data), arithmetic mean, standard deviation, arithmetic percent coefficient of variation 
(CV, calculated as 100 × standard deviation/arithmetic mean), median, minimum, maximum, 
geometric mean, and geometric percent CV (calculated as 100 × sqrt( exp(s2) − 1), where s2
is the observed variance on the natural log-scale).
9.5.2
Statistical Methods for Pharmacodynamic Analyses
MMSE-2 scores
In order to evaluate the change in cognitive function of AD patients, descriptive summary 
statistics of the values and the change from baseline values will be provided for the MMSE-2 
scores obtained at baseline (screening) and from the last day of dosing.
WAIS-IV DSST scores
In order to evaluate the change in cognitive function of AD patients, descriptive summary 
statistics of the values and the change from baseline values will be provided for the DSST 
scores obtained at baseline (Day -1) and each postdose timepoint by treatment.
9.5.3
Statistical Methods for Safety Analyses
Safety will be evaluated by clinical assessment of AEs, 12-lead ECGs, vital signs, laboratory 
safety tests, physical/neurological examinations and C-SSRS. Summary statistics and plots 
will be generated for raw laboratory safety tests, ECGs, and/or VS as well as for change from 
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baseline, as deemed clinically appropriate. Depending on the safety parameter, the difference 
from baseline will either be computed on the original scale (raw change from baseline) or on 
the log scale and back-transformed for reporting (percent change from baseline). Responses 
to the C-SSRS will be tabulated and the individual score will be listed.
9.6
Interim Analyses
No interim analysis is planned.
9.7
Multiplicity
Since there is no hypothesis, no adjustments for multiplicity are needed.
9.8
Sample Size and Power Calculations
 
 
 
 
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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 Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, 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 MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, and 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. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. 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. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
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.
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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 and ICH Guidelines. 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. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. 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.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
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.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
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 medical record 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 
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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 their 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 
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 their 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 their 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.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20), and is self-certified pursuant to the EU-US 
Data Privacy Framework.
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 
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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 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, 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, https://euclinicaltrials.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 
Regulation 536/2014 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 Regulation 536/2014, 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.
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10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
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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.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 8 will be performed by the local laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.
Table 8
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin (and direct 
bilirubin if total bilirubin is 
above the ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose fasting
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, (bilirubin, urobilinogen, nitrite, leukocyte 
esterase) by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
FSH (as needed in PONCBP only)
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates,
cocaine, opiates, cannabinoids, and benzodiazepines)
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-
stimulating hormone; HBsAg=hepatitis B surface antigen; hCG=human chorionic gonadotropin; HIV=human 
immunodeficiency virus; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; 
POCBP=participant of childbearing potential; PONCBP=participant of nonchildbearing potential; RBC=red blood 
cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; ULN=upper 
limit of normal; WBC=white blood cell
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded.
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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 nontherapeutic 
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 includes any pharmaceutical product, 
biological product, vaccine, diagnostic agent, medical device, combination product, or 
protocol-specified procedure whether investigational or marketed (including placebo, active 
comparator product, or run-in intervention), manufactured by, licensed by, provided by, or 
distributed by the Sponsor for human use in this study.
Events meeting the AE definition
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator.
Exacerbation of a chronic or intermittent preexisting condition including either an increase in 
frequency and/or intensity of the condition.
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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 study intervention cause the AE?
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
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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 study 
intervention and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the study intervention 
caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention 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 study intervention? 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 study intervention 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 study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (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 STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION 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.
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Consistency with study intervention profile: Is the clinical/pathological presentation of the 
AE consistent with previous knowledge regarding the study intervention 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 study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
The investigator must review and provide an assessment of causality for each AE/SAE and 
document this in the medical notes.
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the Sponsor.
The investigator may change their opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment.
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals.
New or updated information will be recorded in the CRF.
The investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt 
of the information.
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10.3.6
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).
SAE reporting to the Sponsor via paper CRF
If the EDC tool is not operational, facsimile transmission or secure email 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: Drug–Device Combination Products/Combination Medicinal 
Products: Complaints, 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
Participants of Nonchildbearing Potential (PONCBP)
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, are considered PONCBP:
Premenopausal 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, Müllerian 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
-
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 participants assigned female sex at birth not using 
hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
-
Participants assigned female sex at birth on HRT and whose menopausal status is in 
doubt must discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment.
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Nonparticipant of Childbearing Potential
A nonparticipant assigned female sex at birth is considered fertile and capable of becoming 
pregnant following menarche until becoming postmenopausal unless permanently sterile (see 
below):
Nonparticipants assigned female sex at birth who are in the following categories are not 
capable of becoming pregnant and, therefore, not considered of CBP:
Premenarchal
Premenopausal with 1 of the following:
-
Hysterectomy
-
Bilateral salpingectomy
-
Bilateral oophorectomy
-
Permanent infertility due to an alternate medical cause other than the above (eg, 
Müllerian agenesis, androgen insensitivity).
Postmenopausal
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only contraceptive implant a
IUS a,b
Nonhormonal IUD
Bilateral tubal occlusion (Tubal occlusion includes tubal ligation)
Azoospermic partner (vasectomized or secondary to medical cause, confirmed by medical history) –
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal confirmation of partner 
azoospermia during Medical History. If not, an additional highly effective method of contraception should be used. A 
spermatogenesis cycle is approximately 90 days.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception a,c
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraception a,c
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-vaginal 
intercourse with a partner capable of producing sperm, during the entire period of risk associated with the study 
intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action
Penile/external or vaginal/internal condom with or without spermicided
Cervical cap, diaphragm, or sponge with spermicide
A combination of penile/external condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods)
a
Penile/external condoms must be used in addition to the POCBP’s hormonal contraception 
b
IUS is a progestin releasing IUD 
c
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit 
ovulation
d
Vaginal/internal condom used for contraceptive purposes 
Note: The following are not acceptable methods of contraception: 
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides 
only, and LAM
Penile/external and vaginal/internal condom should not be used together (due to risk of failure with friction) d 
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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.
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 their 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.
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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 is
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 that 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.
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 
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(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 used 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 
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.
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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.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Blood Volume Tables
Panel A
Pre-
Studya
Treatment 
Periods
Post-
Study
Total 
Collections
mL Per 
Collection
Total 
mL/Test
Laboratory Safety Tests 
1
4
1
6
12.5
75
HIV/Hepatitis Screen (at 
the discretion of the 
investigator)
1
0
0
1
5
5
Blood for Planned Genetic 
Analysis  
0
1
0
1
8.5
8.5
 
1
0
0
0
5
5
Blood for donepezil PK
11
10
0
21
3
63
Blood for MK-1167 PK
0
51
0
51
4
204
Total Blood Volume per Participantb
360.5
a
Pre-Study includes screening and Days -3, -2, and -1.
b
If additional pharmacokinetic and/or safety analysis is necessary, additional blood (no more than 50 mL in total) 
may be obtained.
Panel B
Pre-
Studya
Treatment 
Periods
Post-
Study
Total 
Collections
mL Per 
Collection
Total 
mL/Test
Laboratory Safety Tests 
including serum hCG 
(POCBP) or serum FSH 
(PONCBP) and BDS
1
5
1
7
12.5
87.5
HIV/Hepatitis Screen (at the 
discretion of the investigator)
1
0
0
1
5
5
Blood for Planned Genetic 
Analysis  
0
1
0
1
8.5
8.5
1
0
0
0
5
5
Blood for donepezil PK
11
10
0
21
3
63
Blood for MK-1167 PK
0
61
0
61
4
244
Total Blood Volume per Participantb
413
a
Pre-Study includes screening and Days -3, -2, and -1.
b
If additional pharmacokinetic and/or safety analysis is necessary, additional blood (no more than 50 mL in total) 
may be obtained.
CCI
CCI
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10.9
Appendix 9: 12-Lead Electrocardiogram Evaluation Criteria
RHYTHM
Sinus Tachycardia
>110 bpm
HR >110 bpm and HR increase of 
≥25 bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of 
≥5 bpm from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial Premature Complex
>1 beat
≥3 beats
Ventricular Premature Complex
All
≥3 beats
Ectopic Atrial Rhythm
None
None
Junctional Rhythm
Junctional Rhythm with HR 
<40 bpm
Junctional Rhythm with HR 
<40 bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
AXIS
Left Axis Deviation
RBBB With LAHB
New Onset LAHB
Right Axis Deviation
CONDUCTION
1st Degree AV Block
PR ≥230 ms
PR ≥230 ms + Increase of >15 ms; 
or PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB as 
Defined Above
New Onset RBBB (Not Including 
Rate-related)
ICRBBB (QRS <120 ms)
No Exclusion
Nothing
Short PR/Preexcitation Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
Other Intraventricular Conduction Delay
QTc (B or F)
Male
QTc ≥470 ms
QTc ≥500 ms or Increase of ≥60 
ms From Baseline
Female
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P Mitrale 
or P Pulmonale
Definite Evidence of P. Mitrale or 
P. Pulmonale
Ventricular Abnormalities
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
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ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury
In 2 or more contiguous leads
In 2 or more contiguous leads
ST Depression Suggestive of 
Myocardial Ischemia
In 2 or more contiguous leads
In 2 or more contiguous leads
T-wave Inversions Suggestive of 
Myocardial Ischemia
In 2 or more contiguous leads
In 2 or more contiguous leads
Nonspecific ST-T Changes (In 2 or 
More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
AV=atrioventricular; bpm=beats per minute; HR=heart rate: ICRBBB=incomplete right bundle branch 
block; LAHB=left anterior hemiblock; LPHB=left posterior hemiblock; LVH=left ventricular 
hypertrophy; mm=millimeter; ms=milliseconds; QTcB=QT correction using Bazett’s formula; 
QTcF=QT correction using Fredericia formula; RBBB=right bundle branch block; ST/T=ST-segment/T 
wave.
Baseline is defined as predose Day 1.
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10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at pre-study (screening) visit and/or pre-dose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol-specified laboratory value is outside the parameter(s) outlined in the 
inclusion/exclusion criteria (including repeats if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
-
The participant may be excluded from the study.
-
The participant may be included in the study if the abnormal value(s) is NCS (the 
investigator must annotate the laboratory value “NCS” on the laboratory safety test 
source document).
-
The participant may be included in the study if the abnormality is consistent with a 
pre-existing medical condition which is not excluded per protocol (eg, elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical 
condition should be annotated on the laboratory report.
OR
-
The abnormal test may be repeated (refer to items below for continuation of 
algorithm for repeated values).
◦
If the repeat test value is within the normal range, the participant may enter the 
study.
◦
If the repeat test value is still abnormal, the study investigator will evaluate the
potential participant with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in 
question. If such diseases can be ruled out, and if the abnormal laboratory value is 
not clinically relevant, then the participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
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10.11 Appendix 11: The National Institute of Neurological and Communicative 
Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association 
(NINCDS-ADRDA) Criteria for Probable AD
I.
The criteria for the clinical diagnosis of PROBABLE AD include:
Dementia established by clinical examination and documented by the Mini-Mental Test; 
Blessed Dementia Scale, or some similar examination, and confirmed by neuropsychological 
tests;
Deficits in two or more areas of cognition;
Progressive worsening of memory and other cognitive functions;
No disturbance of consciousness;
Onset between ages 40 and 90, most often after age 65; and
Absence of systemic disorders or other brain diseases that in and of themselves could account 
for the progressive deficits in memory and cognition.
II. The diagnosis of PROBABLE AD is supported by:
Progressive deterioration of specific cognitive functions such as language (aphasia), motor 
skills (apraxia), and perceptions (agnosia);
Impaired activities of daily living and altered patterns of behavior;
Family history of similar disorders, particularly if confirmed neuropathologically
III.Other clinical features consistent with the diagnosis of PROBABLE AD, after 
exclusion of causes of dementia other than AD, include:
Plateaus in the course of progression of the illness;
Associated symptoms of depression, insomnia, incontinence, delusions, illusions, 
hallucinations, catastrophic verbal, emotional, or physical outbursts, sexual disorders, and 
weight loss;
Other neurologic abnormalities in some patients, especially with more advanced disease and 
including motor signs such as increased muscle tone, myoclonus, or gait disorder;
Seizures in advanced disease; and
CT normal for age.
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IV.Features that make the diagnosis of PROBABLE AD uncertain or unlikely include:
Sudden, apoplectic onset;
Focal neurologic findings such as hemiparesis, sensory loss, visual field deficits, and 
incoordination early in the course of the illness; and
Seizures or gait disturbances at the onset or very early in the course of the illness.
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10.12 Appendix 12: General and Targeted Neurological Examinations
The General and Targeted Neurological Examination will be performed at the time points 
specified in the SoA (Section 1.3).
Note to the investigator: If at any time abnormalities are observed in the General or Targeted 
Neurological Exams, the investigator should do additional examinations as needed based on 
medical judgment.
10.12.1
The General Neurological Examination
The General Neurological Examination includes all of the modules listed below and is 
intended to be a general screening examination.
10.12.1.1
Module 1 – Mental Status Examination
A. General Level of Arousal (generally assess general level of alertness, attentiveness, and 
concentration throughout the interview. Regarding attentiveness, note evidence of 
impaired attention or concentration. For example, difficulty remembering or following 
instructions or distractibility may be signs of inattention).
B. Thought Processes and Language (generally assess logic, relevance, organization, and 
coherence of participant’s use of language throughout the interview).
C. Orientation (time, place, person).
D. Attention/Concentration.
Ask the participant to count backwards from 100 by 7’s (“Serial 7’s”) or ask to recite 
months backwards or spell a 5 unique letter word (eg, “WORLD”) backwards.
Note: To avoid learning effects, switch between tests throughout the study.
E. Memory (test registration of 3 objects; then test immediate recall 5 minutes later).
Grade: NORMAL or IMPAIRED and describe abnormality (for each, A to E, above). 
Normal performance on Serial 7’s is getting to 65 with no more than 1 error.
10.12.1.2
Module 2 – Cranial Nerve Assessment
A. II – Visual Fields and acuity
B. II, III – Pupil Size and Reactivity
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus).
Observe for nystagmus during eye movements, increased nystagmus at the end of gaze or 
other oculomotor changes (mild nystagmus at extremes of gaze is normal). Note direction 
of nystagmus
D. V – Facial Sensation, Jaw Strength
E. VII – Muscles of Facial Expression (wrinkle brow, squeeze eyes shut, smile)
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F. VIII – Auditory Acuity (assessed using a bed-side screening test [eg, by rubbing fingers 
on each side of participant’s head or by whispering numbers])
G. IX – Gag reflex
H. X – Swallow
I.
XI – Shoulder shrug
J.
Tongue Protrusion (midline)
Score: left and right (except for G, H, J)
Grade: NORMAL or IMPAIRED and describe abnormality
10.12.1.3
Module 3 – Motor System
A. Muscle Tone
1. Ask the participant to relax.
Flex and extend the participant’s elbows and knees (bilaterally).
There is a small, continuous resistance to passive movement.
Observe for involuntary movements (eg, tremor, tics, fasciculations). Observe for 
resistance to passive movement; observe for decreased (flaccid) or increased 
(rigid/spastic) tone.
Score: left and right
Grade: NORMAL, INCREASED or DECREASED
B. Muscle Strength
1. Ask the participant to stand up from sitting without using hands
Grade: NORMAL, IMPAIRED and describe abnormality
Test proximal limb strength by having the participant flex and extend the knees and 
elbows against your resistance.
Test bilaterally and compare one side to the other.
Score: left and right
Grade:
5/5: normal
4/5: movement against resistance impaired
3/5: movement against gravity but not against resistance
2/5: visible movement but not against gravity
1/5: visible contraction
0/5: no visible activity
Test distal limb strength by having the participant conduct dorsiflexion and plantar 
flexion of the participant’s feet; finger abduction and handgrip strength against your 
resistance.
Test bilaterally, and compare one side to the other.
Score: left and right
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Grade:
5/5: normal
4/5: movement against resistance impaired
3/5: movement against gravity but not against resistance
2/5: visible movement but not against gravity
1/5: visible contraction
0/5: no visible activity
C. Pronator Drift
Ask the participant to hold both arms straight forward with, palms up and eyes closed for 
≈10 to 15 seconds as tolerated; watch for how well the arm position is maintained.
Instruct the participant to keep both arms still while you tap them briskly downward. The 
participant should normally be able to maintain extension and supination. Inability to 
maintain extension and supination (and drift into pronation) indicates an upper motor 
neuron deficit.
Score: left and right
Grade: NORMAL or IMPAIRED and describe abnormality
10.12.1.4
Module 4 – Reflexes
A. Biceps
B. Knee
Note: Other deep tendon reflexes may be tested at investigator's discretion (eg, elbow, 
wrist, or Achilles tendon)
Score: left and right
Grade: NORMAL, INCREASED, DECREASED, or ABSENT
C. Babinski
Score: left and right
Grade: NORMAL or ABNORMAL
10.12.1.5
Module 5 – Coordination and Gait
A. Rapid, Rhythmic Alternating Movements
1. Testing each hand separately, ask the participant to tap the distal thumb with the tip of 
each finger, in sequence, as fast as possible.
Score: left and right
Grade: NORMAL or IMPAIRED
Reminder: If the rapid alternate movements are disturbed, the participant will be 
asked to strike their hand on the thigh, raise the hand, turn it over and then strike the 
back of the hand down on the same place. (This test is impaired in cerebellar disease, 
extra pyramidal disease and upper motor neuron weakness.)
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B. Point-to-Point Movements
1. Ask the participant to touch your index finger and their nose alternately several times. 
Move your finger about as the volunteer performs this task.
Score: left and right
Grade: NORMAL or IMPAIRED
Reminder: If the point-to-point testing is disturbed, the participant will be asked to 
place one heel on the opposite knee and then run it down the shin to the big toe. 
Repeat this for both sides. (Impaired tests indicate cerebellar disease.)
C. Romberg
1. Ask the participant to stand with both feet together and eyes closed for 20 to 30 
seconds without support.
Be prepared to catch the participant if they are unstable.
Grade: NORMAL or IMPAIRED
D. Gait
1. Ask the participant to walk across the room, turn and come back (assess posture, 
balance, swinging of arms and movement of the legs).
Grade: NORMAL or IMPAIRED and describe abnormality
Ask the participant to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
10.12.1.6
Module 6 – Sensory
A. Light touch sense: cotton wisp on skin of forearms and legs, bilaterally.
B. Pin prick: safety pin touched lightly to skin of forearms and legs, bilaterally.
C. Temperature: warm or cool object touched to skin of forearms and legs, bilaterally.
D. Vibration: tuning fork vibration detection in hands, feet bilaterally.
E. Position sense: perception of thumb and toe movement, bilaterally.
F. Stereognosis: (identify common objects placed in hand, [eg, coin, key, etc]).
Score: left and right
Grade: NORMAL OR IMPAIRED and describe abnormality (for each A to F)
10.12.2
The Targeted Neurological Examination
The Targeted Neurological Examination, which is intended to focus on tests where drug 
effects can be seen, includes the following tests only:
10.12.2.1
Module 1 – Mental Status Examination
A. General Level of Arousal (generally assess general level of alertness, attentiveness, and 
concentration throughout the interview. Regarding attentiveness, note evidence of 
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impaired attention or concentration. For example, difficulty remembering or following 
instructions or distractibility may be signs of inattention)
10.12.2.2
Module 2 – Cranial Nerve Assessment
B. II, III – Pupil Size and Reactivity
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus)
1. Observe for nystagmus during eye movements, increased nystagmus at the end of 
gaze or other oculomotor changes (mild nystagmus at extremes of gaze is normal). 
Note direction of nystagmus
10.12.2.3
Module 3 – Motor System
B. Muscle Strength
1. Ask the participant to stand up from sitting without using hands
Grade: NORMAL or IMPAIRED and describe abnormality
10.12.2.4
Module 5 – Coordination and Gait
D. Gait
1. Ask the participant to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
10.12.2.5
Module 6 – Sensory
A. Light touch sense: cotton wisp on skin of forearms and legs, bilaterally.
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10.13 Appendix 13: Abbreviations
Abbreviation
Expanded Term
α7 nAChR
alpha 7 nicotinic acetylcholine receptor
ACh
acetylcholine
AChEI
acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AR
adverse reaction
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-24
area under the curve from 0 to 24 hours
BDS
blood drug screen
bid
twice daily
BLA
Biologics License Application
BMI
body mass index
BP
blood pressure
C24
concentration at 24 hours
CCU
Cardiac care unit
CI
confidence interval
Cmax
maximum plasma concentration
CNS
central nervous system
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
CL/F
oral clearance
COVID-19
coronavirus of 2019
CrCl
creatinine clearance
CRF
Case Report Form
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Abbreviation
Expanded Term
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale
CSR
Clinical Study Report
CT
computed tomography
CTFG
Clinical Trial Facilitation Group
CYP
cytochrome P450
CV
coefficient of variation
DBL
database lock
DBP
diastolic blood pressure
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection
eGFR
estimated glomerular filtration rate
EM
exposure multiple
EMA
European Medicines Agency
EU
European Union
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FE
fractional enrichment
FIH
first in human
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice
GI
gastrointestinal
GLP
Good Laboratory Practice
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Abbreviation
Expanded Term
gln
glutamine
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCl
hydrochloride
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
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
ICU
intensive care unit
IEC
Independent Ethics Committee
Ig
immunoglobulin
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
JRCT
Japan Registry of Clinical Trials
LAM
lactational amenorrhea method
MBP
mean blood pressure
nAChR
nicotinic acetylcholine receptor
NCS
not clinically significant
NDA
New Drug Application
NHP
nonhuman primate
CCI
CCI
CCI
CCI
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Abbreviation
Expanded Term
NINCDS-
ADRDA
National Institute of Neurological and Communicative Disorders -
Stroke and the Alzheimer’s Disease and Related Disorders Association
NOAEL
no observed adverse effect level
NOEL
no observed effect level
PAM
positive allosteric modulator(s)
PBO
placebo
PCL
Protocol Clarification Letter
PK
pharmacokinetic
PN
protocol number
PO
orally
POCBP
participant/participants of childbearing potential
PONCBP
participant/participants of nonchildbearing potential
PP
per-protocol
PQC
product quality complaint
PR
pulse rate
PS
polysorbate
QD
once daily
RNA
ribonucleic acid
RR
respiratory rate
SAC
Scientific Advisory Committee
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SIM
Site Imaging Manual
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SOC
standard of care
SOP
Standard Operating Procedures
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Abbreviation
Expanded Term
SPF
sun protection factor
SUSAR
suspected unexpected serious adverse reaction
TEA
Treatment Eligibility Assessment (form)
t1/2
half life
Tmax
time to maximum plasma concentration
UDS
urine drug screen
ULN
upper limit of normal
US
United States (of America)
UTN
Universal Trial Number
Vd
volume of distribution
VAS
Visual Analog Scale
VS
vital signs
Vz/F
apparent volume of distribution
WAIS-IV
Wechsler Adult Intelligence Scale-IV
WBC
white blood cell
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11
REFERENCES
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Barbier AJ, Hilhorst M, Van Vliet A, 
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Pharmacodynamics, pharmacokinetics, 
safety, and tolerability of encenicline, a 
selective α7 nicotinic receptor partial 
agonist, in single ascending-dose and 
bioavailability studies. Clin Ther. 2015 Feb 
1;37(2):311-24.
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[European Medicines Agency 
2017]
European Medicines Agency. Guideline on 
strategies to identify and mitigate risks for 
first-in-human and early clinical trials with 
investigational medicinal products. London: 
European Medicines Agency; 2017. 22 p. 
EMEA/CHMP/SWP/28367/07 Rev. 1.
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[Jack, C. R. Jr., et al 2018]
Jack CR Jr, Bennett DA, Blennow K, 
Carrillo MC, Dunn B, Haeberlein SB, et al. 
NIA-AA research framework: toward a 
biological definition of Alzheimer's disease. 
Alzheimers dement. 2018;14:535-62.
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